Non-Interventional, Cross-sectional Study to Describe NOACs Management in Elderly 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:
c28106106-01
BI Study Number:
1160-0297
BI drug in the scope of 
this NIS:
Dabigatran etexilate (Pradaxa®)
Title:
Non-Interventional, cross-sectional study to describe NOACs 
management in elderly patients with non-valvular atrial 
fibrillation (NVAF) in Spain. RE-BELD Study
Brief lay title
This study observes the usage of non-vitamin K antagonist oral 
anticoagulants (NOACs) in elderly patients with a heart rhythm 
disorder in Spain
Protocol version 
identifier:
1
Date of last version of 
protocol:
Not applicable
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:
This study is initiated, managed and sponsored by:
Joint PASS:
No

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Research question and 
objectives:
This study has been designed in order to describe the current non-
vitamin K antagonist oral anticoagulants (NOACs) management 
in elderly patients in Spain.
Primary objective: To describe the pattern of usage of NOACs 
prescribed according to their Summary of Product Characteristics 
(SmPC), by current NOAC type and dose, in elderly patients 
(≥75 years-old) with non-valvular atrial fibrillation (NVAF) at 
the time of the study visit.
Secondary objectives:
To describe patients characteristics at the time of the study visit 
by current NOAC type stratified by duration since first NOAC 
initiation.
To describe OAC treatment management since first NOAC 
initiation until the study visit by duration since first NOAC 
initiation: previous vitamin K antagonists (VKA) treatment, first 
NOAC treatment duration, dose changes, switch between NOACs 
and reasons for switch, total NOAC treatment duration and 
additional antiplatelet treatment. 
To describe the Clinical Frailty Scale grading, CFS at the time of 
the study visit, by current NOAC type.
To describe first NOAC usage by NOAC type, for primary 
prevention or secondary prevention, at the time of first NOAC 
initiation.
Country(-ies) of study:
Spain
Author:
Mobile: 
Marketing authorisation 
holder(s):
MAH:
This study is initiated, managed and sponsored by:

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MAH contact person:
Not applicable
EU-QPPV:
Not applicable
Signature of EU-
QPPV:
Not applicable
Date:
24 May 2019
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© 2019 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....................................................................................... 4
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 8
4.
ABSTRACT........................................................................................................... 9
5.
AMENDMENTS AND UPDATES..................................................................... 18
6.
MILESTONES..................................................................................................... 19
7.
RATIONALE AND BACKGROUND................................................................ 20
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 22
9.
RESEARCH METHODS .................................................................................... 23
9.1
STUDY DESIGN............................................................................................ 23
9.2
SETTING........................................................................................................ 23
9.2.1
Study sites ............................................................................................... 23
9.2.2
Study population ..................................................................................... 24
9.2.3
Study visits .............................................................................................. 24
9.2.4
Study discontinuation.............................................................................. 25
9.3
VARIABLES .................................................................................................. 25
9.3.1
Exposures ................................................................................................ 25
9.3.2
Outcomes................................................................................................. 25
9.3.2.1
Primary outcomes............................................................................. 25
9.3.2.2
Secondary outcomes......................................................................... 26
9.3.3
Covariates................................................................................................ 27
9.4
DATA SOURCES........................................................................................... 29
9.5
STUDY SIZE.................................................................................................. 30
9.6
DATA MANAGEMENT................................................................................ 31
9.7
DATA ANALYSIS......................................................................................... 31
9.7.1
Main analysis........................................................................................... 32
9.8
QUALITY CONTROL................................................................................... 33
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 34
9.10
OTHER ASPECTS ......................................................................................... 34
9.10.1
Data quality assurance............................................................................. 34

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9.10.2
Study records........................................................................................... 34
9.10.2.1
Source documents ............................................................................ 35
9.10.2.2
Direct access to source data and documents .................................... 35
9.10.3
Completion of study................................................................................ 35
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 36
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 36
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 36
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 38
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 38
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 39
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 41
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS42
13.
REFERENCES .................................................................................................... 43
13.1
PUBLISHED REFERENCES......................................................................... 43
13.2
UNPUBLISHED REFERENCES................................................................... 45
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 46
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 47
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 53

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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
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical, Therapeutic, Chemical classification system
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CFS
Clinical Frailty Scale
CHA2DS2-VASc
Congestive heart failure, Hypertension, Age (> 75),Diabetes 
mellitus, Stroke/TIA, Vascular disease, Age 65-74, SexCategory
CI
Confidence Interval
CRA
Clinical Research Associate
eCRF
Electronic Case Report Form
CRO
Clinical Research Organization
DMP
Data Management Plan
DVP
Data Validation Plan
EHRA
European Heart Rhythm Association
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
FDA
Food and Drug Administration
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practice
HAS-BLED
Hypertension, Abnormal renal and liver function, Stroke (1 point),
Bleeding history or predisposition, Labile INR, Elderly (>65 years),
Drugs and Alcohol.
ICH
Intracranial hemorrhage
ICH-GCP
Harmonized Tripartite Guideline for Good Clinical Practice
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ISF
Investigator Site File
LVEF
Left ventricular ejection fraction
MAH
Marketing Authorization Holder Activities
NIS
Non-Interventional Study
NYHA
New York Heart Association
NOAC
Non-vitamin K antagonist oral anticoagulant
NVAF
Non-valvular atrial fibrillation
OAC
Oral anticoagulant
PASS
Post-Authorization Safety Study
SAE
Serious Adverse Event
SAHS
Sleep apnoea-hypopnoea syndrome
SAP
Statistical Analysis Plan

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SMF
Study Master File
SmPC
Summary of Product Characteristics
SOPs
Standard Operating Procedures
TIA
Transitory ischemic attack
TTR
Time in Therapeutic range
VKA
Vitamin K Antagonist

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3.
RESPONSIBLE PARTIES
Sponsor representatives: 
Medical Advisor cardiovascular
Medical Project 
 
Trial Statistician
GPV Study coordination
Coordinating Investigators:

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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 May 2019
1160-0297
N/A
N/A
Title of study:
Non-Interventional, cross-sectional study to describe NOACs 
management in elderly patients with non-valvular atrial fibrillation 
(NVAF) in Spain.
Rationale and 
background:
Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in 
clinical practice. AF affects between 1-2% of general population, but 
especially in patients aged ≥80 years prevalence can reach between 9-
10% up to 17% of these patients (1-4).  It is known that older age is an 
important risk factor for patients with AF and it is associated with a four 
to five fold increased risk of embolic stroke and with an estimated 
increased stroke risk of 1.45-fold per decade in aging (4). Additionally, 
aging is also associated with an increased risk of major bleeding with 
oral anticoagulant therapy (5). 
The current clinical guidelines on the usage of non-vitamin K antagonist 
oral anticoagulants (NOACs) in patients with atrial fibrillation EHRA 
2018 (6) recommend that patients with an embolic risk factor receive 
preventive anticoagulant therapy, with special emphasis in the frail and 
older patients.
The first oral anticoagulants to prevent the risk of thromboembolic 
events in AF were the vitamin K antagonists (VKA) warfarin and 
acenocumarol. 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. In elderly patients (≥70 years) with NVAF and treated 
with 
VKA, 
TTR 
should 
be 
maintained 
≥60% 
to 
prevent 
thromboembolism and all-cause death and TTR <40% should be 
avoided to prevent major hemorrhage (7). NOACs, with a similar 
benefit as warfarin but with greater safety, even in a very old 
population, offers a new possibility of therapeutic strategy in clinical 
practice. In patients 75 years and older, randomized trials have shown 
NOAC to be as effective as warfarin, or in some cases superior, with an 
overall better safety profile, consistently reducing rates of intracranial 
hemorrhages (4). The non-vitamin K antagonist oral anticoagulants 
(NOAC) maintain the benefits 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.

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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 May 2019
1160-0297
N/A
N/A
However, the usage of NOACs in the elderly population in routine 
clinical practice show deficiencies and can be optimized, showing that 
under-dosing of NOACs is common in this population (8). Other studies 
suggest that as many as 34% of elderly patients on NOACs were on an 
incorrect dose or were prescribed the medication despite a 
contraindication (9) and more than half were found to be on an 
inappropriately low dose (10). These errors could lead to increased 
bleeding risk and/or increased risk of treatment failure (11). In general, 
oral anticoagulants (OAC) remain underutilized in older age groups.
The benefit / risk balance of anticoagulation in elderly patients and AF 
has already been analyzed in different studies. The risk of hemorrhagic 
stroke was lower in the NOAC group than in the warfarin group (12). In 
another study, the rates of hemorrhagic and thromboembolic events in 
patients older than 90 years under treatment with NOACs at VKAs were 
comparable (13). Elderly patients treated with high doses of NOACs 
had a statistically similar incidence of stroke, a lower statistical 
incidence of intracranial hemorrhage (ICH) and a higher net clinical 
benefit, compared with those treated with low doses (14).
In addition to age, other characteristics of the patient should be 
considered at the time of selecting an appropriate anticoagulant 
treatment. The female sex as a risk factor for stroke and 
thromboembolism in patients with atrial fibrillation should also be 
considered. Thromboembolic risk related to atrial fibrillation (AF) may 
differ between men and women, and this may affect the response to 
anticoagulant therapy and warrant a sex-specific management of 
patients with AF. Bleeding risk seems to be higher in women mainly 
related with the women’s lower body weight (15) and women with AF 
are at increased risk of stroke, particularly elderly women (16). 
Comprehensive stroke risk assessment, including sex as a risk factor, 
should be undertaken in all AF patients.
In conclusion, challenges remain about NOACs usage in NVAF in 
elderly patients and effective strategies should be developed to improve 
the outcomes in elderly patients in clinical practice. An integral geriatric 
assessment (17) and patient profile (18) should be considered, including 
the age, sex, frailty (19) and comorbidities, before initiating oral 
anticoagulation. Based on these assumptions, it’s considered interesting 
to describe the current the anticoagulation management in elderly 
patients in Spain.

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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 May 2019
1160-0297
N/A
N/A
Research question 
and objectives:
This study has been designed in order to describe the current non-
vitamin K antagonist oral anticoagulants (NOACs) management in 
elderly patients in Spain.
Primary objective: To describe the pattern of usage of NOACs 
prescribed according to their Summary of Product Characteristics 
(SmPC), by current NOAC type and dose, in elderly patients (≥75 
years-old) with non-valvular atrial fibrillation (NVAF) at the time of the 
study visit.
Secondary objectives:
To describe patients characteristics at the time of the study visit by 
current NOAC type stratified by duration since first NOAC initiation.
2.
To describe OAC treatment management since first NOAC 
initiation until the study visit by duration since first NOAC 
initiation: previous vitamin K antagonists (VKA) treatment, first 
NOAC treatment duration, NOAC dose changes, switch 
between NOACs and reasons for switch, total NOAC treatment 
duration and additional antiplatelet treatment. 
3.
To describe the Clinical Frailty Scale grading, CFS (19), at the 
time of the study visit, by current NOAC type.
4.
To describe first NOAC usage by NOAC type, for primary 
prevention or secondary prevention, at the time of first NOAC 
initiation.
Study design:
This is an observational, multicenter and cross-sectional study in NVAF 
elderly patients currently on NOAC treatment for their stroke 
prevention. 
It will be conducted in approximately 50 sites in Spain, by investigators 
from the following specialties: cardiologists, hematologists and 
geriatricians. It is planned to have a 9-month recruitment period from 
first site initiated, or until the sample size is achieved.  
The design of the study impose a single visit to be performed for the 

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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 May 2019
1160-0297
N/A
N/A
informed consent signature and data collection that will coincide with 
one of those performed by the patients as part of the routine follow-up 
of their disease, without interfering with the 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.

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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 May 2019
1160-0297
N/A
N/A
Population:
Approximately 500 elderly patients with NVAF currently on NOAC 
treatment are planned to be included in the study. To minimize selection 
bias at the patient level, consecutive patients from each site who meet 
entry criteria will be enrolled. The number of patients per site to be 
included in the study will be initially set up to a maximum of 10 patients 
per site. Once the 50% of the participating sites have been initiated, the 
recruitment will become competitive until the end of the study and the 
limitation of 10 patients per site will be removed to allow sites to 
continue with the recruitment, until overall sample size is achieved.
Patients will be included in the study if all of the following criteria are 
met:
1.
Patients are willing and provide written informed consent prior 
to participate in this study
2.
Patients ≥ 75 years-old at the time of the study visit.
3.
Patients with a diagnosis of non-valvular atrial fibrillation 
(NVAF).
4.
Patients who are being treated with NOAC treatment 
according to the indication approved in the SmPC:
5.
Patients who have started the NOAC treatment at least 3 
months prior to the study visit.
Patients will be excluded from participating in this study if the 
following criterion is met:
1.
Current participation in any clinical trial of a drug or device.
2.
Patients who have any contraindication for NOAC treatment, 
according to the SmPC.
Variables:
For the primary and secondary objectives, the following variables will 
be obtained, if available, at the time of study visit (enrolment) and at the 
time of first NOAC initiation.
Variables collected for the primary objective:
-
Current NOAC (active substance, dose, start date).
Additional variables collected for the secondary objectives:
-
Demographic characteristics: Age, sex, height, weight, BMI, 
caregiver (yes/no), place where patient is living. 

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Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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 May 2019
1160-0297
N/A
N/A
-
Smoking and alcohol consumption.
-
Analytical results (from last available blood sample analysis):
-
Kidney function.
-
Liver function.
-
Hemoglobin and platelet levels.
-
NVAF diagnosis date, type, Modified EHRA scale for AF related 
symptoms (23).
-
Procedures and interventions: Cardioversion / Ablation; Coronary 
interventions: Percutaneous coronary intervention (PCI)/Coronary 
Artery Bypass Grafting (CABG); Pacemaker carrier.
-
History of thromboembolic and bleeding events.
-
History and current antiplatelet treatment. 
-
Other concomitant treatments (total number of current concomitant 
treatments; Type).
-
Comorbidities and Clinical Risk Factors: Heart failure NYHA 
classification (24), LVEF %); Coronary artery disease, diabetes, 
peripheral vascular disease, diabetes, chronic kidney disease, liver 
disease, cancer, Sleep apnoea-hypopnoea syndrome (SAHS) 
(yes/no), hypertension, previous stroke, transitory ischemic attack
(TIA) 
or 
thromboembolism, 
vascular 
disease, 
ischemic 
cardiomyopathy, vascular disease, comorbidity Charlson index (25).
-
CHA2DS2-VASc score. 
-
HAS-BLED score.
-
Clinical Frailty Scale (CFS) grading – modified Rockwood scale 
(19).
-
In case of previous treatment with VKA: treatment duration and 
reasons for VKA treatment switch.
-
NOAC treatment management (since first NOAC until study visit):
- NOAC dose changes.
- NOAC switch.
- First NOAC start date, for primary or secondary prevention.
No specific safety outcome has been defined in this study.

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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 May 2019
1160-0297
N/A
N/A
Data sources:
Data will be collected through an eCRF which will include all the study 
variables. Investigator will enter patient data in eCRF. Variables 
collected at the time of the study visit (including those related to the first
NOAC initiation) will be obtained based on and limited to those 
available in the medical records of the selected patients. Demographic 
characteristics, smoking habit and alcohol consumption may be asked to 
the patient at the study visit if not available in the medical records. 
LVEF measurement will be obtained from the last images available for 
the patient. 
Clinical Frailty Scale (19), 
Modified EHRA scale for AF related 
symptoms (23), NYHA classification for heart failure (24), CHA2DS2-
VASc and HAS-BLED scores will be assessed by the investigators at 
the study visit by evaluating the patient’s functional status and medical 
records and the values will be directly included in the eCRF.
Final score for the Comorbidities Charlson Index (25) will be 
automatically calculated based on the answers individually entered by 
the investigator in the eCRF for each index item.
Any required missing data to calculate the score for the scales or the 
Comorbidities Charlson Index may be asked to the patient at the study 
visit if not available in the medical records and should be documented, 
however the final score number obtained by the investigator from this 
information will not need to be included in medical records.
Study size:
It is planned that a total of approximately 500 patients will be recruited 
for the study.
Data Analysis
A Data Management Plan (DMP) and Statistical Analysis Plan (SAP) 
will be prepared to describe all processes, treatment and specifications 
for data collection, cleaning, validation and analysis.
Since the study is essentially descriptive, the variables included in the 
study objectives will be analyzed with measures of central tendency 
(mean and median), variability/dispersion (standard deviation and 
interquartile ranges), absolute and relative frequencies, and ranges. 95% 
confidence intervals will be provided as appropriate.
All eligible patients (all enrolled patients fulfilling all inclusion criteria 
and no exclusion criteria) will be included in the analysis. Missing data 

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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 May 2019
1160-0297
N/A
N/A
will not be imputed. Number of missing values will be presented for 
each outcome.
For the primary objective, the pattern of usage of NOAC will be 
described as the percentage of patients by NOAC type and dose. 
For the secondary objectives, the following descriptive analyses are 
planned:
1. Patient’s characteristics at the time of the study visit will be 
summarized descriptively by current NOAC type.  
 
 
2. For OAC treatment management, descriptive analysis of previous 
VKA treatment (yes/no), VKA treatment duration in years, reason 
for switch to NOAC, first NOAC treatment duration, first NOAC 
dose and dose changes, switch to new NOAC, new NOAC 
treatment duration, new NOAC dose and dose changes, reason for 
switch will be done. Duration since NVAF diagnosis until first 
NOAC initiation, duration of first NOAC treatment and total time 
in NOAC treatment will be described. Also, the number of 
patients that switched their first NOAC and mean number of 
switches will be presented. Antiplatelet treatment description will 
be also considered for this outcome. 
3. Clinical Frailty Scale (19) grading at the time of the study visit by 
current NOAC type will be described as the number of patients on 
each category of frailty, and summarized descriptively in the 
following two categories: Frailty patients (CFS scoring >4) and 
Non-frailty patients (CFS scoring ≤4).
4. First NOAC usage will be described by NOAC type, for primary 
or secondary prevention, at the time of first NOAC initiation.

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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 May 2019
1160-0297
N/A
N/A
Milestones:
The times described below may be modified by the administrative 
processing periods for study initiation
-
EU PAS Register: May 2019
-
Final Protocol: May 2019
-
Start of data collection: July 2019
-
End of data collection: April 2020
-
Final study report: November 2020

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5.
AMENDMENTS AND UPDATES
None 

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6.
MILESTONES
Table 1
Milestones
Milestone
Planned Date
EU PAS Register
30 May2019
EC approval
31 June 2019
Start of data collection
25 July 2019
End of data collection
27 April 2020
Final report of study results:
25 November 2020

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7.
RATIONALE AND BACKGROUND
Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in clinical practice. AF affects 
between 1-2% of general population, but especially in patients aged ≥80 years prevalence can 
reach between 9-10% up to 17% of these patients (1-4).  It is known that older age is an 
important risk factor for patients with AF and it is associated with a four to five fold 
increased risk of embolic stroke and with an estimated increased stroke risk of 1.45-fold per 
decade in aging (4). Additionally, aging is also associated with an increased risk of major 
bleeding with oral anticoagulant therapy (5). 
The current clinical guidelines on the usage of non-vitamin K antagonist oral anticoagulants
(NOACs) in patients with atrial fibrillation EHRA 2018 (6) recommend that patients with an 
embolic risk factor receive preventive anticoagulant therapy, with special emphasis in the 
frail and older patients.
The first oral anticoagulants to prevent the risk of thromboembolic events in AF were the 
vitamin K antagonists (VKA) warfarin and acenocumarol. 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. In 
elderly patients (≥70 years) with NVAF and treated with VKA, TTR should be maintained 
≥60% to prevent thromboembolism and all-cause death and TTR <40% should be avoided to 
prevent major hemorrhage (7). NOACs, with a similar benefit as warfarin but with greater 
safety, even in a very old population, offers a new possibility of therapeutic strategy in 
clinical practice. In patients 75 years and older, randomized trials have shown NOAC to be as 
effective as warfarin, or in some cases superior, with an overall better safety profile, 
consistently reducing rates of intracranial haemorrhages (4). The non-vitamin K antagonist 
oral anticoagulants (NOAC) maintain the benefits 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.
However, the usage of NOACs in the elderly population in routine clinical practice show 
deficiencies and can be optimized, showing that under-dosing of NOACs is common in this 
population (8). Other studies suggest that as many as 34% of elderly patients on NOACs were 
on an incorrect dose or were prescribed the medication despite a contraindication (9) and 
more than half were found to be on an inappropriately low dose (10). These errors could lead 
to increased bleeding risk and/or increased risk of treatment failure (11). In general, OAC 
remains underutilized in older age groups.
The benefit / risk balance of anticoagulation in elderly patients and AF has already been 
analyzed in different studies. The risk of hemorrhagic stroke was lower in the NOAC group 
than in the warfarin group (12). In another study, the rates of hemorrhagic and 
thromboembolic events in patients older than 90 years under treatment with NOACs at VKAs 
were comparable (13). Elderly patients treated with high doses of NOACs had a statistically 
similar incidence of stroke, a lower statistical incidence of ICH and a higher net clinical 
benefit, compared with those treated with low doses (14).
In addition to age, other characteristics of the patient should be considered at the time of 
selecting an appropriate anticoagulant treatment. The female sex as a risk factor for stroke 
and thromboembolism in patients with atrial fibrillation should also be considered. 

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Thromboembolic risk related to atrial fibrillation (AF) may differ between men and women, 
and this may affect the response to anticoagulant therapy and warrant a sex-specific 
management of patients with AF. Bleeding risk seems to be higher in women mainly related 
with the women’s lower body weight (15) and women with AF are at increased risk of stroke, 
particularly elderly women (16). Comprehensive stroke risk assessment, including sex as a 
risk factor, should be undertaken in all AF patients.
In conclusion, challenges remain about NOACs usage in NVAF in elderly patients and 
effective strategies should be developed to improve the outcomes in elderly patients in 
clinical practice. An integral geriatric assessment (17) and patient profile (18) should be 
considered, including the age, sex, frailty (19) and comorbidities, before initiating oral 
anticoagulation. Based on these assumptions, it’s considered interesting to describe the 
current the anticoagulation management in elderly patients in Spain.

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8.
RESEARCH QUESTION AND OBJECTIVES
This study has been designed in order to describe the current non-vitamin K antagonist oral 
anticoagulants (NOACs) management in elderly patients in Spain.
Primary objective: To describe the pattern of usage of NOACs prescribed according to their
Summary of Product Characteristics (SmPC), by current NOAC type and dose, in elderly 
patients (≥75 years-old) with non-valvular atrial fibrillation (NVAF) at the time of the study 
visit.
Secondary objectives:
1.
To describe patients characteristics at the time of the study visit by current NOAC 
type stratified by duration since first NOAC initiation.
2.
To describe OAC treatment management since first NOAC initiation until the study 
visit by duration since first NOAC initiation: previous vitamin K antagonists (VKA)
treatment, first NOAC treatment duration, dose changes, switch between NOACs and 
reasons for switch, total NOAC treatment duration and additional antiplatelet 
treatment. 
3.
To describe the Clinical Frailty Scale grading, CFS (19), at the time of the study visit,
by current NOAC type.
4.
To describe first NOAC usage by NOAC type, for primary prevention or secondary 
prevention, at the time of first NOAC initiation.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is an observational, multicenter and cross-sectional study in NVAF elderly patients 
currently on NOAC treatment for their stroke prevention. 
AF is classified as non-valvular AF in the absence of mitral stenosis or cardiac valvular 
prosthesis, since NOACs are not recommended for patients with mechanical heart valve 
(level of evidence B) or moderate to severe mitral stenosis (level of evidence C) (22).
The study will be conducted in approximately 50 sites in Spain. Investigators from different
specialties are planned to be included as follows: 35 cardiologists, 10 hematologists and 5 
geriatricians. 
The design of the study impose a single visit to be performed for the informed consent 
signature and data collection 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.
9.2
SETTING
Approximately 500 elderly patients with NVAF currently on NOAC treatment are planned to 
be included in the study. To minimize selection bias at the patient level, consecutive patients 
from each site who meet entry criteria will be enrolled. It is planned to have a 9-month 
recruitment period from first site initiated, or until the sample size is achieved.
The number of patients per site to be included in the study will be initially set up to a 
maximum of 10 patients per site. Once the 50% of the participating sites have been initiated, 
the recruitment will become competitive until the end of the study and the limitation of 10 
patients per site will be removed to allow sites to continue with the recruitment.
9.2.1
Study sites
Cardiology, hematology, geriatric services at a hospital setting, specialty medical offices and 
nursing homes, who regularly prescribe NOACs for stroke prevention in NVAF patients may
be invited to participate.
It is necessary to ensure that study population is representative of the entire national territory. 
Therefore, patients may be recruited from sites with different level of medical care (e.g, 
primary hospital, secondary hospital, private care) in several geographical areas according to 

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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 NOAC.
As a pre-study activity, sites will need to answer a site feasibility questionnaire in order to 
determine that the site has adequate facilities and investigator is qualified and meets the 
needs of the study, recruitment targets, quality and timelines in compliance with the 
applicable regulatory requirements.
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. Patients are willing and provide written informed consent prior to participate in 
this study
2. Patients ≥ 75 years-old at the time of the study visit.
3. Patients with a diagnosis of non-valvular atrial fibrillation (NVAF).
4. Patients who are being treated with NOAC treatment according to the indication 
approved in the SmPC.
5.
Patients who have started the NOAC treatment at least 3 months prior to the 
study visit.
Patients will be excluded from participating in this study if the following criterion is met:
1. Current participation in any clinical trial of a drug or device.
2. Patients who have any contraindication for NOAC treatment, according to the 
SmPC.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the investigator site file at the study site.
9.2.3
Study visits
Patients will be invited to participate in this study during a routine medical visit for any 
purpose with their physician. Investigator will provide to patients the “patient information 
and informed consent form” and will explain the study to the patient. If patients agree to 
participate, after signing the informed consent, investigator will assess the Clinical Frailty 
Scale (19), the Modified EHRA scale for AF related symptoms (23), the NYHA classification
of heart failure  (24) (refer to Annex 3) and the CHA2DS2-VASc and HAS-BLED scales, 
and include the scores directly in eCRF after evaluating the patient’s functional status and 
patient’s medical records. The investigator will review the medical records in order to 
complete other variables needed to address study objectives that will mainly be obtained 

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directly from patient medical records or requested to the patient at the study visit if not 
available in medical records (refer to Section 9.4). 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. Administrative reasons (i.e. study rejected by the hospital director)
3. Violation of GxP (as applicable), 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 be currently on treatment with NOAC for their NVAF, according to 
the indication approved in their  SmPC, and initiated it at least 3 months before the study 
visit. Prescription of the treatments will have been done under the sole responsibility of the 
healthcare professional and before considering the participation in the study. 
As this is an 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 outcome
The primary outcome is the pattern of usage of non-vitamin K oral anticoagulants (NOACs)
prescribed according to their Summary of Product Characteristics (SmPC), based on the 
percentage of patients by NOAC type and dose the patient is taking at the time of the study 
visit. Timeframe to complete data collection for this outcome is one day, the study visit day.
Table 2
Primary variable collected at the time of the study visit
Variable
Obtained from medical 
records
Current NOAC active 
substance and dose
x

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9.3.2.2
Secondary outcomes
Secondary outcomes are:
1. Patient’s characteristics at the time of the study visit by the NOAC type that the 
patient is taking at the time of the study visit. Patients will be also stratified by the 
duration since the first NOAC initiation date until the study visit date (> 4months / ≤4 
months). (see Related patient’s characteristics covariates: refer to Section 9.3.3, 
Table 3). 
2. OAC treatment management (since first NOAC initiation until the study visit date), 
based on the following variables: 
- Previous vitamin K antagonist (VKA) treatment (yes/no), VKA treatment duration 
in years, reason for switch to NOAC, 
- Duration since NVAF diagnosis until first NOAC initiation,
- Duration of first NOAC treatment (first NOAC active substance, start and stop date, 
first NOAC dose and its dose changes), 
- Switch to new NOAC (active substance, start/stop date, dose and dose 
changes, 
reason for switch to new NOAC): number of patients that switch their first or further 
NOAC and mean number of switches.
- Total time in NOAC treatment
- History and current antiplatelet treatment (yes/no, start date, end date, active 
substance). 
Figure 1
OAC treatment management
3. Clinical Frailty Scale grading, CFS, (19) at the time of the study visit, by current 
NOAC type.
First NOAC 
initiation
Study 
visit
NOAC switches and/or dose changes
Antiplatelet treatment
Previous  
VKA?

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4. The first NOAC usage by NOAC type, for primary prevention or secondary 
prevention, at the time of first NOAC initiation.
Timeframe to complete data collection for the secondary outcomes is one day, the study visit
day.
9.3.3
Covariates
The following covariates, related to the secondary outcome, will be collected from medical 
records or at the study visit (refer to section 9.4) to describe the patient’s characteristics:

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Table 3
Patient characteristics at the time of the study visit
Variable*
Obtained 
from 
medical 
records
Obtained at 
the study 
visit
Demographic characteristics: Age, sex, height, weight, 
BMI, caregiver (Yes/No), place where patient is living
(Home alone; At home
with partner/other
family 
member/a friend; Other’s home (e.g family member’s); 
Nursing home)
x
x
Smoking habit (past/current/non-smoker) and alcohol 
consumption (casual/habitual/abuse/dependence)
x
x
Analytical lab results (from last available blood sample 
analysis):
- Kidney function: serum creatinine (mg/dl), creatinine 
clearance (Cockcroft-Gault calculation)
- Liver function: AST/ALT, total bilirubin
- Hemoglobin and platelet levels
x
NVAF:
- Diagnosis date (month and year)
- Type (persistent, long standing persistent, permanent, 
paroxysmal) 
- Modified EHRA scale for AF related symptoms (23)
(Refer to Annex 3).
x
x 
(mEHRA 
scale)
Procedures and interventions:
- Cardioversion/Ablation (Yes/No)
- Coronary interventions (Yes/No): Percutaneous coronary 
intervention
(PCI)/Coronary Artery Bypass Grafting 
(CABG) 
- Pacemaker carrier (Yes/No)
x
History of thromboembolic events (Yes/No, number): TIA, 
ischemic stroke, hemorrhagic stroke, embolism systemic, 
deep vein thrombosis, pulmonary embolism, stable angina, 
unstable angina, myocardial infarction with/without ST 
segment elevation; and bleeding
events (Yes/No): 
intracranial, digestive, genitourinary,
gingival, nasal,
pulmonary, articular-muscular, conjunctival.
x
Other concomitant treatments (Total number of current 
concomitant drugs; Type (Yes/No, number): ARB or ACE 
inhibitor, 
Beta-blocker, 
Calcium 
channel 
blockers, 
Diuretics, Amiodarone, Statin, Proton pump inhibitor, H2-
x

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Variable*
Obtained 
from 
medical 
records
Obtained at 
the study 
visit
receptor antagonist, , Digoxin, NSAIDs, Verapamil / 
Dronedarone, 
Other 
antiarrhythmics, 
ketoconazole 
systemic), ciclosporine, itraconazol)
Comorbidities and Clinical Risk Factors:
- Heart Failure (Yes/No, New York Heart Association 
(NYHA) classification (24) (Refer to Annex 3); Left 
Ventricular Ejection Fraction, LVEF, %) 
- Coronary artery disease (Yes/No)
- Sleep apnoea-hypopnoea syndrome (SAHS) (Yes/No)
- Hypertension (Yes/No)
- Comorbidity Charlson index (25) (Refer to Annex 3) 
(Yes/No; total score): myocardial infarction
(already 
collected 
for
history 
of 
thromboembolic 
events),
congestive heart failure (already collected for the NHYA 
scale scoring), cerebral and peripheral vascular disease, 
dementia, 
chronic 
obstructive 
pulmonary 
disease, 
connective 
tissue 
disease, 
peptic 
ulcer 
disease, 
mild/moderate/severe liver disease, diabetes, diabetes with 
end-organ damage,  hemiplegia, moderate/severe renal 
disease,  any solid tumor, metastatic solid tumor, leukemia, 
lymphoma AIDs, age (already collected as a demographic 
characteristic).
x
x
(NYHA 
classification,  
Charlson 
Index)
CHA2DS2-VAS (total score)
x
HAS-BLED(total score)
x
* Refer to section 9.4 for more details about how these variables will be collected.
9.4
DATA SOURCES
Variables collected at the time of the study visit (including those related to the time of the 
first NOAC initiation) will be obtained based on and limited to those available in the medical 
records of the selected patients.
Demographic characteristics, smoking habit and alcohol consumption may be asked to the 
patient at the study visit if not available in the medical records.
The variables used to determine the kidney and liver function, as well as the hemoglobin and 
platelet levels can be obtained from the last analytical results available in the medical charts. 
Creatinine clearance will be automatically determined with the serum creatinine if the 
Cockcroft-Gault calculation is not available in medical charts. LVEF measurement will be 
obtained from the last images available for the patient.

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Clinical Frailty Scale (19), Modified EHRA scale for AF related symptoms (23) and NYHA 
classification (24) (Refer to Annex 3 for these scales), CHA2DS2-VASc, HAS-BLED scores,
will be assessed by the investigators at the study visit by evaluating the patient’s functional 
status and medical records and the values will be directly included in the eCRF. 
Final score for the Comorbidities Charlson Index (25) will be automatically calculated based 
on the answers individually entered by the investigator in the eCRF for each index item. 
Any required missing data to calculate the score for the scales or the Comorbidities Charlson 
Index may be asked to the patient at the study visit if not available in the medical records and 
should be documented, however the final score number obtained by the investigator from this 
information will not need to be included in medical records.
9.5
STUDY SIZE
It is planned that a total of approximately 500 patients will be recruited for the study. Based 
on such a sample size estimate, categorical variables of binomial proportions (e.g. sex) will 
be estimated with the precision (i.e. width of descriptive 95% confidence interval) described 
in the following Table 4. Calculations of the confidence intervals (CI) are based on the 
Clopper-Pearson method:
Table 4
Width of 95% confidence interval by prevalence of attribute:
Prevalence of attribute
Sample size
500
10% Expected n
50
95% CI width
5.46%
20% Expected n
100
95% CI width
7.20%
30% Expected n
150
95% CI width
8.22%
40% Expected n
200
95% CI width
8.76%
50% Expected n
250
95% CI width
8.94%

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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 the method and procedure for each data management step for the study, from 
electronic Case Report Form (eCRF) design up to final database delivery.
The eCRFs will include programmable edit checks to obtain immediate feedback if data are 
missing, out of range, illogical or potentially erroneous. The Edit Checks Specifications (Data 
Validation Plan (DVP)) is included in the eCRF specification documentation. These checks 
will be performed once data is entered into the eCRF. Thus the data entered into 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.
AE reconciliation will be performed quarterly from study initiation date.
Data quality reviews are planned to be performed in the study with the purpose of data 
cleaning and to detect possible quality issues in advance. Details will be explained in the NIS 
Monitoring Manual.
When data management is outsourced, the designated contract organization will be 
responsible for the development and implementation of the data management and validation
plans.
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. 
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 analyze 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 

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of central tendency (mean and median), variability/dispersion (standard deviation and 
interquartile ranges), absolute and relative frequencies, and ranges.
A Statistical Analysis Plan (SAP), will be prepared to describe all processes, treatment and 
specifications for the planned statistical analysis.
9.7.1
Main analysis
All eligible patients (all enrolled patients fulfilling all inclusion criteria and no exclusion 
criteria) will be included in the analysis. Missing data will not be imputed. Number of
missing values will be presented for each outcome.
For the primary objective, the pattern of usage of NOAC will be described as the percentage 
of patients by NOAC type and dose.
For the secondary objectives, the following descriptive analyses are planned:
1. Patient’s characteristics at the time of the study visit will be summarized descriptively by 
current NOAC type.  
 
All covariates related to 
patient’s characteristics (refer to Section 9.3.3, Table 3) will be analyzed descriptively by 
NOAC type and by the duration since the first NOAC initiation. Standardized differences 
between Pradaxa® and other NOACs will be estimated for these covariates. For this, a 
minimum of 50 patients is required for each group.
2. For OAC treatment management, descriptive analysis of previous VKA treatment 
(yes/no), VKA treatment duration in years, reason for switch to NOAC, first NOAC 
treatment duration, first NOAC dose and dose changes, new NOAC treatment duration, 
new NOAC dose and dose changes. Duration since NVAF diagnosis until first NOAC 
initiation and total time in NOAC treatment will be described. Also, the reason for 
switches, the number of patients that switched their first or further NOAC and mean 
number of switches will be presented. Antiplatelet use will be also summarized.
3. Clinical Frailty Scale grading at the time of the study visit by current NOAC type will be 
described as the number of patients on each category of frailty (19) as evaluated by the 
investigator according to patient’s records. In addition, CFS score will be summarized in 

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the following two categories: Frailty patients (CFS scoring >4) and Non-frailty patients 
(CFS scoring ≤4).
4. First NOAC usage will be described by NOAC type, for primary prevention or secondary 
prevention, at the time of first NOAC initiation.
9.8
QUALITY CONTROL
The NIS monitoring manual will define all aspects related to the monitoring activities for the 
study, to ensure that it is performed in a manner that will provide meaningful data, the rights 
and well-being of the study patients are protected, and the conduct of the study is compliant 
with protocol and all applicable regulation.
All relevant issues, including protocol deviations, detected during the study will be handled 
and followed-up until their resolution or closure. A register of the issues and related actions 
will be kept.
On-site and remote monitoring will be performed by a Contract Research Organisation 
(CRO) appointed by BI.
Source data verification in a sample of sites is planned for this study and detailed in the 
monitoring manual.
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.
All study relevant documentation will be stored in the study master file (SMF). In addition,
each site will have an Investigator Site File (ISF) containing all study documents relevant for 
the site. Relevant documentation on the participating investigators, including their curricula 
vitae, will be filed in ISF.

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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.
Variables collected at the time of the study visit will be obtained based on and limited to 
those available in the medical records of the selected patients (refer to section 9.4)
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, 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. 
Due to regulatory requirements, patients are not allowed to start the NOAC treatment on the 
study visit date. For this, a minimum of three months of NOAC treatment before study 
participation has been stablished, which limits the NOAC population.
As patients are included after first NOAC initiation and need to be treated by a NOAC at the 
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. Besides, sample size may be limited for some of the planned subgroup 
analyses, resulting in decreased precision.
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
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
Electronic Case Report Forms (eCRFs) for individual patients will be provided by the 
sponsor (eCRF will be outsourced to a designated contract organization), 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 reported on 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, except the value of the score in 
CFS, CHA2DS2-VASc, HAS-BLED that will be included in the eCRF directly by the 
investigators. 
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) 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
In Spain, the Sponsor will send the final report to competent authorities and national 
authority between 3 and six months after the completion of the study that is defined as the 
database lock date. 

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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) and BI local study documents. 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/ICH GCP.
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 (CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate 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 authorisation 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 hospitalisation, 
-
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 hospitalisation 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 hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
No AESIs have been defined for this study.

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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 BI 
drug in the scope of this NIS. For this reason the following AE collection and reporting 
requirements have been defined.
Once informed consent is signed the following must be collected in the eCRF by the 
investigator if identified during chart review and study visit data collection until the end of 
the study visit:
-
all adverse drug reaction (ADRs) (serious and non-serious) associated with Pradaxa®, 
-
all AEs with fatal outcome in patients exposed to Pradaxa®,  
All ADRs may 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 characterised 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).
•
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).

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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: 
Table 5
Expedited reporting of AEs and Drug Exposure during pregnancy
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
All pregnancy monitoring
forms
in 
patients or partner exposed to Pradaxa®
7 calendar days

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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 eCRF 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.
The summary study results will be distributed to national health authority and ethics 
committees. They will be also made public in CT.gov and EUPAS Register. 
The results of this study will be published in a national journal and/or 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. Petidier Torregrossa R, Abizanda Soler P, Noguerón García A, et al. Oral 
anticoagulation therapy in the elderly population with atrial fibrillation. A review 
article. Rev Esp Geriatr Gerontol. 2018 Jul 30.
5. Lip G.Y.H., Clementy N., Pericart L., Banerjee A. and Fauchier L. Stroke and 
Major Bleeding Risk in Elderly Patients Aged ≥75 Years With Atrial Fibrillation.  
The Loire Valley Atrial Fibrillation Project. Stroke. 2014;46:143–150  
6. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Georg 
Haeusler K, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, 
Collins R, Camm AJ, Heidbüchel H; ESC Scientific Document Group. The 2018 
European Heart Rhythm Association Practical Guide on the use of non-vitamin K 
antagonist oral anticoagulants in patients with atrial fibrillation: executive summary. 
EP Europace, Volume 20, Issue 8, 1 August 2018, Pages 1231–1242,
7. Inoue H, Kodani E, Atarashi H et al. Time in Therapeutic Range and Disease 
Outcomes in Elderly Japanese Patients With Nonvalvular Atrial Fibrillation. Circ J. 
2018 Aug 28. 
8. Grant SJ, Kothari S, Gimotty PA, Gooneratne NS, Cuker A. Quality of direct oral 
anticoagulant prescribing in elderly patients with non-valvular atrial fibrillation: 
results from a large urban health system. J Thromb Thrombolysis. 2018 Jul;46(1):1-
6. 
9. Pattullo CS, Barras M, Tai B, McKean M, Donovan P. New oral anticoagulants 
(NOACs)—appropriateness of prescribing in real-world setting. Intern Med J 2016, 
46: 812–818
10. Barra ME, Fanikos J, Connors JM, Sylvester KW, Piazza G, Goldhaber SZ. 
Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med 2016, 129: 
1198–1204

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11. Stöllberger C, Brooks R, Finsterer J, Pachofszky T. Use of direct-acting oral 
anticoagulants in nonagenarians: a call for more data. Drugs Aging 2016, 33:315–
320
12. Chao TF, Liu CJ, Lin YJ et al. Oral Anticoagulation in Very Elderly Patients With 
Atrial Fibrillation: A Nationwide Cohort Study.Circulation. 2018, Jul 3;138(1):37-
47
13. Giustozzi, M.G., Vedovati M.C., Verso M. et al. Effectiveness and safety of oral 
anticoagulants in patients aged 90 years or older with Atrial Fibrillation. European 
Heart Journal, Volume 39, Issue suppl_1, August 2018.
14. Alnsasra H, Haim M, Senderey AB, et al. Net Clinical Benefit of Anticoagulant 
Treatments in Elderly Patients with Non-Valvular Atrial Fibrillation: Experience 
From the Real World. Heart Rhythm 2018 Aug 18. pii: S1547-5271(18)30816-6.
15. Law SWY, Lau WCY, Wong ICK, Lip GYH, Mok MT, Siu CW, Chan EW. Sex -
Based Differences in Outcomes of Oral Anticoagulation in Patients With Atrial 
Fibrillation. 
J 
Am 
Coll 
Cardiol. 
2018 
Jul 
17;72(3):271-282. 
doi: 
10.1016/j.jacc.2018.04.066. Epub 2018 Jul 9.
16. Wagstaff AJ, Overvad TF, Lip GYH, Lane DA. Is female sex a risk factor for 
stroke and thromboembolism in patients with atrial fibrillation? A systematic 
review and meta-analysis. QJM: An International Journal of Medicine, Volume 
107, Issue 12, 1 December 2014, Pages 955–967
17. Roberto Martín-Asenjo, Héctor Bueno, María Teresa Vidán. Anticoagulación en el 
anciano: ¿son suficientes guías y algoritmos para ejercer bien la medicina o todavía 
queda lugar para el arte?  Rev Esp Geriatr Gerontol. 2018 Aug 8
18. Tayaa S, Berrut G, de Decker L, Chevalet P. Direct oral anticoagulants in non -
valvular atrial fibrillation in elderly: for a treatment adapted to patient profile. 
Geriatr Psychol Neuropsychiatr Vieil. 2018 Sep 1;16(3):229-240.
19. Pablo Díez-Villanueva, Albert Arizá -Solé, María Teresa Vidán et al.
Recommendations of the Geriatric Cardiology Section of the Spanish Society of 
Cardiology for the Assessment of Frailty in Elderly Patients With Heart Disease. 
Rev Esp Cardiol. 2019;72(1):63–71.

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20. 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#antic
oagulantes-orales.
21. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and 
frailty in elderly people. CMAJ. 2005; 173:489-495
22. Camm AJ, Lip GYH, de Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 
focused update of the ESC Guidelines for the management of atrial fibrillation. An 
update of the 2010 ESC Guidelines for the management of atrial fibrillation 
developed with the special contribution of the European Heart Rhythm Association 
Authors/Task Force Members. Eur Heart J. 2012;33:2719-47.
23. Kirchhof et al 2016 ESC Guidelines for the management of atrial fibrillation 
developed in collaboration with EACTS. European Heart Journal (2016) 37, 2893–
2962.
24. Villar R, Meijide H, Castelo L, Mema A, Serrano J, Vares Mª, Ramos V. Escalas en 
práctica clínica: cardiología. Galicia Clin 2010; 71 (1): 31-36.
25. Charlson M, Szatrowski TP, Peterson J, Gold J (1994) Validation of a combined 
comorbidity index. J Clin Epidemiol 47: 1245–1251. 
13.2
UNPUBLISHED REFERENCES
Not applicable.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Title
Data Management Plan
Statistical Analysis Plan
Monitoring Manual
Study Master File Plan

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
ENCePP Checklist for Study Protocols (revision 4)
Adopted by the ENCePP Steering Committee on 15/10/2018
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 sec tion 
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 presented in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
Study title: Non-Interventional, cross-sectional study to describe NOACs 
management in elderly patients with non-valvular atrial fibrillation (NVAF) 
in Spain. RE-BELD Study.
EU PAS Register® number: Study will be registered in the EU Pass Register.
Study reference number (if applicable): 1160-0297
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 Progress report(s)
1.1.4 Interim 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 performed annually
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
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, other 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., rate, risk, prevalence)
3.4
Does the protocol specify measure(s) of 
association? (e.g. risk, odds ratio, excess risk, rate ratio, 
hazard ratio, risk/rate difference, number needed to harm 
(NNH))
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?
9.2.2
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period
9.2

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Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.2.2 Age and sex
9.2.2
4.2.3 Country of origin
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)
9.2.2
Comments:
No follow-up is foreseen.
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)
9.3.1
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 categorised according to time 
windows?
9.3.1
5.4
Is intensity of exposure addressed? 
(e.g. dose, duration)
9.3.1
5.5
Is exposure categorised based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
5.6
Is (are) (an) appropriate comparator(s) 
identified?
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?
9.3.2
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3.2
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, use of 
validation sub-study)

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Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.4
Does the protocol describe specific outcomes 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease or treatment, compliance, disease 
management)
Comments:
Descriptive outcomes
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol address ways to measure
confounding? (e.g. confounding by indication)
7.2
Does the protocol address selection bias? (e.g. 
healthy user/adherer bias)
9.9
7.3
Does the protocol address information bias?
(e.g. misclassification of exposure and outcomes, time-
related bias)
Comments:
Section 8: Effect measure 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 and other characteristics?
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

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.2.3 Covariates and other characteristics?
(e.g. age, sex, clinical and drug use history, co-morbidity, 
co-medications, lifestyle)
9.3.3
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), Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates and other characteristics?
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 Are the statistical methods and the reason for 
their choice described? 
9.7
10.2 Is study size and/or statistical precision 
estimated?
9.5
10.3 Are descriptive analyses included?
9.7
10.4 Are stratified analyses included?
9.7.1
10.5 Does the plan describe methods for analytic 
control of confounding?
10.6 Does the plan describe methods for analytic 
control of outcome misclassification?
10.7 Does the plan describe methods for handling 
missing data?
9.7.1
10.8 Are relevant sensitivity analyses described?
Comments:
Only descriptive summaries will be done.
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:

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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?
9.9
12.1.2 Information bias?
9.9
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 uptake, duration of 
follow-up in a cohort study, patient recruitment, precision of 
the estimates)
9.2.1
Comments:
Section 13: Ethical/data protection 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
Clinical Frailty Scale- Spanish Translation (19)
P. Díez-Villanueva et al/Rev Esp Cardiol. 2019;72(1):63-71(Clinical Frailty Scale. 
Reproduced with permission of Rockwood et al (21)

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EHRA scoring related-symptoms (23)
Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, 
Casadei B, et al. Guías ESC 2016 sobre el diagnóstico y 
tratamiento de la fibrilación auricular, desarrollada en 
colaboración 
con 
la 
EACTS. 
Rev 
Esp 
Cardiol 
2017;70(1):43.e1-e84 (23)
NYHA classification of heart failure (24)
Villar R, Meijide H, Castelo L, Mema A, Serrano J, Vares Mª, Ramos V. 
Escalas en práctica clínica: cardiología. Galicia Clin 2010; 71 (1): 31-36 
(24)
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Comorbidities Charlson Index (25)
Charlson M, Szatrowski TP, Peterson J, Gold J (1994) Validation of a 
combined comorbidity index. J Clin Epidemiol 47: 1245–1251 (25)
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