Pradaxa Initiation Post-Stroke Study: SITS-Pradaxa 1. A Retrospective Analysis From the SITS-AF Registry on Treatment Initiation of Dabigatran Etexilate in Non-valvular Atrial Fibrillation Patients Hospitalized With Acute Ischemic Stroke
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Protocol for observational studies based on existing data
TITLE PAGE
Document Number:
c03412460-01
BI Study Number:
1160-0235
BI Investigational
Product(s):
Dabigatran etexilate (Pradaxa®)
Title:
Pradaxa Initiation Post-Stroke Study: SITS-Pradaxa 1. A 
retrospective analysis from the SITS-AF Registry on 
treatment initiation of dabigatran etexilate in non-valvular 
atrial fibrillation patients hospitalized with acute ischemic 
stroke
Lay Title
This study uses the SITS Registry to find out when patients 
with a heart rhythm disorder (atrial fibrillation) start 
treatment with dabigatran after they had a stroke
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
05 July 2017
PASS:
No
EU PAS register 
number:
EUPAS17165
Active substance:
B01AE07 - dabigatran etexilate (Pradaxa® )
Medicinal product:
Dabigatran etexilate
Product reference:
  EU/1/08/442/001-019
Procedure number:
EMEA/H/C/000829
Joint PASS:
No
Research question and 
objectives:
Primary Objective:

To evaluate the timing of dabigatran treatment 
initiation in patients with non-valvular atrial 
fibrillation (NVAF) after hospitalization for first ever
ischaemic stroke (the index event) in order to prevent 
secondary stroke.
Secondary Objectives:

To describe baseline characteristics for patients 

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treated with dabigatran according to time of 
dabigatran initiation.

To describe self-reported factors important for the 
physician’s decision as to the time of dabigatran
initiation in the post-ischemic stroke setting.
To describe self-reported factors important for 
physician’s decision as to which dabigatran dose was 
used in the post-ischemic stroke setting.
 
 
 
 
 
 
 
 
Countries of study:
Data from all patients in European countries* actively 
registered in the SITS Registry until 31 July 2018, will be 
considered for analysis. 
(*countries such as, Italy, United Kingdom, Czech 
Republic, Sweden, Germany, Poland, Spain, Finland, 
Portugal, Slovakia, Denmark, Estonia, Norway Belgium, 
Hungary, Slovenia, Croatia, Austria, Lithuania, France,
Greece, Netherlands, Ireland, Ukraine and Iceland)
Authors:
 
E-mail:
E-mail: 
Address:

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Phone: 
Fax: 
Trial Clinical Monitor
Phone 
Fax 
E-mail: 
Marketing 
authorisation holder:
MAH contact person:
Date:
05 July 2017
Page 1 of 42
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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Protocol for observational studies based on existing data
BI Study Number 1160-0235
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 4
2.
LIST OF ABBREVIATIONS................................................................................ 6
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 ................................................. 17
9.
RESEARCH METHODS .................................................................................... 18
9.1
STUDY DESIGN............................................................................................ 18
9.2
SETTING........................................................................................................ 18
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..............................................................................19
...................................................................................19
9.3.3
Covariates................................................................................................ 20
9.4
DATA SOURCES........................................................................................... 20
9.5
STUDY SIZE.................................................................................................. 21
9.6
DATA MANAGEMENT................................................................................ 22
9.7
DATA ANALYSIS......................................................................................... 22
9.7.1
Main analysis........................................................................................... 22
....................................................................................... 23
9.7.3
Interim analysis ....................................................................................... 24
9.8
QUALITY CONTROL................................................................................... 24
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 24
9.10
OTHER ASPECTS ......................................................................................... 25
9.10.1
Ethical approval and informed consent................................................... 25
9.11
SUBJECTS...................................................................................................... 26
9.12
BIAS................................................................................................................ 26

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10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 27
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
14.
APPENDICES ..................................................................................................... 33
Appendix 1: CHADS2 Stroke Risk Score................................................................... 33
Appendix 2: CHA2DS2-VASc Stroke Risk Score....................................................... 34
Appendix 3: HAS-BLED Bleeding Risk SCORE ...................................................... 35
Appendix 4: List of stand-alone documents ............................................................... 36
Appendix 5: ENCePP checklist for study protocols................................................... 37

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Protocol for observational studies based on existing data
BI Study Number 1160-0235
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS
AE
Adverse Event
AF
Atrial Fibrillation
CHAD2 score
Stroke Risk score based on a point system, which includes history of 
Congestive heart failure, Hypertension, Age (≥ 75), Diabetes 
mellitus, Stroke/TIA.
CHA2DS2-
VASc score
Stroke Risk score based on a point system, which includes history of 
Congestive heart failure, Hypertension, Age (≥ 75), Diabetes 
mellitus, Stroke/TIA, Vascular disease, Age 65-74, Sex category
CI
Confidence Interval
EMA
European Medicines Agency
ENCePP
European Network of Centers for Pharmacoepidemiology and
Pharmacovigilance
EUPAS
The European Union electronic Register of Post-Authorisation 
Studies (EU PAS Register)
GVP
Good Pharmacovigilance Practices
HAS-BLED
Bleeding Risk score based on a point system, which includes 
Hypertension, Abnormal renal and liver function, Stroke (1 point),
Bleeding history or predisposition, Labile INR, Elderly (>65 years),
Drugs and Alcohol
ICO
International Coordinating Office (at SITS International)
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
LV EF
Left Ventricular Ejection Fraction
MAH
Marketing authorisation holder
MI
Myocardial Infarction
mRS
modified Rankin Scale
N.A.
Not applicable
NIHSS
National Institute of Health Stroke Scale
NOAC
Non-vitamin K Oral Anticoagulation
NVAF
Non-valvular Atrial Fibrillation
OAC
Oral Anticoagulant
p.o.
per os (oral)
PASS
Post-Authorisation Safety Study
q.d.
quaque die (once a day)
SITS
Safe Implementation of Treatment in Stroke (Registry)
SITS-MOST
Safe Implementation of Thrombolysis in Stroke-Monitoring Study
SmPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TIA
Transient Ischaemic Attack
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMM
Team Member Medicine
VKA
Vitamin K Antagonist

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3.
RESPONSIBLE PARTIES
SITS International
Study coordinator: 
Study advisor: 
 
 Study administrative operator: 
SITS Executive Assistant: 
Database 
 
SITS User Service and IT 
 
Network and Research Executive: 
Boehringer Ingelheim
Team Member Medicine (TMM): 
Trial Clinical Monitor (TCM):

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa 
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
05 July 2017
1160-0235
1.0
N.A.
Title of study:
Pradaxa Initiation Post-Stroke Study: SITS-Pradaxa 1. A 
retrospective analysis of existing data from the SITS-AF 
Registry on treatment initiation of dabigatran etexilate in non-
valvular atrial fibrillation patients hospitalized with acute 
ischemic stroke
Rationale and 
background:
Dabigatran etexilate (Pradaxa) is the first non-VKA oral 
anticoagulant (NOAC) for stroke prevention in non-valvular 
atrial fibrillation (NVAF) patients. Compared with warfarin, 
dabigatran 150 mg twice daily exhibited lower rates of stroke 
and systemic embolism, but similar rates of major haemorrhage; 
whereas treatment with dabigatran 110 mg twice daily showed 
similar rates of stroke and systemic embolism, but lower rates 
of major haemorrhage. Both dosages of dabigatran etexilate 
were associated with lower rates of intracranial haemorrhage. 
Dabigatran has been approved in most countries worldwide 
including Europe and US to reduce the risk of stroke and 
systemic embolism in patients with NVAF. In addition, the 
results from the RE-LY study concerning the use and outcome 
of anticoagulant therapy with dabigatran in NVAF patients have 
been confirmed in routine clinical practice data. In RE-LY, 
severe, disabling stroke within the previous 6 months, or any 
stroke within the previous 14 days was excluded and therefore, 
data in the acute setting on secondary stroke prevention is 
sparse.
The initiation of warfarin for the secondary prevention of 
ischemic stroke in NVAF has been established over the years of 
its use and is based on the severity of the index event. It ranges 
between 2-3 days for TIA up to 3-4 weeks for large ischemic 

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Protocol for observational studies based on existing data
BI Study Number 1160-0235
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa 
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
05 July 2017
1160-0235
1.0
N.A.
insults. For dabigatran the time ranges of initiation after the 
index event have not yet been established. 
Therefore, the aim of this study is to explore the current use of 
dabigatran etexilate for stroke prevention in NVAF patients in 
the post-stroke setting in routine clinical practice. 
In this study, the SITS Registry the entered data of 
approximately 1000 eligible patients, that initiated dabigatran 
after the index event, will be extracted for retrospective 
analysis.
Research 
question and 
objectives:
Primary Objective:

To evaluate the timing of dabigatran treatment initiation in 
patients with non-valvular atrial fibrillation (NVAF) the 
after hospitalization for first ever ischaemic stroke, in order 
to prevent secondary stroke.
Secondary Objectives:

To describe baseline characteristics for patients treated with 
dabigatran according to time of dabigatran initiation.

To describe self- reported factors important for the 
physician’s decision as to the time of dabigatran initiation in 
the post-ischemic stroke setting.

To describe self- reported factors important for physician’s 
decision as to which dabigatran dose was used in the post-
ischemic stroke setting.
 
 
 
 

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Protocol for observational studies based on existing data
BI Study Number 1160-0235
c03412460-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa 
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
05 July 2017
1160-0235
1.0
N.A.
 
 
 
Study design:
This is a retrospective observational  study using existing data 
from the SITS registry 
Population:
NVAF patients presenting with their first ever ischemic acute 
stroke.
Variables:

Patient characteristics such as age, stroke severity based on 
NIHSS, selected comorbidities, CHADS2, CHA2DS2-VASc
and bleeding (HAS-BLED) risk scores, prior oral 
anticoagulation treatment (dabigatran, Factor Xa Inhibitors, 
VKA) at index stroke date, the timing of dabigatran 
treatment initiation for secondary prevention of stroke when 
initiated within 3 months. 

Physicians’ self-reported factors important for their 
decisions when to initiate dabigatran in the post-ischemic 
stroke setting and factors important for physician’s decision 
which dabigatran dose is used in the post-ischemic stroke 
setting for prevention of stroke in NVAF. 

 
 
Data sources:
SITS-AF Registry data of approximately 1000 dabigatran 
treated patients in European countries registered in the SITS-AF 
Registry (expected by 31st July 2018).
Study size:
Approximately 1000 NVAF patients who are treated with 
dabigatran etexilate within 3 months of their first ischemic 

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Protocol for observational studies based on existing data
BI Study Number 1160-0235
c03412460-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa 
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
05 July 2017
1160-0235
1.0
N.A.
stroke (index event) constitute the main analysis population. 
 
 
 
 
 
Data analysis:
Descriptive statistics (absolute numbers and relative
frequencies, means, standard deviations, medians, inter quartile 
ranges, minimum and maximum values, 95% confidence 
intervals and proportions, as appropriate) for baseline and 
demographic characteristics for all included patients will be 
provided as appropriate for the variable of interest.
The main analysis will focus on NVAF patients presenting with 
first ischemic acute stroke and treated with dabigatran within 3 
months of index event.
We will describe the timing of dabigatran treatment initiation 
for secondary prevention of stroke when treatment is initiated 
within 3 months in the post-stroke setting. 
We will summarize the self- reported factors (i.e. as collected in 
the Registry using a dedicated question) important for the 
physician’s decision for the timing when to initiate dabigatran 
and the self-reported factors important for which dabigatran 
dose is used in the post-ischemic stroke setting for prevention 
of stroke. Descriptions will also be stratified according to time 
of dabigatran initiation if sample size allows.
Dabigatran patients will be described stratified by timing of 
dabigatran treatment initiation, newly diagnosed NVAF or 
prevalent NVAF, prior treatment with anticoagulation including 
type of anticoagulation therapy, stroke severity measured by 

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Protocol for observational studies based on existing data
BI Study Number 1160-0235
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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa 
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
05 July 2017
1160-0235
1.0
N.A.
NIHSS score, dose of dabigatran, if the sample size allows. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Individual patient safety related information will not be 
captured during this study. Thus, individual safety reporting is 
not applicable.
Milestones:
Individual patient data are collected in the SITS-AF Registry 
since the presentation of ‘Extended data entry option for atrial 
fibrillation and oral anticoagulant’, 1st July 2014. 
After approximately 1000 dabigatran treated patients from 
European Centres are registered in SITS-AF (expected by July 
2018), the data will be extracted and a retrospective final 
analysis will be performed. 

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5.
AMENDMENTS AND UPDATES
Not applicable

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6.
MILESTONES
Milestone
Planned Date
Start of study/data 
collection
17 July 2017
End of data collection
31 July 2018
(The time-point when approximately 1000 dabigatran 
treated patients with completed observation time are
expected to be registered in the database and data 
extraction will be done for the analysis)
Registration in the EU PAS 
register
13 July 2017 (registration no. EUPAS 17165) 
Final report of study results:
31 December 2018
(Considering that the observation time for 1000 
dabigatran treated patients is completed by 31 July 
2018.) 

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7.
RATIONALE AND BACKGROUND
Stroke is the third most common cause of death in industrialised countries after myocardial 
infarcts and tumour diseases. [P90-55974] Stroke is also the most common cause of 
permanent disability. About 85% of all strokes are ischaemic, the remaining part 
haemorrhagic. One year after a total anterior circulation infarct, 60% of the patients have died 
and 35% have so severe neurological deficits that independent activities of daily living are 
restricted. With milder strokes, about 40% die or remain dependent. [R96-0250] Since the 
incidence of stroke is strongly age-related, the number of stroke victims is expected to 
increase substantially over the next decades when the proportion of the population over the 
age of 70 is estimated to grow from about 13% to 20%. Even within the next decade, the 
number of stroke victims is expected to increase by about 15%. [R17-1269]
The burden of stroke is heavy for the victims and for society. The yearly direct and indirect 
costs for stroke in Europe can be estimated to about 25 billion Euros. Since the stroke 
incidence is expected to be about 750.000 in ten years, these costs might increase by about 
10-15% if we do not succeed to prevent more strokes and improve the effect of acute stroke 
intervention.
Atrial fibrillation (AF) and stroke
Atrial fibrillation (AF) is the most common arrhythmia and the prevalence of AF is about 0.4 
to 1% in the general population, rising to 8% in those subjects over 80 years.[R03-1233, R12-
2675, P10-00760] The number of patients with AF is likely to increase 2.5-fold during the 
next 50 years. [R03-1233] Patients with AF have a 5 fold increased risk of ischemic stroke 
compared to persons without AF.[R96-0252] AF related strokes are more severe, are more 
likely to cause disability or to recur, and carry a higher mortality risk than strokes in patients 
without AF.[R09-4892, R10-0658, R10-0340] Clinical practice guidelines developed by the 
American College of Cardiology, American Heart Association, European Society of 
Cardiology, and American College of Chest Physicians recommend that all patients with AF 
and a CHADS2 or CHA2DS2-VASc score ≥2 should receive long-term oral 
anticoagulation.[P10-10141, P11-03902, P12-01676] In the American College of Chest 
Physicians and European Society of Cardiology guidelines, oral anticoagulation also is 
recommended in patients with a CHADS2 or CHA2DS2-VASc score of 1.[ P10-10141] 
Vitamin K antagonists (e.g. warfarin) were the only oral anticoagulants available until 2010 
and updated guidelines include the newer oral anticoagulants as alternatives to vitamin K 
antagonists for stroke prevention. [P11-03902, P12-01676, P11-03903, P17-04650]
Anticoagulation treatment in patients with AF for stroke preventions 
Long-term anticoagulation treatment reduces the incidence of ischemic stroke in patients with 
AF. In a meta-analysis, adjusted-dose warfarin reduced the risk of stroke by 64% compared 
to placebo and by approximately 40% compared to antiplatelet therapy.[P07-07953] Warfarin 
treatment is underused, particularly in elderly population and maintaining appropriate 
anticoagulation levels with warfarin is often difficult because of variable dose responses, 
multiple drug-drug and drug-food interactions, a slow onset and offset of action. Warfarin-
treated patients require routine coagulation monitoring, dose adjustments, and dietary 
precautions to ensure a balance between therapeutic anticoagulation and bleeding risk.

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Dabigatran, the first new Oral Anticoagulants
Dabigatran etexilate (Pradaxa) is the first non-Vitamin K Antagonist oral anticoagulant 
(NOAC) for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. Dabigatran, 
a direct thrombin inhibitor, was evaluated in the phase III Randomized Evaluation of Long-
term Anticoagulation Therapy (RE-LY) study. [P09-11669] Compared with warfarin, 
dabigatran 150 mg twice daily exhibited lower rates of stroke and systemic embolism, but 
similar rates of major haemorrhage; whereas treatment with dabigatran 110 mg twice daily 
showed similar rates of stroke and systemic embolism, but lower rates of major haemorrhage. 
Dabigatran has been approved more than 100 countries world-wide including Europe and US 
to reduce the risk of stroke and systemic embolism in patients with NVAF.
The European approved current version of Pradaxa® Summary of Product Characteristics 
(SmPC) can be found on the EMA Webpage:

http://ec.europa.eu/health/documents/community-register/html/h442.htm.
The US approved version of the SmPC can be found on the FDA webpage:

https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.pr
ocess&ApplNo=022512
Data from clinical studies such as RE-LY and RELY-ABLE [P09-11669, P13-08115] where 
the safety of dabigatran in stroke prevention has been demonstrated for up to 5 years were 
confirmed by studies in real world clinical practices in different patient populations. [P14-
15648, P15-10687] However, it remains important to continue to address further real world 
clinical questions, which were so far not assessed in studies.
In RE-LY, severe, disabling stroke within the previous 6 months, or any stroke within the 
previous 14 days was excluded and therefore, data on the initiation of dabigatran treatment 
post-ischemic stroke for secondary stroke prevention in NVAF patients is sparse. 
The initiation of warfarin for the secondary prevention of ischemic stroke in NVAF has been 
established over the years of its use and is based on the severity of the index event. It ranges 
between 2-3 days for TIA to 3-4 weeks for large ischemic insults. For dabigatran these 
initiation ranges after the index event have not yet been established. Therefore, the aim of this 
study is to explore the current real world use of dabigatran for stroke prevention in NVAF 
patients in the post-stroke setting. Therefore data on the timing of dabigatran treatment 
initiation will be described by analysing data on NVAF patients after hospitalization for acute 
ischemic stroke in this study.

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8.
RESEARCH QUESTION AND OBJECTIVES
Primary objective:

To evaluate the timing of dabigatran treatment initiation in patients with non-valvular 
atrial fibrillation (NVAF) after hospitalization for first ever ischaemic stroke (the 
index event), in order to prevent secondary stroke.
Secondary objectives:

To describe baseline characteristics for patients treated with dabigatran according to 
time of dabigatran initiation.

To describe self-reported factors important for the physician’s decision as to the time 
of dabigatran initiation in the post-ischemic stroke setting.

To describe self-reported factors important for physician’s decision as to which 
dabigatran dose was used in the post-ischemic stroke setting.
 
 
 
 
 

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is an observational, multinational, multicentre, study in patients with NVAF presenting 
to a hospital with a first acute ischemic stroke. The study is based on existing data recorded in 
the SITS International Registry by physicians in European countries, such as Italy, United 
Kingdom, Czech Republic, Sweden, Germany, Poland, Spain, Finland, Portugal, Slovakia, 
Denmark, Estonia, Norway Belgium, Hungary, Slovenia, Croatia, Austria, Lithuania, France, 
Greece, Netherlands, Ireland, Ukraine and Iceland. All patients with NVAF will be included 
that present with the first ever ischemic stroke. For these patients baseline and demographics 
variables are available such as medical history including comorbidities and concomitant 
medications. Characteristics will further be used to estimate common stroke (CHADS2, 
CHA2DS2-VASc) and bleeding (HAS-BLED) risk scores. Details on NVAF and secondary 
stroke prevention: time since first diagnosis, prior anticoagulation treatment, dose, and stroke 
severity of index event measured by National Institute of Health Stroke Scale (NIHSS) score, 
are recorded in the registry. 
For patients that receive dabigatran within 3 months of the index event, details on post-stroke 
treatment (time from hospital admission – start and dose of dabigatran treatment for stroke 
prevention in NVAF, concomitant medication) will be analysed. Variables for physician’s 
decision when to initiate oral anticoagulation with dabigatran post-ischemic stroke and the 
dose selected will be analysed. 
 
In addition any start/stop of dabigatran treatment and doses prescribed will also be assessed at 
discharge and at 3 months after the index event. 
9.2
SETTING
Patients with NVAF presenting with their first ever acute ischemic stroke who are registered 
in the SITS International Registry from 1 July 2014 until approximately 31 July 2018 will be 
included in the study.
Inclusion criteria

Patients with non-valvular Atrial Fibrillation (NVAF) 

Patients presenting with their first acute ischemic stroke 

≥ 18 years of age
Exclusion criteria

Documentation that the patient was enrolled or is planned to be enrolled in an 
investigational clinical trial at the time of the onset of the index event and for the 
duration of the data collection

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9.3
VARIABLES
9.3.1
Exposures
Patient disposition will be provided according to post-stroke treatment (i.e. dabigatran, VKA, 
factor Xa inhibitors and no OAC therapy). Index event is defined as the acute ischemic stroke
that led to hospital admission for eligible patients (baseline visit).
Dabigatran treated patients will be further stratified by newly diagnosed NVAF or prevalent 
NVAF, prior treatment with anticoagulation including type of anticoagulation therapy
(dabigatran, VKA, Factor Xa Inhibitors, no anticoagulation) stroke severity measured by 
NIHSS score, dose of dabigatran, and timing of dabigatran treatment initiation.
We will describe the timing of dabigatran treatment initiation for secondary prevention of 
stroke within 3 months after index event in the post-stroke setting. Timing of dabigatran 
treatment initiation will be summarized as a continuous variable as well as a categorical 
variable (see section 9.3.2.1). For patients with dabigatran treatment initiated 28 days or more
after index event, further analysis maybe carried out to determine their characteristics. These 
analyses will be detailed in a separate statistical analysis plan (see Appendix 4). 
9.3.2
Outcomes
9.3.2.1
Primary outcomes

The time lapsed from the index event to the initiation of the dabigatran treatment. 
This will be further categorized in specified time periods.
The following time periods will be considered, but could be revised (e.g. merging 
categories) depending on sample size 0-24h, >24-72h, >3-7d >7-14d, >14-28d, >28d-
3m.
9.3.2.2
Secondary outcomes

Description of baseline characteristics for patients treated with dabigatran according 
to time of dabigatran initiation.

Description of self-reported factors important for physician’s decision when to initiate 
dabigatran in the post-ischemic stroke setting for prevention of stroke and safety in 
NVAF.

Description of self-reported factors important for physician’s decision which 
dabigatran dose is used in the post-ischemic stroke setting for secondary prevention of 
stroke and safety in NVAF.

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Definitions
Ischemic stroke is defined as an event characterised by sudden onset of acute focal 
neurological deficit (e.g. resulting in an impairment of speech, motor function, cognition, 
gazes, vision, and/or neglect) presumed to be caused by cerebral ischemia/infarction after 
exclusion of haemorrhage by imaging scans.
The index event is the date of first ever ischemic stroke.
The 3 month follow-up data point for patients is 90 (+/- 10) days after the index event.  
Major intracranial haemorrhage is defined as symptomatic intracranial bleeding at any time 
after start of dabigatran treatment and within 3 months from index event. 
The evaluation of intracranial haemorrhage will be done using the available CT/MRI scan 
after start of dabigatran treatment and within 3 months from index event. 
Major extracranial haemorrhage is derived from safety documentation in the SITS registry.
Death is defined as all cause death. 
9.3.3
Covariates
Patient characteristics such as age, stroke severity,(according to NIHSS) comorbidities, 
CHADS2, CHA2DS2-VASc) and bleeding (HAS-BLED) risk scores (see appendices 1-3), 
prior oral anticoagulation treatment (dabigatran, Factor Xa Inhibitors, VKA, no OAC 
therapy), are regarded as potential covariates.
Patient characteristics will be assessed at index stroke date.
9.4
DATA SOURCES
SITS – International Stroke Treatment Registry (ISTR)
Data from the SITS-International AF registry will be extracted for the purpose of analysis. 
The SITS-International registry is an ongoing, prospective, internet-based, academic-driven, 
multinational, stroke register. All centres registering patients in the SITS registry are required 
to accept the basic rules of participating in registry: consecutive registration of all patients 
with stroke symptoms receiving alteplase (if the centre registers only patients treated with 
intravenous thrombolysis), irrespective of whether treatment was on- or off-label. If the 
centre registers all stroke patients in the registry, consecutive registration of all patients with 

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stroke symptoms is obligatory. Death is collected separately in the SITS registry; however it 
is linked to the other outcomes at the 3 month time point from the index event. Register data 
has some inherent limitations. One of the most important limitations is we do not have any 
regular monitoring for source data verification, although monitoring was done during the 
period when the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-
MOST) was done [P07-00880]. In 2011-12, Karolinska Trial Alliance performed an 
independent monitoring of some selected Swedish centres and verified that data entered in 
the registry from these centres are accurate. Moreover, it is important to note that all results 
published based on SITS data with regard to baseline and demographic characteristics and 
outcome are comparable to other published data from randomised trials, registry data and 
centre data. SITS registry has a logical automatic validation system, which prevents the entry 
of erroneous or impossible data in the registry, to some extent. Regular checking of online 
report and prompt action by contacting centre is also a part of the work for SITS International 
Coordination members. Moreover, data are downloaded and cleaned regularly for scientific 
publications.
The SITS registry has implemented extended data entry for AF and oral anticoagulation since 
June 2014.
Specification of data collection from the index stroke event
At baseline: Demographic data, NIHSS and pre-stroke mRS, blood pressure, laboratory 
values (plasma glucose, cholesterol, coagulation status, liver function, kidney function,) 
medical history including comorbidities and concomitant medication, results of imaging 
scans, CHADS2, CHA2DS2-VASc and bleeding risk by HAS-BLED scores.
At 24 hours: NIHSS score, blood pressure, laboratory and imaging scans if performed. 
During hospital stay: details of concomitant medications, additional imaging scans prior to 
start of dabigatran treatment, any start/stop/change dabigatran treatment any results of the 
imaging scans
At 7 day or discharge if occurred earlier than 7 days: Date/time discharge, NIHSS scores, 
blood pressure, type of stroke and AF, medications
 
SITS is an academic-driven, non-profit, international collaboration. It is an initiative by the 
medical profession aimed at driving excellence in acute and secondary stroke treatment, and 
to develop new knowledge and leading research.
9.5
STUDY SIZE
Approximately 1000 NVAF patients who are treated with dabigatran etexilate within 3 
months of index event constitute the main analysis population.
In order to address the further objective on characterisation of NVAF, the analysis population 
will be broadened to include all European patients with NVAF aged ≥18 presenting with their 
first acute ischemic stroke, regardless of subsequent oral anticoagulation use within the time 
period until approximately 1000 dabigatran patients are registered in SITS-AF. 

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Data will be extracted from the SITS-AF registry from the European dataset for retrospective 
analysis. The number of patients included in the study is not driven by a formal sample size 
calculation but rather by available patient numbers, only descriptive or exploratory analyses 
will be performed for this study.
9.6
DATA MANAGEMENT
Data in the SITS registry are entered on-line through the SITS website. 
Each investigator/study nurse has a personal access code which must be kept secret and used 
only by the owner. All data entry from a centre can be made by each member of the local 
team, but once the data entry is confirmed (i.e., cannot be changed), the person who made the 
confirmation will be identified on the data entry form.
For the purpose of analysis, a download will be made in Excel/ CSV format which will then 
be transferred in the appropriate advance data analysis software such as STATISTICA/ SAS.
9.7
DATA ANALYSIS
Descriptive statistics (absolute and relative frequencies, means, standard deviations, medians, 
inter quartile ranges, minimum and maximum values, 95% confidence intervals and 
proportions, as appropriate) for baseline and demographic characteristics for all included 
patients will be provided. 
For the baseline characteristics we will calculate percentage proportions by dividing the 
number of events by the total number of patients, excluding missing or unknown cases as we 
generally did for all previous SITS-MOST and/or SITS-ISTR publications [P07-00880, P08-
11746].
In the separate statistical analysis plan further sensitivity analyses may be added (see 
Appendix 4). 
9.7.1
Main analysis
The main analysis will focus on NVAF patients presenting with first ischemic acute stroke 
and treated with dabigatran within 3 months of index event: 
For patients initiated on dabigatran within 3 months of index event, the time to dabigatran
treatment initiation will be summarized as a continuous variable as well as categorical; the 
following time periods will be considered, but could be revised (e.g. merging categories) 
depending on sample size 0-24h, >24-72h, >3-7d >7-14d, >14-28d, >28d-3m.
There will be a descriptive analysis of self-reported factors important for physicians decision 
when to initiate dabigatran and which dose in the post-ischemic stroke setting for prevention 
of stroke and safety in NVAF. This analysis will be done overall as well as by timing and by 
dose of dabigatran, respectively.

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In addition, baseline and demographic characteristics will be presented stratified by timing 
and dose of dabigatran as well as by newly diagnosed NVAF or prevalent NVAF, prior 
treatment with anticoagulation including type of anticoagulation therapy, stroke severity 
measured by NIHSS score, if the sample size allows. Timing and dose of dabigatran 
treatment initiation will additionally the summarized for relevant baseline subgroups, e.g. 
based on stroke severity, if the sample size allows.

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9.7.3
Interim analysis 
Not applicable.
9.8
QUALITY CONTROL
The automatic quality control of data is included in the SITS-Registry. This includes 
immediate feedback if data are missing, out of range data, illogical or potentially erroneous 
data. In addition to automatic quality control, regular online data monitoring is performed by 
SITS International Coordinating Office (ICO) members. All changes in the registry are 
automatically logged in the database
In addition to online data monitoring, raw data are downloaded every 6 months to check for 
inconsistency, completeness. Normally investigators are informed by newsletter regarding the 
completeness of data entry for overall registry and asked to complete the missing data. In 
case of major inconsistency or high rate of missing data investigators are contacted 
personally by e-mail. 
9.9
LIMITATIONS OF THE RESEARCH METHODS
Non-interventional study based on existing data
The quality of a study based on existing data relies on accuracy of recorded data. Important 
data may not be available. In the absence of randomisation and blinding, it can be difficult to 
control for bias and confounders.
Selection bias
There is a risk of selection bias at the patient level. Sites might preferentially include 
"interesting" cases to the SITS study. To minimize selection bias at the patient level, centres 
were reminded by e-mail every 3 months that all consecutive patients from each site who 
meet entry criteria must be included in the SITS-Registry.
Lost to follow up
As with all observational studies a loss to follow up can occur. In this study this will affect 
the patients with a pre-planned follow up (patients initiating dabigatran within the 3 months 
after the index event). However, considering the short time period of the follow up and the 
lost to follow up at 3 months in the general SITS Registry being 20%, a similar percentage of 
lost to follow up is expected in this study as well.
 
  
Channeling bias

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Channeling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest: e.g., if dabigatran would be more often prescribed to higher risk patients 
compared to other treatments, 
 
 In order to assess potential channeling bias patients not 
receiving dabigatran within 3 months of the index event will be assessed. For example, 
patients initiating VKAs, other NOACs or no oral anticoagulation therapy will be assessed 
according to important patient baseline characteristics (e.g. age, sex, comorbidities, stroke 
and bleeding risk scores, concomitant medications).
 
Confounding
As in any observational study, confounding may affect the estimation of association between 
variables and clinical outcome events of interest and statistical techniques such as adjustment 
for covariates, stratified analyses, matching, etc. can be used to correct for these. But as only 
major confounders for selected research questions can be captured, unmeasured confounding 
may remain.
Exploratory analyses
No formal power calculation has been done for this descriptive study and up to 1,000 patients 
with an index stroke are planned to be included. Follow-up is limited to three months after 
index stroke. Subgroup analyses, in particular those restricted to dabigatran patients, are only 
exploratory in nature. Exploratory analyses are usually not the definitive answer to the 
question at hand, but can be useful to define hypotheses to be tested in subsequent 
confirmatory studies.
9.10
OTHER ASPECTS
9.10.1
Ethical approval and informed consent
The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) of the 
Regional Ethical Review Board in Stockholm, Sweden (see website www.epn.se/en) has 
given approval for the SITS-Monitoring Study II (SITS-MOST II) protocol. 
SITS-MOST II is an ‘over-arching’ protocol that describes all research and analyses that 
SITS international is performing with the collected data in the SITS Registry, including this 
study 1160.235 (a part of the SITS-AF protocol in the SITS Registry).
The appendices in the SITS-MOST II protocol also include a patient information and 
informed consent form, describing the purpose of the SITS Registry and the reason why the 
patient is asked to collect their medical data in the SITS registry (see also Section 10).
The SITS-MOST II protocol and the EC approval document will be archived in the electronic 
Trial Master File (TMF), see Appendix 4.

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9.11
SUBJECTS
Patients with non-valvular Atrial Fibrillation (NVAF) presenting with their first acute 
ischemic stroke and 18 years or older are study subject (see Section 9.2).
9.12
BIAS
To assess potential channeling bias baseline characteristics of all patients fulfilling the 
in/exclusion criteria and were included in SITS-AF registry in the defined time period will be 
described based on the treatment they receive for stroke prevention in NVAF within 3 months 
of the index event.
Differences in the patients that are initiated with dabigatran versus patients initiating with 
VKA, Factor Xa Inhibitors or no oral anticoagulation therapy will be described and set in 
context to the observed results in the dabigatran treated patient set (see also Section 9.9).

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10.
PROTECTION OF HUMAN SUBJECTS
All data entered into the SITS International AF registry are encrypted in order to maintain 
patient data privacy. The individual patient and its research data is identified by a unique 
registry identification number. Access to data is strictly controlled by permitting each user a 
unique username and password. Additionally, each user has restrictions in viewing data sets, 
depending on their activity role in the database. Each data entry is centrally monitored by 
internal quality checks, such as automatic range checks and a full audit trail is maintained.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
According to the European Medicines Agency (EMA) Guideline on Good Pharmacovigilance 
Practices (GVP), Adverse Event (AE) reporting is not required for Non-Interventional Study 
(NIS) which is based on secondary data use. 
As an observational study, based on existing data, all patient data is de-identified and will be 
analysed in aggregate. Individual patient safety related information will not be captured 
during this study. Thus, individual safety reporting is not applicable. Safety reporting will be 
done cumulatively in aggregate in the study report.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
After finalisation of the final report, manuscripts based on the results of the study are planned 
to be submitted to peer-reviewed medical journals. The steering committee will appoint a 
writing committee who will publish the manuscripts in the name of all investigators. A list of 
all investigators will be included in the original manuscript.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P90-55974
WHO Task Force. Stroke-1989. Recommendations on stroke prevention, 
diagnosis and therapy. Report of the WHO Task Force on Stroke and other
Cerebrovascular Disorders. Stroke 20 (10): 1407-1431 (1989)
P06-10925
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ
Validation of clinical classification schemes for predicting stroke: results from 
the National Registry of Atrial Fibrillation.
JAMA 285 (22), 2864 - 2870 (2001)
P07-00880
Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for 
acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-
Monitoring Study (SITS-MOST): an observational study. Lancet 369 (9558):
275-282 (2007)
P07-07953
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to 
prevent stroke in patients who have non-valvular atrial fibrillation. Ann Intern 
Med, 146 (12), 857–867 (2007)
P08-11746
Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase 3-4.5 h 
after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 372
(9646):1303-1309 (2008)
P09-11669
Connolly SJ, Ezekowitz MD, Yusuf S, et al. (RE-LY study). Dabigatran 
versus warfarin in patients with atrial fibrillation. N Engl J Med, 361 (12), 
1139–1151 (2009)
P10-00760 
Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for 
the Management of Patients with Atrial Fibrillation: a report of the American 
College of Cardiology/American Heart Association Task Force on Practice 
Guidelines and the European Society of Cardiology Committee for Practice 
Guidelines (Writing Committee to Revise the 2001 Guidelines for the 
Management of Patients With Atrial Fibrillation): developed in collaboration 
with the European Heart Rhythm Association and the Heart Rhythm Society. 
Circulation 114: e257-354 (2006)
P10-10141
Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of 
atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of 
the European Society of Cardiology (ESC). Eur Heart J, 31 (19), 2369–2429
(2010)
P11-03902 
Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused 
updates incorporated into the ACC/AHA/ESC 2006 guidelines for the 
management of patients with atrial fibrillation: a report of the American 

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College of Cardiology Foundation/American Heart Association Task Force on 
practice guidelines. Circulation 123 (10), e269–e367 (2011)
P11-03903
Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused 
update on the management of patients with atrial fibrillation (update on 
dabigatran): a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. J 
Am Coll Cardiol 57 (11), 1330–1337 (2011)
P12-01676 
You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial 
fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: 
American College of Chest Physicians Evidence-Based Clinical Practice 
Guidelines. Chest 141 (2) (Suppl), e531S–e575S (2012)
P13-08115 
Connolly SJ, Wallentin L, Ezekowitz MD, et al. The Long Term Multi-Center 
Observational Study of Dabigatran Treatment in Patients with Atrial 
Fibrillation: (RELY-ABLE) Study. Circulation 128 (3), 237-243 (2013)
P14-15648 
Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, 
Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, 
Worrall C, Kelman JA. Cardiovascular, bleeding, and mortality risks in elderly 
Medicare patients treated with dabigatran or warfarin for non-valvular atrial 
fibrillation. Circulation 131 (2), 157–164 (2015)
P15-10687 
Villines TC, Schnee J, Fraeman K, Siu K, Reynolds MW, Collins J, 
Schwartzman E. A comparison of the safety and effectiveness of dabigatran 
and warfarin in non-valvular atrial fibrillation patients in a large healthcare 
system. Thromb Haemost. 114 (6), 1290-1298 (2015)
P17-04650
Shahid F, Shantsila E, Lip GYH. What do the guidelines suggest for non-
vitamin K antagonist oral anticoagulant use for stroke prevention in atrial 
fibrillation? Eur Heart J 18 (Suppl I), 118-124 (2016)
R96-0250 
Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and 
natural history of clinically identifiable subtypes of cerebral infarction. Lancet
337 (8756, 1521-1526 (1991)
R96-0252 
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk 
factor for stroke: the Framingham Study. Stroke 22 (8), 983-988 (1991)
R03-1233 
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial 
fibrillation in adults: national implications for rhythm management and stroke 
prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation 
(ATRIA) Study. JAMA 285 (18), 2370-2375 (2001)
R09-4892
Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. 
The Framingham Study. Stroke 27 (10), 1760–1764 (1996)

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R10-0340
Dulli DA, Stanko H, Levine RL. Atrial fibrillation is associated with severe 
acute ischemic stroke. Neuroepidemiology 22 (2), 118–123 (2003)
R10-0658 
Jorgensen HS, Nakayama H, Reith J, et al. Acute stroke with atrial fibrillation. 
The Copenhagen Stroke Study. Stroke, 27 (10), 1765–1769 (1996)
R10-5332
Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM.
Refining clinical risk stratification for predicting stroke and thromboembolism 
in atrial fibrillation using a novel risk factor-based approach: the Euro Heart 
Survey on Atrial Fibrillation.
Chest 137 (2), 263 - 272 (2010)
R10-6394
Pisters R, Lane DA, Nieuwlaat R, Vos CB de, Crijns HJGM, Lip GYH
A novel user-friendly score (HAS-BLED) to assess 1-year risk of major 
bleeding in patients with atrial fibrillation: the Euro Heart Survey.
Chest 138 (5), 1093 - 1100 (2010)
R12-2675 
Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in 
elderly subjects (the Cardiovascular Health Study). Am J Cardiol 74 (3), 236-
241 (1994)
R17-1269
Wahlgren NG. Introduction. In: Wahlgren NG, editor. Update on Stroke 
Therapy 2000-2001, Stockholm: Karolinska Stroke Update, 17-19 (2001)

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14.
APPENDICES 
APPENDIX 1: CHADS2 STROKE RISK SCORE
CHADS2 components
Points
Congestive heart failure
1
Hypertension
1
Age 75 years or older
1
Diabetes mellitus
1
Prior cerebral ischemia (i.e., stroke, TIA)
2
Maximum score
6
CHADS2 score is based on a point system in which 2 points are assigned for a history of 
stroke or transient ischemic attack and 1 point each is assigned for age 75 years or older, 
hypertension, diabetes, or clinical heart failure or impaired left ventricular systolic function 
(generally interpreted as an ejection fraction ≤ 40%). A CHADS2 score of 0 identifies 
patients at low stroke risk, a score of 1 to 2 identifies patients at moderate stroke risk, and a 
score greater than 2 identifies patients at high stroke risk [P06-10925].

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APPENDIX 2: CHA2DS2-VASC STROKE RISK SCORE
CHA2DS2VASc score
Risk factors for stroke and thrombo-embolism in non-valvular AF
Major risk factors
Clinically relevant non-major 
risk factors
Previous stroke, TIA, or systemic 
embolism Age ≥ 75 years
Heart failure or moderate to severe 
LV systolic dysfunction (e.g. LV 
EF ≤40 %) Hypertension - Diabetes 
mellitus  Female sex - Age 65-74 
years Vascular disease
Risk factor-based approach expressed as a point based scoring system, 
with the acronym CHA2DS2-VASc
(Note: maximum score is 9 since age may contribute 0, 1, or 2 points)
Risk factor
Score
Congestive heart failure/LV dysfunction
1
Hypertension
1
Age ≥75
2
Diabetes mellitus
1
Stroke/TIA/systemic embolism
2
Vascular disease*
1
Age 65-74
1
Sex category (i.e. female sex)
1
Maximum score
9
* Myocardial infarction, complex aortic plaque and PAD
The CHA2DS2-VASc risk score is based on a point system in which 2 points are assigned for 
a history of stroke or TIA, or age ≥75; and 1 point each is assigned for age 65–74 years, a 
hypertension, diabetes, cardiac failure, vascular disease and female sex. On the basis of the 
risk strata defined in previous guidelines, a CHA2DS2-VASc score of 0 corresponds to “low 
risk”, a score of 1 corresponds to “intermediate risk”, and a score of 2 or more corresponds to 
“high risk” [R10-5332].

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APPENDIX 3: HAS-BLED BLEEDING RISK SCORE 
Clinical characteristics comprising the HAS-BLED bleeding risk 
score
Letter
Clinical characteristic
Points awarded
H
Hypertension
1
A
Abnormal renal and liver
function (1 point each)
1 or 2
S
Stroke
1
B
Bleeding
1
L
Labile INRs
1
E
Elderly (e.g. age >65 years)
1
D
Drugs or alcohol (1 point each)
1 or 2
Maximum score
9
Hypertension is defined as history of hypertension and current uncontrolled systolic blood 
pressure >160 mmHg. ‘Abnormal kidney function’ is defined as the presence of chronic 
dialysis or renal transplantation or serum creatinine ≥200 µmol/L. ‘Abnormal liver function’ 
is defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant 
hepatic derangement (e.g. bilirubin >2 x upper limit of normal, in association with aspartate 
aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal). 
‘Bleeding’ refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding 
diathesis, anaemia, etc. ‘Labile INRs’ refers to unstable/high INRs or poor time in therapeutic 
range (e.g. <60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet 
agents, non-steroidal anti-inflammatory drugs, or alcohol abuse, etc. If a patient is not on 
VKA the value for ‘labile INRs’ will be set to 0. Further details will be given in the separate 
statistical analysis plan (see Appendix 4).
A HAS-BLED score of ≥3 indicates ‘high risk’ for AF patients to develop a bleed and some 
caution and regular review of the patient is needed following the initiation of antithrombotic 
therapy, whether with VKA or aspirin [R10-6394].

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Protocol for observational studies based on existing data
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APPENDIX 4: LIST OF STAND-ALONE DOCUMENTS
The final version of the following stand-alone documents will be archived in the Trial Master 
File (TMF)

Statistical analysis plan (and revisions, if applicable)

SITS-MOST II protocol (and amendments, if applicable)

Ethics Committee approval(s) for the SITS-MOST II protocol (and amendments, if 
applicable)

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05 July 2017
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Protocol for observational studies based on existing data
BI Study Number 1160-0235
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APPENDIX 5: ENCEPP CHECKLIST FOR STUDY PROTOCOLS

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05 July 2017
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Protocol for observational studies based on existing data
BI Study Number 1160-0235
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Boehringer Ingelheim
05 July 2017
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Protocol for observational studies based on existing data
BI Study Number 1160-0235
c03412460-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
05 July 2017
Page 40 of 42
Protocol for observational studies based on existing data
BI Study Number 1160-0235
c03412460-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
05 July 2017
Page 41 of 42
Protocol for observational studies based on existing data
BI Study Number 1160-0235
c03412460-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
05 July 2017
Page 42 of 42
Protocol for observational studies based on existing data
BI Study Number 1160-0235
c03412460-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies