Non-Interventional, Cross-sectional Study to Describe NOACs Management ss in Patients With Non-valvular Atrial Fibrillation (NVAF) in Spain.
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c18718851-01
BI Study Number:
1160-0287
BI Investigational
Product(s):
Dabigatran etexilate (Pradaxa®)
Title:
Non-Interventional, cross-sectional study to describe NOACs 
management in patients with non-valvular atrial fibrillation 
(NVAF) in Spain. RE-CONOCE Study.
Brief lay title
This study observes the use of new oral anticoagulants (NOACs) 
in patients with a heart rhythm disorder in Spain.
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
24 July 2017
PASS:
No
EU PAS register 
number:
Study will be registered in EU PAS register
Active substance:
B01AE07 - Dabigatran etexilate
Medicinal product:
Dabigatran etexilate
Product reference:
EU/1/08/442
Procedure number:
EMEA/H/C/829
Marketing authorisation 
holder(s):
MAH:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
This study is initiated, managed and sponsored by:
Joint PASS:
No
Research question and 
objectives:
Primary objective: 
The primary objective of the study is to describe the usage of 
NOACs in patients with NVAF, in the hospital setting, based on 
the baseline characteristics at the time of first NOAC initiation.

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Secondary objectives:
-  To evaluate the appropriateness of prescribed therapy based on 
Spanish health authorities’ recommendations (positioning 
therapeutic report)
-   To describe NOAC treatment management.
- To describe the patient’s knowledge about anticoagulant 
treatment, independent of NOAC type.
Country of study:
Spain
Author:
 (Trial Clinical Monitor)
Mobile: 
Marketing authorisation 
holder(s):
MAH:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
This study is initiated, managed and sponsored by:
Date:
24 Jul 2017
Page 2 of 44
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated 
companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise 
used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE…………………………………………………………….……………...1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 13
6.
MILESTONES..................................................................................................... 14
7.
RATIONALE AND BACKGROUND................................................................ 15
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 16
9.
RESEARCH METHODS .................................................................................... 17
9.1
STUDY DESIGN............................................................................................ 17
9.2
SETTING........................................................................................................ 18
9.2.1
Study sites ............................................................................................... 18
9.2.2
Study population ..................................................................................... 18
9.2.3
Study visits .............................................................................................. 18
9.2.4
Study discontinuation.............................................................................. 19
9.3
VARIABLES .................................................................................................. 19
9.3.1
Exposures ................................................................................................ 19
9.3.2
Outcomes................................................................................................. 19
9.3.2.1
Primary outcomes............................................................................. 19
9.3.2.2
Secondary outcomes......................................................................... 20
9.3.3
Covariates................................................................................................ 22
9.4
DATA SOURCES........................................................................................... 22
9.5
STUDY SIZE.................................................................................................. 23
9.6
DATA MANAGEMENT................................................................................ 23
9.7
DATA ANALYSIS......................................................................................... 24
9.7.1
Main analysis........................................................................................... 24
9.8
QUALITY CONTROL................................................................................... 25
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 26
9.10
OTHER ASPECTS ......................................................................................... 26
9.10.1
Data quality assurance............................................................................. 26

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9.10.2
Study records........................................................................................... 26
9.10.2.1
Source documents ............................................................................ 27
9.10.2.2
Direct access to source data and documents .................................... 27
9.10.3
Completion of study................................................................................ 27
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 28
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 28
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 28
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ................................................................................................................ 30
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 30
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 31
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 33
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
34
13.
REFERENCES .................................................................................................... 35
13.1
PUBLISHED REFERENCES......................................................................... 35
13.2
UNPUBLISHED REFERENCES................................................................... 36
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 37
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 38
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 44

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
AF
Atrial Fibrillation
ALT
AST
BP
CA
ALanine Transaminase
ASpartate Transaminase
Blood Pressure
Competent Authority
CHA2DS2-
VASc score
Congestive heart failure, Hypertension, Age (> 75),
Diabetes mellitus, Stroke/TIA, Vascular disease, Age 65-74, Sex 
Category
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRA
CRO
Clinical Research Associate
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DMP
eCRF
Data Management Plan
Electronic Case Report Form
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
HAS-BLED
Hypertension, Abnormal renal and liver function, Stroke (1 point), 
Bleeding history or predisposition, Labile INR, Elderly (>65 years), 
Drugs and Alcohol
ICH
IEC
IntraCraneal Hemorrhage
Independent Ethics Committee
INR
IRB
ISF
International Normalized Ratio 
Institutional Review Board
Investigator Site File
LPVM
MAH
Local PharmacoVigilance Manager
Marketing Authorization Holder
NIS
Non-Interventional Study
NVAF
NOAC
Non Valvular Atrial Fibrillation
New Oral Anticoagulant
PASS
Post-Authorization Safety Study
RWE
SAE
Real World Evidence
Serious Adverse Event
SAP
SmPC
Statistical Analysis Plan
Summary of Product Characteristics

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TTR
VKA
Time in Therapeutic Range
Vitamin K Antagonists

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3.
RESPONSIBLE PARTIES
Medical Advisor
Trial Clinical Monitor
LPVM
Coordinating Investigator
Coordinating Investigator
Coordinating Investigator

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa®
Name of active ingredient:
B01AE07 - Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
24 Jul 2017
1160-0287
Title of study:
Non-Interventional, cross-sectional study to describe NOACs 
management in patients with non-valvular atrial fibrillation (NVAF) in 
Spain. RE-CONOCE study.
Rationale and 
background:
Atrial fibrillation (AF) affects 1-2% of general population, but 
specially persons between 80 - 85 years, in whom the prevalence can 
reach 17% (1-3). In Spain, the latest data showed that prevalence of 
NVAF between general population is 4,4% in patients > 40 years-old 
and rises steeply above 60 years of age (3).
One of the most concerning sequelae associated with AF is ischemic 
stroke with an incidence of about 5 % per year in the absence of 
appropriate prophylaxis (4). The current clinical guidelines for the 
management of atrial fibrillation recommend that patients with an 
embolic risk factor receive preventive anticoagulant therapy (5).
The first oral anticoagulants to prevent the risk of thromboembolic 
events in AF were the vitamin K antagonists (VKA) warfarin and 
acenocoumarol. The management of these agents remains problematic 
because they require frequent routine coagulation monitoring and dose 
adjustment to maintain the intensity of anticoagulation within a safe 
and effective range. However, data show that 80% of patients 
receiving acenocoumarol in Spain, maintain a percentage of 
International Normalized Ratio (INRs) in therapeutic range between 
44% -59% (6,7) and mean time in therapeutic range (TTR) of only 
64% (6). Another recent study has showed that 40% of patients with 
NVAF who were receiving anticoagulation therapy with VKA in 
primary care in Spain had poor anticoagulation control (8).
The NOAC maintain the benefits of anticoagulant therapy and may 
increase perception of quality of life and satisfaction among patients 
because they do not necessitate the strict monitoring required for VKA. 
Likewise, maintaining a stable level of anticoagulation with NOACs 
prevents uncontrolled patients, improving patient outcomes and 
avoiding bleeding events (9).
The importance of this proposed novel study lies in the new scenario in 
anticoagulation therapy in Spain which involves: 
-
Recent publications in RWE which compares efficacy and 

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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa®
Name of active ingredient:
B01AE07 - Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
24 Jul 2017
1160-0287
safety among different NOACs (10).
-
Recent launch of Praxbind to market (June 2016).
-
Changes in anticoagulants’ prescription Spanish National 
guidelines - positioning therapeutic report (November 2016). (11)
-
Launch of new alternative (Edoxaban) to market (September 
2016).
All this topics could influence the prescription habits and positioning 
the different NOACs in different patient’s profile, according their 
clinical characteristics. Furthermore, patient could play a new role in 
this scenario, with a higher empowerment in decisions about his 
condition. Based on this assumption, it’s considered interesting to 
describe the current the anticoagulation management in Spain.
Research question 
and objectives:
This study has been designed in order to describe the current 
anticoagulation management in Spain. 
Primary objective: The primary objective of the study is to describe 
the usage of NOACs in patients with NVAF, in the hospital setting, 
based on the baseline characteristics at the time of first NOAC 
initiation. 
Secondary objectives:
-
To evaluate the appropriateness of prescribed therapy based on 
Spanish health authorities’ recommendations (positioning 
therapeutic report)
-
To describe NOAC treatment management.
-
To describe the patient’s knowledge about anticoagulant 
treatment, independent of NOAC type.
Study design:
This is an observational, multicentre, cross-sectional study based on 
newly collected data that will be conducted in cardiology departments, 
in at least 102 centers in Spain.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa®
Name of active ingredient:
B01AE07 - Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
24 Jul 2017
1160-0287
Population:
Patients, in the hospital setting, will be included in the study if all of 
the following criteria are met:
1.
The patient is willing and provides written informed consent to 
participate in this study
2.
The patient is at least 18 years of age
3.
The patient has a diagnosis of non-valvular atrial fibrillation 
(NVAF)
4.
The patient is on treatment with NOAC according to its
approved local SmPC and has initiated his first NOAC starting from 
November 2016
Patients will be excluded from participating in this study if they 
currently participate in any clinical trial of a drug or device.
To minimize selection bias at the patient level, 10 consecutive patients 
from each site who meet entry criteria will be enrolled.
Variables:
Variables collected at time of first NOAC initiation (baseline data 
collected from medical records):
- Demographic characteristics (age, gender, work status, life status)
- Alcohol consumption
- Physical activity
- Systolic BP/Diastolic BP
- CHA2DS2-VASc
- HAS-BLED
- AF diagnosis date
- In case of previous treatment with VKA: treatment duration (start and 
stop date if available) and reasons for VKA treatment switch
- First NOAC initiated (active substance, dose, start date)
- Kidney function (serum creatinine (mg/dl), creatinine clearance (CG 
equation) obtained from medical charts or auto-calculated)
- Liver function (AST/ALT, total bilirubin)
- Other concomitant diseases (focused on those related with stroke and 
systemic embolism prevention in patients with NVAF)
- Concomitant treatments (focused on those related with stroke and 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa®
Name of active ingredient:
B01AE07 - Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
24 Jul 2017
1160-0287
systemic embolism prevention in patients with NVAF)
- To evaluate the reason of NOAC initiation.
Variables collected at time of study visit / enrolment (new data):
- In order to answer the secondary objective regarding patient’s 
knowledge, all patients at study visit will be asked some questions 
by the physician.
- In order to answer the secondary objective regarding treatment 
management, the following variables will be collected: 
- History of NOAC treatments prior to current NOAC (if 
applies):
- Dose changes: start date – end date, new dose, reason
- NOAC switch: start date – end date, dose and/or dose changes 
and reason
- Frequency of visits to the physician
- History of thromboembolic and bleeding events at time of enrolment
Even though this NIS is based on already existing (retrospective) data
and also new data obtained at the visit date, AE management and AE 
reporting becomes relevant as data extraction from patient’s individual 
medical records will be performed (study data collection) and 
reviewed. AE management and reporting has to be implemented and 
followed as outlined in section 11.
Data sources:
Patient data will be collected from patient medical charts and will be 
entered to an eCRF by the Investigator. Most of data will be available 
in the charts but as a routine clinical practice, some data could be 
missing.
Data regarding the ad hoc questionnaire will be obtained from an 
interview between the physician and the patient according to 
instructions. Investigator will enter these data into the eCRF system.
Study size:
It is planned that a total of approximately 1000 patients will be 
recruited for the study. Additional details regarding sample size 
considerations are provided in Section 9.5. 
Data analysis:
A Data Management Plan (DMP) and Statistical and Epidemiological 
Analysis Plan (SEAP), will be prepared to describe all processes, 
treatment and specifications for data collection, cleaning, validation 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa®
Name of active ingredient:
B01AE07 - Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
24 Jul 2017
1160-0287
and analysis.
Since the study is descriptive, the variables included in the study 
objectives will be summarized overall and by factors of interest. All 
results will be summarized with measures of central tendency (mean 
and 
median), 
variability/dispersion 
(standard 
deviation 
and 
interquartile ranges), absolute and relative frequencies, and ranges. 
The analysis population will consist of all eligible patients (i.e. all 
patients fulfilling all inclusion criteria and no exclusion criteria). If 
patients have missing values for an outcome, those patients will be 
excluded for that outcome’s analysis. 
Missing data will not be 
imputed.
Milestones:
-
Final Protocol: Jul 2017
-
Start of data collection: November 2017
-
End of data collection: May 2018
-
Final study report: October 2018

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Sep 2017
Start of data collection
Nov 2017
End of data collection
May 2018
Registration in the EU PAS 
register
Jul 2017
Final report of study results:
Oct 2018

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7.
RATIONALE AND BACKGROUND
Atrial fibrillation (AF) affects 1-2% of general population, but specially persons between 80 -
85 years, in whom the prevalence can reach 17% [1-3]. In Spain, the latest data showed that 
prevalence of NVAF in general population is 4.4% in patients > 40 years-old and rises 
steeply above 60 years of age [3].
One of the most concerning sequelae associated with AF is ischemic stroke with an incidence 
of about 5 % per year in the absence of appropriate prophylaxis [4]. The current clinical 
guidelines for the management of atrial fibrillation recommend that patients with an embolic 
risk factor receive preventive anticoagulant therapy [5].
The first oral anticoagulants to prevent the risk of thromboembolic events in AF were the 
vitamin K antagonists (VKA) warfarin and acenocoumarol. The management of these agents 
remains problematic because they require frequent routine coagulation monitoring and dose 
adjustment to maintain the intensity of anticoagulation within a safe and effective range. 
However, data show that between 43,8 % to 59 % of the population receiving acenocumarol 
in Spain are within the recommended INR target of 2.0 – 3.0. [6]. Another recent study has 
showed that 40% of patients with NVAF who were receiving anticoagulation therapy with 
VKA in primary care in Spain had poor anticoagulation control [8].
The New Oral AntiCoagulants (NOACs) maintain the overall benefit of anticoagulant 
therapy and may increase perception of quality of life and satisfaction among patients 
because they not necessitate the strict monitoring required for VKA. Likewise, maintaining a 
stable level of anticoagulation with NOACs prevents uncontrolled patients, improving patient 
outcomes and avoiding bleeding events [9].
The importance of this proposed novel study lies in the new scenario in anticoagulation 
therapy in Spain which involves:
-
Recent publications in RWE which compares efficacy and safety among different 
NOACs [10]
-
Recent launch of Praxbind® to market (June 2016)
-
Changes in anticoagulants’ prescription Spanish National guidelines - positioning 
therapeutic report (November 2016) [11]
-
Launch of new alternative (Edoxaban) to market (September 2016).
All these topics could influence the prescription habits and positioning the different NOACs
in different patient’s profile, according their clinical characteristics. Furthermore, patients
could play a new role in this scenario, with a higher empowerment in decisions about their
condition. Based on this assumption, it’s considered interesting to describe the current
anticoagulation management in Spain.

Boehringer Ingelheim
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8.
RESEARCH QUESTION AND OBJECTIVES
This study has been designed in order to describe the current anticoagulation management in 
Spain. 
Primary objective: 
To describe the usage of NOACs in patients with NVAF, in the hospital setting, based on the 
baseline characteristics at the time of first NOAC initiation. Baseline clinical and 
demographic characteristics of patients will be described according to NOAC used. 
Secondary objectives:
-
To evaluate the appropriateness of prescribed therapy based on Spanish health 
authorities recommendations (positioning therapeutic report) 
-
To describe NOAC treatment management.
-
To describe the patients’ knowledge about anticoagulant treatment, independent of 
NOAC type.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This observational multi-centre and cross-sectional study will be conducted in cardiology 
departments, in at least 102 centres in Spain. 
The design of the study impose an only visit to be performed that will coincide with one of 
those performed by the patients as part of routine follow-up of their disease, without 
interfering with usual clinical practice of the investigator.
A specific therapeutic strategy has already been assigned to each included patient, based on 
routine practice and without interference with the physician’s prescription habits. The 
observational nature of the study is ensured as no diagnostic or therapeutic intervention 
outside of routine clinical practice will be applied. 
Figure 1 Study design
Figure 1 has been designed according to Spanish Health Authorities recommendations, which 
recommend start OAC treatment with VKA. However in some circumstances, NOAC could 
be considered as primary treatment choice according to the positioning therapeutic report:
1. Clinical reasons:
-
Patients with known hypersensitivity or with specific contraindications to the use 
of acenocoumarol or warfarin.
-
Patients with a history of intracranial hemorrhage (ICH) (except during the acute 
phase)
-
Patients with ischemic stroke who present high-risk clinical and neuroimaging 
criteria for ICH.
-
Patients on VKA treatment who suffer from severe arterial thromboembolic 
events despite good INR control.
2. Situations related to INR control:
-
Patients who have started treatment with VKA in which it is not possible to 
maintain INR control within range (2-3) despite good therapeutic compliance.

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-
Impossibility of access to conventional INR control.
9.2
SETTING
Approximately 1.000 patients with NVAF currently on NOAC treatment and having initiated 
their first NOAC starting from November 2016 (Health Authorities positioning report 
publication) are planned to be included in the study. To minimize selection bias at the patient 
level, 10 consecutive patients from each site who meet entry criteria will be enrolled. 
It is necessary to ensure that study population is representative of the entire national territory. 
Therefore, patients will be recruited from Hospitals (different levels of medical care: primary 
hospital, secondary hospital) in different geographical areas according to the distribution of 
the overall population in this area. Site selection will be performed in order to secure 
representativeness of the NVAF population treated with NOACs.
9.2.1
Study sites
Cardiology departments, in a hospital setting, who regularly prescribe NOACs for stroke 
prevention in NVAF patients, will be selected to participate. The study will be performed 
among all the national territory. Site feasibility assessments will be performed by the CRO 
during the process of site selection. 
9.2.2
Study population
To be eligible to participate in the study, patients must meet the following selection criteria. 
The patient will be considered included when he/she agrees to participate in the study by
signing the informed consent. 
Patients will be included in the study if all of the following criteria are met:
1. The patient is willing and provides written informed consent to participate in this 
study
2. The patient is at least 18 years of age
3. The patient has a diagnosis of non-valvular atrial fibrillation (NVAF)
4. The patient is on treatment with NOAC according to its approved local SmPC and has 
initiated his first NOAC starting from November 2016
Patients will be excluded from participating in this study if they currently participate in any 
clinical trial of a drug or device.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the study file at the study site.
9.2.3
Study visits
The design of the study imposes a single visit to be performed that will coincide with one of 
those performed by the patients as part of routine follow-up of their disease, without 
interfering with usual clinical practice of the investigator. After signing the informed consent 

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(if patient agreed to participate in the study) patients will be asked to answer the questions 
necessary to evaluate the patient’s knowledge about anticoagulant treatment at the unique 
study visit. Other variables needed to address study objectives will be obtained directly from 
patient medical records. The end of the single study visit is the end of the study for each 
patient.  
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study
3. Violation of the study protocol, or the contract by a study site or investigator, disturbing 
the appropriate conduct of the study
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
9.3
VARIABLES
9.3.1
Exposures
Patients in this study will have been prescribed a NOAC treatment for their NVAF and 
initiated it in the time period from November 2016 to present. Prescription of the treatments 
will have been done under the sole responsibility of the healthcare professional and before the 
study visit. The study population will be treated with NOAC according to the approved local 
Summary of Product Characteristics (SmPC). 
As this is a non-interventional observational study, designed to reflect as faithfully as 
possible real-life clinical practice, the decision to start treatment with NOAC is prior to and 
independent of the participation of the patient in the study and based on medical judgment 
criteria and routine clinical practice. In addition, no intervention, either diagnostic or 
therapeutic, will be applied to patients other than that used for routine clinical practice.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome is the usage of NOACs, in patients with NVAF, in the hospital setting, 
based on the baseline characteristics at the time of first NOAC initiation. Baseline (at time of 
first NOAC initiation) variables will be analysed descriptively by NOAC type. Treatment 
groups will be defined according to first NOAC prescribed. The time frame for assessing this 
outcome is 7 months (recruitment period). 

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Table 9.3.2.1: 1 
Baseline variables at time of first NOAC initiation
Variables
Obtained from patient 
medical records
Age
X
CHA2DS2-VASc
X
HAS-BLED
X
9.3.2.2
Secondary outcomes
The secondary outcomes are:
-
Appropriateness of NOAC prescription based on national recommendations 
(positioning therapeutic report) (11) is planned. The reasons for NOAC initiation 
will be described using the following checklist. The time frame is the duration of the 
study visit, at the time of patient enrolment. Answers to this checklist will be 
validated with baseline variables already collected from medical records: 
□
Patients with known hypersensitivity or with specific contraindications to 
the use of acenocoumarol or warfarin.
□
Patients with a history of intracranial hemorrhage (ICH) (except during the 
acute phase)
□
Patients with ischemic stroke who present high-risk clinical and 
neuroimaging criteria for ICH.
□
Patients on VKA treatment who suffer from severe arterial thromboembolic 
events despite good INR control.
□
Patients who have started treatment with VKA in which it is not possible to 
maintain INR control within range (2-3) despite good therapeutic 
compliance.
□
Impossibility of access to conventional INR control.
□
Other
□
Unknown
-
NOAC treatment management. The following variables will be collected at time of 
patient enrolment: 
-
history of thromboembolic and bleeding events, 
-
frequency of visits to the physician, 
-
first NOAC (start - end date, dose),
-
dose change/adjustment (start date - end date, new dose, reason for change)  
-
new NOAC initiation (start - end date, new treatment, new dose, reason for 
change) 
Prior VKA use and reasons for switch (already collected as a baseline variable) 
will be also considered for this outcome. The time frame is the duration of the 
NOAC treatment, since first NOAC treatment initiation until the study visit 
date. 

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-
Patient’s knowledge about his condition. Answers (yes/no) to the questions below 
will be described for the whole study population, independent of NOAC type. “Yes” 
and “No” patient’s answers must be validated by the physician (the physician will 
ensure that the answer is accurate by asking “Why” “Which” “What” additional 
questions to validate the answer). The time frame is the duration of the interview 
with the patient during the study visit, at the time of patient enrolment. 
a) Do you know why you are being treated with an anticoagulant? Yes/No.
b) Do you know which the effect of the anticoagulant treatment is? Yes/No.
c) Do you know what could happen if you don’t take the anticoagulant 
treatment? Yes/No.
d) Do you mind taking the anticoagulant treatment? Yes/No.
Table 9.3.2.2:1
Treatment management variables at time of enrolment
Variables
Obtained from 
patient medical 
records
Obtained at the 
study visit by 
direct interview 
with the patient
In case of previous treatment with VKA: 
treatment duration (start and stop date if 
available) and reasons for VKA treatment switch
X *
First NOAC initiated (active substance, dose, 
start date, end date)
X *
History of thromboembolic and bleeding events
X
X (if applicable)
History of NOAC treatments prior to current 
NOAC (if applies):
- Dose changes: start date – end date, new 
dose, and reason
- NOAC switch: start date – end date, dose
and/or dose changes and reason
X
X (if applicable)
Frequency of visits to the physician: 
“How many times a year do you visit the 
cardiologist?”
X
* Already obtained for primary objective. 

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9.3.3
Covariates
Table 9.3.3: 1 
Covariates: Baseline variables at time of first NOAC initiation
Variables
Obtained from patient 
medical records
Demographic characteristics (gender, work status, life status)
X
Alcohol consumption
X
Physical activity
X
Systolic BP/Diastolic BP
X
AF diagnosis date
X
In case of previous treatment with VKA: treatment duration 
(start and stop date if available) and reasons for VKA treatment 
switch
X
First NOAC initiated (active substance, dose, start date, end 
date)
X
Kidney function (serum creatinine (mg/dl), creatinine clearance 
(CG equation) obtained from medical charts or auto-calculated)
X
Liver function (AST/ALT, total bilirubin)
X
Concomitant and relevant previous diseases (Ischaemic stroke 
or TIA, Systemic embolism, Heart Failure, Coronary artery 
disease, Ischemic cardiomyopathy, Left ventricular dysfunction, 
Cerebrovascular disease, Renal disease, Liver disease, Bleeding, 
Hypertension, Diabetes mellitus, Hyperlipidemia, COPD, 
Gastric and duodenal ulcers, Dementia, Anemia, Rheumatic 
disease, Cancer, Prosthetic heart valves, Others)
X
Concomitant treatments (ARB or ACE inhibitor, Beta-blocker, 
Calcium channel blockers, Diuretics, Amiodarone, Statin, Proton-
pump 
inhibitor, 
H2-receptor 
antagonist, 
Aspirin, 
Other 
Antiplatelet agents, Digoxin, NSAIDs, Verapamil / Dronedarone, 
Other antiarrhythmics, ketoconazol (systemic), ciclosporine, 
itraconazol, Others)
X
9.4
DATA SOURCES
Data collection will be limited to those available in the medical records of selected patients. 
Variables collected at time of first NOAC initiation (see Table 9.3.2.1: 1 and Table 9.3.3 :1 )
will be obtained based on patient’s medical records. 

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Patient knowledge about his condition and other variables collected at time of patient 
enrolment (new data, see Table 9.3.2.2: 1) will be obtained by interviewing the patient. 
9.5
STUDY SIZE
It is planned that a total of approximately 1000 patients will be recruited for the study.
Based on such sample size estimates, categorical variables of binomial proportions (e.g. 
gender) will be estimated with the precision (i.e. width of descriptive 95% confidence 
interval) described in the table 9.5: 1.
Table 9.5: 1 Width of 95% confidence interval by precision
Prevalence of attribute
Sample size
1000
10% Expected n
100
95% CI width
3.73
20% Expected n
200
95% CI width
4.95
30% Expected n
300
95% CI width
5.67
40% Expected n
400
95% CI width
6.06
50% Expected n
500
95% CI width
6.18
9.6
DATA MANAGEMENT
The data will be entered by the investigators themselves and/or authorized personnel directly 
in the electronic case report form (eCRF). A data management plan (DMP) will be created to 
describe all functions, processes, and specifications for data collection, cleaning and 
validation. The eCRFs will include programmable edits to obtain immediate feedback if data 
are missing, out of range, illogical or potentially erroneous. 
AE reconciliation will be performed quarterly from study initiation date.

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When data management is outsourced, the designated contract organization will be 
responsible for the development and implementation of the data management plan and 
preparation of the data handling report according to the sponsor´s standards.
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.
9.7
DATA ANALYSIS
Analyses will be performed by Boehringer Ingelheim’s designees. The analysis population 
will consist of all eligible patients (i.e. all patients fulfilling all inclusion criteria and no 
exclusion criteria). If patients have missing values for an outcome, those patients will be 
excluded for that outcome’s analysis. 
In this non-interventional study, retrospective data from medical charts and data at the study 
visit will be collected for non-valvular AF patients. Once the study has been completed and 
all data from the last patient have been recorded, the database will be closed and statistical 
analysis will be performed.
The proposed methods for statistical analysis presented below are a summary of the methods 
that will be applied in the study to analyse the data collected and to answer the study 
objectives. 
Since the study is descriptive the variables included in the study objectives will be 
summarized overall and by factors of interest. All results will be summarized with measures 
of central tendency (mean and median), variability/dispersion (standard deviation and 
interquartile ranges), absolute and relative frequencies, and ranges. 
A Statistical and Epidemiological Analysis Plan (SEAP), will be prepared to describe all 
processes, treatment and specifications for and the planned statistical analysis.
9.7.1
Main analysis
The primary outcome is the usage of NOACs in patients with NVAF, based on the baseline 
characteristics at the time of first NOAC initiation. Baseline (at time of first NOAC initiation) 
variables will be analyzed descriptively by NOAC type. Standardized differences between 
Dabigatran Etexilate and each of the other NOACs separately will be estimated for these 
variables.

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For the secondary outcomes, the following analyses are planned: 
Appropriateness of NOACs prescription based on national recommendations (positioning 
therapeutic report) (11) is planned to be done for the entire eligible patients.
For NOAC treatment management, descriptive analysis of history of thromboembolic and 
bleeding events, frequency of visits to the physician, first NOAC (start - end date, dose), dose 
change/adjustment (start date - end date, new dose, reason for change) and new NOAC 
initiation (start - end date, new treatment, new dose, reason for change) will be done. Prior 
VKA use and reasons for switch (already collected as a baseline variable) will be also 
considered for this outcome.
Variables regarding patient knowledge collected at time of patient enrolment will be analysed 
descriptively (independent of NOAC type). Each question will be analyzed separately.
9.8
QUALITY CONTROL
The eCRF will include programmable edit checks to obtain feedback if data is missing, out of 
range, illogical or potentially erroneous. These checks will be performed once data is entered 
into the eCRF. Thus the data entered in to the eCRF will be validated within the system and 
the physician will receive alerts for missing or inconsistent data. In case any changes of 
already entered data will be required, an audit trail will be available. 
No regular source data verification is planned in this study. However, in case of decreasing 
compliance (i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause 
audit or risk-based monitoring visit could be performed.
Strict and continuous quality control will be maintained to ensure the accuracy and scientific 
rigor of the data obtained, maintaining uniform conditions for collecting the information. 
Quality control will be carried out by qualified personnel designated for this purpose.
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Independent Ethics Committee (IECs) or by regulatory authorities. 
The quality assurance auditor will have access to all medical records, the investigator’s study-
related files and correspondence, and the informed consent document of this study.

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9.9
LIMITATIONS OF THE RESEARCH METHODS
A NIS is the most suitable design to obtain information about the use of medicines in 
everyday therapeutic practice and thus for investigating questions in everyday therapeutic 
practice. However, there are some limitations inherent to this design.
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are 
less restrictive than the ones of a randomized clinical trial, which will permit the enrolment of 
a broader patient population. 
The choice of NOAC was done before the study visit and it is done at the discretion of the 
investigator. However, as the setting is limited to the hospital setting (Cardiology Services), 
patients treated in other clinical settings will not be part of this study. Patients seen by their 
physician less than twice per year are therefore less likely to be included in the study. Patients 
with higher frequency of visits are more likely to be included in the study and could be over-
represented in the sample. Additionally, having 10 patients recruited in each site, patients 
from the larger practice hospitals will also be under-represented.
As patients are included after first NOAC initiation and need to be treated by a NOAC at time 
of enrolment, any patient having prematurely discontinued any NOAC treatment between the 
time of first NOAC initiation and the start of the enrolment period will not be included in the 
study. The sample may therefore not be representative of all patients having initiated a 
NOAC since November 2016.
 
Channeling bias is a form of confounding that occurs when a drug is preferentially prescribed 
to patients with different baseline characteristics. Standardized differences will be applied 
when assessing channeling bias.
9.10
OTHER ASPECTS
Not applicable
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, via 
remote data capture. 

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9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
9.10.2.2
Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IEC review and 
regulatory inspection, providing direct access to all related source data / documents. eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical study monitor, 
auditor and inspection by health authorities (e.g. US Food and Drug Administration (FDA)). 
The Clinical Research Associate (CRA) / Clinical Monitor Local (CML) and auditor may 
review all eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 9.10.2.1
9.10.3
Completion of study
The EC/competent authority in Spain needs to be notified about the end of the study (last 
patient out), or early termination of the study. 

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) (to the extent applicable to the NIS setting and required by 
local regulations), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Independent Ethics Committee (IEC) and Competent Authority 
(CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the study records. A signed copy of 
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorized
monitors (CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.

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Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IEC and the competent authority.

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11.
MANAGEMENT AND REPORTING OF ADVERSE
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalization
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 

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and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
The following are considered as AESIs:
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
Once informed consent is signed the following must be collected by the investigator if 
identified during chart review data collection period and study visit data collection
-
all adverse drug reaction (ADRs) (serious and non-serious), 
-
all AEs with fatal outcome 
All ADRs , including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).

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•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken Pradaxa®, the investigator must report any drug exposure during 
pregnancy, which occurred in a female subject or in a partner to a male subject to the Sponsor 
by means of Part A of the Pregnancy Monitoring Form. The outcome of the pregnancy 
associated with the drug exposure during pregnancy must be followed up and reported by 
means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study: 
Type of Report
Timeline
All serious ADRs associated with 
Pradaxa®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Pradaxa®
immediately within 24 hours
All non-serious ADRs associated with 
Pradaxa®
7 calendar days

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All pregnancy monitoring forms
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
Pradaxa® according to the local regulatory requirements for spontaneous AE reporting at the 
investigator’s discretion by using the locally established routes and AE report forms. The 
term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.
Final study report will be distributed to national health authority and ethics committees. 
The results of this study will be published in a national journal and presented in regional or
national congresses.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1]
Barrios V, Calderon A, Escobar C, de la Figuera M. Patients with atrial fibrillation in 
a primary care setting: Val-FAAP study. Rev Esp Cardiol (Engl Ed) 2012 
Jan;65(1):47-53.
[2]
Cea-Calvo L, Redon J, Lozano JV, Fernandez-Perez C, Marti-Canales JC, Llisterri 
JL, et al. [Prevalence of atrial fibrillation in the Spanish population aged 60 years or 
more. The PREV-ICTUS study]. Rev Esp Cardiol 2007 Jun;60(6):616-24.
[3]
Gomez-Doblas JJ, Muniz J, Martin JJ, Rodriguez-Roca G, Lobos JM, Awamleh P, et 
al. Prevalence of atrial fibrillation in Spain. OFRECE study results. Rev Esp Cardiol 
(Engl Ed) 2014 Apr;67(4):259-69
[4]
Garber JL, Willenborg KL, Rose AE.  Analysis of anticoagulant prescribing in non-
valvular atrial fibrillation and development of a clinical tool for guiding anticoagulant 
selection . J Thromb Thrombolysis. 2015 Aug;40(2):248-54.
[5]
Kirchhof P, Benussi S, Kotecha D et al. 2016 ESC Guidelines for the management of 
atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016 Oct 
7;37(38):2893-2962.
[6]
Ansell J, Hollowell J, Pengo V, Martinez-Brotons F, Caro J, Drouet L. Descriptive 
analysis of the process and quality of oral anticoagulation management in real-life 
practice in patients with chronic non-valvular atrial fibrillation: the international study 
of anticoagulation management (ISAM). J Thromb Thrombolysis 2007 Apr;23(2):83-
91.
[7]
Clua Espuny JL, Dalmau Llorca MR, Aguilar MC. [Characteristics of oral anti-
coagulation treatment in high-risk chronic auricular fibrillation]. Aten Primaria 2004 
Nov 15;34(8):414-9.
[8]
Barrios V, Escobar C, Prieto L, et al. Anticoagulation Control in Patients With 
Nonvalvular Atrial Fibrillation Attended at Primary Care Centers in Spain: The 
PAULA Study. Rev Esp Cardiol (Engl Ed). 2015 Sep;68(9):769-76.
[9]
Connolly SJ, Ezekowitz MD, Yusuf S et al. RE-LY Steering Committee and 
Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N 
Engl J Med 17(361):1139–1151.
[10]
Graham DJ, Reichman ME, Wernecke M et al. Stroke, Bleeding, and Mortality Risks 
in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for 
Nonvalvular Atrial Fibrillation. JAMA Intern Med. 2016 Nov 1;176(11):1662-1671
[11]
General criteria and recommendations for the use of direct oral anticoagulants 
(NOAC) in the prevention of stroke and systemic embolism in patients with non-
valvular atrial fibrillation. Spanish Health Authority Therapeutic Positioning Report. 
Version 5 (2016). Available at: 
https://aemps.gob.es/medicamentosUsoHumano/informesPublicos/home.htm#anticoa
gulantes-orales.
[12]
López-Sendon J, Merino JL. Mal control de la anticoagulación en la fibrilación 
auricular. Hasta cuándo? Rev Esp Cardiol. 2015;68(9):740–742.

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13.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Title
<1>
Patient information and Informed Consent Form
<2>
Investigator  List
<3>
Statistical Analysis Plan (SAP)
<4>
Data Management Plan (DMP)
<5>
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form)
<6>
Pregnancy Monitoring Form

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist
is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology, which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example, in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). The Checklist is a supporting document and does not replace the 
format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
Study title:
Non-Interventional, cross-sectional study to describe NOACs management in 
patients with non-valvular atrial fibrillation (NVAF) in Spain. RE-CONOCE Study.
Study reference number:
1160-0287
Section 1: Milestones
Yes
No
N/A
Section
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
6
1.1.6 Final report of study results.
6
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Comments:
Study progress reports for EC and authorities will be done annually
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
8
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in 
the risk management plan, an emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
7
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
No hypothesis testing is planned in this descriptive study in section 9.7
Section 3: Study design
Yes
No
N/
A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
3.4
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
Descriptive study. No measures of occurrence or measures of association are performed
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period?
10.2

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Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.2.2 Age and sex?
9.2
4.2.3 Country of origin?
9.2
4.2.4 Disease/indication?
9.2
4.2.5 Duration of follow-up?
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2
Comments:
Cross-sectional study. No follow-up is carried out
Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured?
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
9.3
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.7
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
Comments:
Observational study. Patients treated as per routine clinical practice.
Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study)
6.4
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management)
9.3

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Comments:
Descriptive outcomes
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding by 
indication if applicable?
7.2
Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
9.9
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
7.3
Does the protocol address the validity of the 
study covariates?
Comments:
This study is only descriptive
Section 8: Effect modification
Yes
No
N/
A
Section
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect) 
Comments:
This study is only descriptive
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.4
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.4
9.1.3 Covariates?
9.4
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily 
dosage,  prescriber)
9.3
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates?
9.4
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
10.2
Comments:
Unique patient identification code numbers will be used.
Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.1 Is the choice of statistical techniques described? 
9.7
10.2 Are descriptive analyses included?
9.7
10.3 Are stratified analyses included?
9.7
10.4 Does the plan describe methods for adjusting for 
confounding?
10.5 Does the plan describe methods for handling 
missing data?
9.7
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
This study is only descriptive
Section 11: Data management and quality 
control
Yes
No
N/
A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.6
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results? 
Comments:
Section 12: Limitations
Yes
No
N/
A
Section
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
9.2

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Section 12: Limitations
Yes
No
N/
A
Section
Number
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment)
9.2
Comments:
This study is only descriptive
Section 13: Ethical issues
Yes
No
N/
A
Section
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10.1
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
10.1
Comments:
Section 14: Amendments and deviations
Yes
No
N/
A
Section
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
5
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/
A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12
Comments:

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ANNEX 3. ADDITIONAL INFORMATION
Not applicable

 
 
 
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