Characterization of Patients Following Acute Venous Thromboembolism (VTE) and Safety and Effectiveness of Dabigatran Etexilate (DE) in the Treatment and Secondary Prevention of Acute Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) in Comparison to Vitamin K Antagonist (VKA) in Routine Clinical Practice - RE-COVERY DVT/PE
Conditions: Venous Thromboembolism
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c03118416-03
BI Study Number:
1160.188
BI Investigational
Product(s):
Not applicable.
Title:
ChaRactErization of patients following aCute venous 
thrOmboembolism (VTE) and assessment of safety and 
effectiveness of dabigatran etexilate (DE) in the tReatment 
and secondarY prevention of acute deep vein thrombosis 
(DVT) and pulmonary embolism (PE) in comparison to 
vitamin K antagonist (VKA) in routine clinical practice  -
RE-COVERY DVT/PE
Brief lay title
RE-COVERY DVT/PE: global study on treatment and 
secondary prevention of acute venous thromboembolism
Protocol version 
identifier:
3.0 
Date of last version of 
protocol:
16 Nov 2016
PASS:
Yes
EU PAS register 
number:
EUPAS11368
Active substance:
Dabigatran etexilate
Medicinal product:
Dabigatran etexilate
Product reference:
Not applicable
Procedure number:
Not applicable
Joint PASS:
No
Research question and 
objectives:
There are two primary objectives in this study:

To characterize the DVT / PE patient population 
including the initial acute event phase.  All patients 
with a DVT and/or PE will be enrolled for cross-
sectional characterization of the VTE patient 
population and descriptions of current treatment 

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patterns, and stratified by geographical location.

To analyze the safety and effectiveness of dabigatran 
etexilate regimens in the treatment of DVT and PE 
over 1 year of follow-up in comparison to a VKA 
regimen.  
Additional further exploratory objectives are:

To evaluate geographical variations in health care 
resource utilization and patient satisfaction with 
their treatment in routine clinical practice.

To conduct stratified analysis for the safety and 
effectiveness of dabigatran etexilate according to 
dose.
The following research questions will be investigated: 

With the approval of dabigatran etexilate and other
non-vitamin K oral anticoagulant (NOACs), what 
treatments are being administered for acute VTE in 
routine clinical practice in the different regions of the 
world?    

When presenting with an acute VTE event, what 
factors influence the choice of treatment for the 
event?

What is the safety and effectiveness of dabigatran 
etexilate versus VKA under conditions of routine 
clinical practice? 

What health care resources are utilized in patients who 
are treated with dabigatran etexilate or VKA for an 
acute VTE under conditions of routine clinical 
practice?  

For patients who are treated with either dabigatran 
etexilate or VKA, what is patients’ satisfaction with
their treatment under conditions of routine clinical 
practice?
Country(-ies) of 
study:
Global study including countries from North and South 
America, Europe, Middle East and Asia.
Author:
Phone:  
Fax:  
Marketing 
authorization 
holder(s):
MAH contact person:

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EU-QPPV:
Phone: 
Signature of EU-
QPPV:
The signature of the EU-QPPV is provided electronically
Date:
01 Sep 2017
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Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 4
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 13
6.
MILESTONES..................................................................................................... 15
7.
RATIONALE AND BACKGROUND................................................................ 16
7.1
MEDICAL BACKGROUND ..........................................................................16
7.2
EPIDEMIOLOGY ...........................................................................................16
7.3
RATIONALE FOR THE STUDY...................................................................18
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 20
9.
RESEARCH METHODS .................................................................................... 21
9.1
STUDY DESIGN.............................................................................................21
9.2
SETTING.........................................................................................................22
9.2.1
Inclusion criteria...................................................................................... 23
9.2.2
Exclusion criteria..................................................................................... 23
9.2.3
Removal of subjects from the study........................................................ 23
9.2.4
Visit schedule.......................................................................................... 24
9.3
VARIABLES ...................................................................................................25
9.3.1
Data points............................................................................................... 25
9.3.1.1
Baseline visit data points .....................................................................26
9.3.1.2
Hospital discharge or at 14 days after diagnosis of VTE event (whichever 
occurs later)..........................................................................................................27
9.3.1.3
Follow-up visit data points...................................................................28
9.3.2
Outcome measures .................................................................................. 28
9.3.3
Assessment of outcome measures........................................................... 29
9.4
DATA SOURCES............................................................................................31
9.5
STUDY SIZE...................................................................................................31
9.6
DATA MANAGEMENT.................................................................................33
9.7
DATA ANALYSIS..........................................................................................34
9.7.1
Study design............................................................................................ 34
9.7.2
Planned analyses ..................................................................................... 34

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9.7.2.1
Main analyses.......................................................................................34
...................................................................................35
9.7.2.3
Safety analyses.....................................................................................36
9.7.2.4
Schedule of planned analyses ..............................................................36
9.7.3
Handling of missing data......................................................................... 37
9.8
QUALITY CONTROL....................................................................................37
9.9
LIMITATIONS OF THE RESEARCH METHODS.......................................37
9.10
OTHER ASPECTS ..........................................................................................39
9.10.1
Data quality assurance............................................................................. 39
9.10.2
Study records........................................................................................... 39
9.10.2.1 Source documents................................................................................39
9.10.2.2 Direct access to source data and documents........................................40
9.10.3
Completion of study................................................................................ 40
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 41
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .......................................................................................................41
10.2
STATEMENT OF CONFIDENTIALITY.......................................................41
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 42
11.1
DEFINITION OF ADVERSE EVENTS .........................................................42
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING ......................................................................................................43
11.3
REPORTING TO HEALTH AUTHORITIES.................................................45
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 46
13.
REFERENCES .................................................................................................... 47
13.1
PUBLISHED REFERENCES..........................................................................47
13.2
UNPUBLISHED REFERENCES....................................................................50
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 51
ANNEX 2. ENCEPP ChECKLIST FOR STUDY PROTOCOLS ............................... 52
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 59
Annex 3.1
Morisky medication adherence scale ....................................................60
Annex 3.2
Perception of anticoagulant treatment questionnaire 2 .........................61

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2.
LIST OF ABBREVIATIONS
ACS
Acute coronary syndrome
ADR
Adverse drug reaction
AE
Adverse Event
AESI
Adverse event of special interest
AF
Atrial fibrillation
b.i.d.
bis in die (two times a day)
CA
competent authority
CBC
Complete blood count
CCS
Canadian cardiovascular society
CI
Confidence Interval
CRA
CRNMB
Clinical Research Associate
Clinically relevant non major bleeding
DE
Dabigatran etexilate
DVT
ECG
Deep vein thrombosis
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EU
European Union
GCP
GEP
GPP
Good Clinical Practice
Good epidemiology practices
Good pharmacoepidemiology practices
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
ISTH
International Society on Thrombosis and Haemostasis
ISF
Investigator Site File
LMWH
MAH
Low molecular weight heparin
Marketing authorization holder 
Mg
NCB
Milligram
Net clinical benefit
NOAC
Non-vitamin K anticoagulant
NSTEMI
Non-ST elevation myocardial infarction
PACT-Q2
Perception of anticoagulant treatment questionnaire 2
PE
Pulmonary embolism
SAE
Serious Adverse Event
SEAP
Statistical and epidemiological analysis plan 
STEMI
ST elevation myocardial infarction
Tn
Cardiac troponin
TTR
Time in therapeutic range
UA
Unstable angina
UFH
Unfractionated heparin
V-Q
ventilation/perfusion (scan)
VKA
Vitamin K antagonist
vs
Versus
VTE
Venous thromboembolism

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3.
RESPONSIBLE PARTIES
Therapeutic Area 
– Cardiovascular 
Medicine
 of Global Epidemiology Team 
Cardiovascular
Team Member Medical Affairs
Team Member Epidemiology
Trial Clinical Monitor (TCM)
Trial Statistician
Steering Committee 

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Dabigatran etexilate
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
28 May 2015
1160.188
3.0
01 Sep 2017
Title of study:
ChaRactErization of patients following aCute venous 
thrOmboembolism (VTE) and assessment of safety and 
effectiveness of dabigatran etexilate (DE) in the tReatment and 
secondarY prevention of acute deep vein thrombosis (DVT) and 
pulmonary embolism (PE) in comparison to vitamin K 
antagonist (VKA) in routine clinical practice  - RE-COVERY 
DVT/PE
Rationale and 
background:
The collection of clinical practice data is important for studying 
large patient numbers that include a broad spectrum of co-
morbidities and co-medication use with the use of a new drug.  
Observational studies can provide complementary data, 
including safety data and health care resource utilization.  This 
can expand the knowledge previously collected from randomized 
clinical trials, which generally have stricter entry criteria and 
structured monitoring schemes. 
With the recent approval of NOACs for the treatment and 
prevention of recurrent VTE, the use of older, traditional 
treatments, such as VKA, may change and it is therefore 
important to understand how patients with different 
characteristics are treated in routine clinical practice.  In 
addition, there may be geographical differences in treatment 
patterns based on a number of factors including patient co-
morbidities and co-medication use or cost and access to newer 
therapies.
Dabigatran etexilate safety and efficacy with the 150 mg b.i.d. 
dose has been demonstrated in large randomized clinical trials 
for several indications (e.g., VTE, stroke prevention in atrial 
fibrillation (AF)). However, the safety and effectiveness of 110 
mg b.i.d. dabigatran etexilate compared with VKA for treatment 
of VTE has not been investigated in randomized clinical trials.  
Health authorities, however, have also requested the lower dose 
(110 mg b.i.d) for use in the treatment of VTE in special 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Dabigatran etexilate
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
28 May 2015
1160.188
3.0
01 Sep 2017
populations (e.g., elderly or patients concomitantly taking 
verapamil).  This observational study provides an opportunity to 
collect clinical data in a broader patient population including all 
available dosages of dabigatran etexilate.
Research 
question and 
objectives:
There are two primary objectives in this study:

To characterize the DVT / PE patient population including 
the initial acute event phase.  All patients with a DVT 
and/or PE will be enrolled for cross-sectional 
characterization of the VTE patient population and 
descriptions of current treatment patterns, and stratified by 
geographical location.

To analyze the safety and effectiveness of dabigatran 
etexilate regimens in the treatment of DVT and PE over 1 
year of follow-up in comparison to a VKA regimen.  
Additional further exploratory objectives are:

To evaluate geographical variations in health care 
resource utilization and patient satisfaction with their 
treatment in routine clinical practice.

To conduct stratified analysis for the safety and 
effectiveness of dabigatran etexilate according to dose.
The following research questions will be investigated: 

With the approval of dabigatran etexilate and other 
NOACs, what treatments are being administered for acute 
VTE in routine clinical practice in the different regions of 
the world?    

When presenting with an acute VTE event, what factors 
influence the choice of treatment for the event?

What is the safety and effectiveness of dabigatran etexilate
versus VKA under conditions of routine clinical practice? 

What health care resources are utilized in patients who are 
treated with dabigatran etexilate or VKA for an acute VTE 
under conditions of routine clinical practice?  

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Dabigatran etexilate
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
28 May 2015
1160.188
3.0
01 Sep 2017

For patients who are treated with either dabigatran 
etexilate or VKA, what is patients’ satisfaction with their 
treatment under conditions of routine clinical practice?
Study design:
RE-COVERY is a large, multi-national, multi-center
observational study based on new data collection.  The study will 
enroll and characterize patients diagnosed with an acute DVT 
and/or PE. Patients treated with dabigatran etexilate or VKA will 
be followed up for the occurrence of outcome events for up to one 
year.
Population:
Setting: Participation of a country requires the approval of 
dabigatran etexilate for the VTE indication prior to study 
initiation within that country.  Selected sites within each country 
should include those physicians (e.g., specialist and general 
practitioners) and facilities (e.g., general practice offices, 
specialist offices, hospitals, outpatient care centers and 
anticoagulation clinics) that reflect the clinical practice within 
that country. 
Patient Population:  Objective 1:  The study will enroll and 
characterize patients diagnosed with an acute DVT and/or PE. 
Objective 2:  Patients treated with dabigatran etexilate or VKA 
will be followed up for the occurrence of outcome events for up 
to one year.  
Variables:
For Objective 1: 
The patient’s baseline characteristics including demographic 
information, co-medication and co-morbidities, basic physical 
examination and laboratory information, VTE event information 
including treatment selected, event type, and history of VTE 
event will be collected at the time of the acute VTE event.    
The following primary outcome measures will be analyzed on 
data that is collected at the time of the acute VTE event:

Demographic information (age and gender)

VTE event information (event type and treatment for 
event)

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Dabigatran etexilate
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
28 May 2015
1160.188
3.0
01 Sep 2017
For Objective 2:
The same baseline outcome measures will be collected as 
described above at time of the acute VTE event.  During the 
follow-up of patients treated with dabigatran etexilate or VKA, 
details regarding changes to their anticoagulation therapy (e.g.,
dose adjustments, discontinuation of treatment, and reason for 
discontinuation); outcome events, adverse drug reactions and 
changes to concomitant medications will be collected.  Health 
care resource utilization and patient’s satisfaction with their 
anticoagulation therapy will be assessed using the Perception of 
anticoagulation treatment questionnaire 2 (PACT-Q2).
The following primary outcomes will be analyzed:

Primary safety outcome measure: Major bleeding and 
clinically relevant non major bleeding (International 
Society on Thrombosis and Haemostasis (ISTH) criteria)

Primary effectiveness outcome measure:  symptomatic 
recurrent VTE including VTE-related mortality
The following secondary outcomes will be analyzed:

Recurrent DVT and/or PE 

VTE-related mortality 

All-cause mortality
Data sources:
RE-COVERY is a study based on new data collection. Data will 
be collected based on assessment of the patient (e.g., physical 
examination and patient interview), review of hospital / medical 
records and available laboratory and diagnostic test reports.  
Patient reported outcomes will be assessed using a validated 
questionnaire.  
Study size:
It is planned that approximately 6000 patients will be enrolled 
for Objective 1 and up to 5000 patients will be enrolled for
Objective 2 from approximately 300 sites around the world
Data analysis:
Patient demographics and baseline characteristics will be 
summarized descriptively. Multivariable regression models and 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Dabigatran etexilate
Name of active ingredient:
Dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
28 May 2015
1160.188
3.0
01 Sep 2017
propensity score based methods will be used for the comparative 
analyses of dabigatran etexilate and VKA patients.
Milestones:
It is planned that data collection will start by August 2015 and is 
planned to be completed by December 2018.  The final study 
report is planned to be completed in the first quarter of 2019
assuming recruitment is completed within 2 years.

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
Protocol
Amendment or update
Reason
1
16 Nov 2016
Cover 
page
Middle East added as a 
participating region.
Expanded country 
participation.
2
16 Nov 2016
Abstract
Reference to recruitment 
of patients within 30 
days was removed.
The allowable window 
to recruit patients into 
Objective 1 was 
increased.
3
16 Nov 2016
9.1
The allowable window to 
recruit patients into 
Objective 1 was 
increased to 6 months. 
To provide sites 
sufficient time to 
ensure consecutive 
enrollment of patients 
into the study.
4
16 Nov 2016
9.2.1
Revision to inclusion 2 
criterion to allow up to 6 
months to enroll patients 
into Objective 1. 
To provide sites 
sufficient time to 
ensure consecutive 
enrollment of patients 
into the study.
5
16 Nov 2016
9.3.1.3
If the specific reversal 
agent for dabigatran is 
given to a patient, 
information will be 
collected.
To ensure that details 
regarding the use of the 
dabigatran reversal 
agent are collected in a 
consistent manner.
6
16 Nov 2016
11:3
The section was 
removed.
The relevant 
information for sites is 
located in the ISF.
7
16 Nov 2016
11.4
AE reporting to 
regulatory authorities 
will be done by the 
MAH in accordance with 
local and international 
regulatory requirements.  
To provide 
clarification regarding 
reporting 
responsibilities.
8
18 Aug 2017
Cover 
page
Change in Author name
To reflect change of 
TCM
9
18 Aug 17
Abstract; 
9.1; 9.3.2; 
9.9
Primary outcome 
measure for obj 2 to 
include clinically 
relevant non major 
bleeds. 
Expanded primary 
outcome

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10
Abstract
Sample size for obj 2 
changed to 5,000 and last 
patient out pushed to 
December 2018
Sample size and 
timelines revised based 
on expanded primary 
outcome
11
9.2.4
Added description on 
how to handle Obj 1 and 
2 patients whose 
anticoagulation treatment 
was discontinued or 
changed
To provide guidance 
on ePRO collection 
and fup requirement 
for obj 2 patients
whose anticoagulation 
treatment was 
discontinued or 
changed
12
9.3.3
Added ISTH criteria for 
clinically relevant non-
major bleed
Provide definition in 
the protocol as 
CRNMB is now 
included in primary 
outcome
13
9.3.11
Added examples of 
objective testing for VTE
To provide 
clarification on what 
constitute objective 
testing of VTE
14
9.5; Table 
9.5.2
Statistical analysis 
assumptions updated 
including sample size 
assessment for primary 
outcome
Statistical assumptions 
updated because of 
change in primary 
outcome
15
11.2
Serious and non-serious 
ADRs for DE will be 
collected and reported 
from time of event.
Serious and non serious 
ADRs to VKA will be 
collected from time of 
event for obj2 only.
All serious and non-
serious ADRs will be 
collected from time of 
informed consent.
Clarification around 
ARDs collection and 
reporting for DE and 
VKA for obj 1 and 2

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6.
MILESTONES
Status reports will be generated on a regular basis and are dependent on recruitment, strategic 
decisions and regulatory requests, if applicable.  The schedule of reports will be maintained 
throughout the study and will be filed with the study documentation.  The planned major 
milestone dates are summarized below.
Milestone
Date
Start of data collection
01 February 2016 (actual)
End of data collection
31 December 2018 (planned)
Registration in the EU PAS 
register
22 October 2015 (actual)
Final report of study results:
Second quarter of 2019 (planned)

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7.
RATIONALE AND BACKGROUND
7.1
MEDICAL BACKGROUND
VTE includes 2 related events: DVT and PE.  The venous thrombus usually develops in the 
deep veins of the leg or pelvis.  Thrombus from a DVT can propagate and/or embolize to the 
pulmonary circulation, resulting in a PE, which can turn into an acute life-threatening 
condition.  Up to 50% of patients with DVT have evidence of a silent PE, and up to 70% of 
patients with a PE have a DVT.  About 90% of all PEs originate as a venous thrombus in a 
proximal, larger diameter leg or pelvic veins, leading to an occlusion or partial occlusion of 
larger sized pulmonary vessels. 
Risk factors for the development of venous thrombosis include vessel wall injury or 
endothelial dysfunction, hemodynamic changes, and hypercoagulability, otherwise known as 
Virchow’s triad [R12-2781].  Other risk factors include major trauma, hip or leg fracture, 
orthopedic replacement of joints in the leg, immobilization, certain malignancies, history of 
prior VTE and genetic thrombophilia.
7.2
EPIDEMIOLOGY 
The annual incidence of VTE is approximately 1-2 per 1000 individuals in Western countries 
[R04-2883, R05-0300, R12-2781].  VTE is estimated to be the third most common 
cardiovascular disorder after coronary heart disease and stroke.  VTE is responsible for more 
than 180,000 hospitalizations per year in the US [P11-07302, P12-04560].  Over 750,000 
VTE events are estimated to occur per year in six major European Union (EU) countries 
(France, Germany, Italy, Spain, Sweden, and UK [R09-0200]).  
Treatment Options
Anticoagulant therapy is the standard treatment for venous blood clots, preventing new blood 
clots from forming, and preventing existing blood clots from getting larger and leading to 
dissolution of the existing clot after successful treatment.  Rapid anticoagulation will 
minimize the risk of thrombus extension and PE in patients with VTE.  Treatment duration is 
determined by the individual patient’s clinical presentation.  There are a number of factors 
that influence the type of anticoagulant therapy and treatment duration, including: the 
presence or absence of one or more risk factors for VTE (i.e., major orthopedic surgery), the 
acuteness of the thrombotic condition, the risk of recurrence, the risk of bleeding including 
bleeding due to underlying conditions (e.g., cancer) and issues that can affect compliance 
(e.g., parenteral versus oral administration and the degree of medical monitoring necessary to 
ensure efficacy and safety of the treatment).  
Current guidelines for the United States (American College of Chest Physicians 
antithrombotic guidelines) and Europe (European Society of Cardiology), for the acute 
treatment of VTE recommend the initial administration of a parenteral anticoagulant, usually 
a low-molecular-weight heparin (LMWH), unfractionated heparin (UFH) or fondaparinux for 
5-10 days.  Parenteral treatment is followed by treatment with an oral vitamin K antagonist 
(VKA) such as warfarin that is titrated to a target International Normalized Ratio (INR) of 2 
to 3 or dabigatran etexilate or edoxaban.  Alternatively rivaroxaban or apixaban may be 
started immediately or after 1 to 2 days of LMWH, UFH or fondaparinux. Both rivaroxaban 
and apixaban require dose increases over 3 weeks (for rivaroxaban) or 1 week (for apixaban).  

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Anticoagulation treatment should last at least 3 months.  Longer treatment may be 
recommended depending on the nature of the initial event (i.e. DVT versus PE), the risk of 
recurrence and the risk for bleeding [P12-01518, P14-16368].  Patients with an unprovoked 
acute VTE should also receive extended anticoagulation therapy assuming that they are not at 
high risk for bleeding [P12-01518, P14-16368]. 
Optimal treatment duration for acute VTE and the secondary prevention of recurrent VTE is 
not definitively known. The two terms “acute treatment” and “secondary prevention” are not 
precisely defined and might overlap.  Current guidelines recommend treatment for 3 months
over shorter treatment durations [P12-01518, P14-16368].  An extended duration of 
anticoagulation treatment should be considered for those patients with the greatest risk of 
VTE recurrence, i.e., those with an unprovoked DVT and/or PE; recurrent VTE, co-
morbidities, such as cancer, chronic inflammation of the peripheral veins, and a strong 
genetic pre-disposition to thrombosis.
For patients with a chronic risk of recurrent VTE, there is evidence that when oral 
anticoagulation therapy is stopped, the risk of recurrence will increase to pre-treatment levels
[P08-08095, R09-4888]. Therefore, the decision to continue treatment for prevention of 
recurrent VTE must consider the risk factors for recurrence as well as any risk factors for 
bleeding.  The risk of bleeding increases in patients with a prior history of bleeding events, 
the presence of certain co-morbidities (e.g., gastrointestinal ulceration, inflammation or 
malignancy or other metabolic disorders that might alter hemostasis such as cirrhosis or 
chronic renal disease or concomitant medications that alter hemostasis (i.e. antiplatelet 
agents)).  These risks must be reviewed periodically, and therefore, treatment decisions 
should be individualized and periodically reviewed.
Another critical factor that must be taken into consideration is a patient’s history of 
medication compliance.  VKAs have been the standard of care for oral anticoagulation 
therapy for decades but because of the narrow therapeutic window and their mechanism of 
action which is sensitive to diet-related alterations in vitamin K absorption, VKAs have been 
challenging to administer.  A recent review of the pattern of anticoagulation after VTE in 
over 46,000 patients in the UK showed that the mean percentage of time in the therapeutic 
range (TTR) (i.e., INR of 2 to 3) was only 57% [R12-2550].  Similarly, in another study
conducted in the US, the mean TTR was 53.7% for patients with AF and being treated with 
warfarin for stroke prevention.  The TTR improved with time on treatment, increasing from 
47.6% for patients treated for less than 6 months to 57.5% for those patients treated for 
greater than 6 months.  Female gender, younger age and lower income bracket were 
independently associated with poorer anticoagulation control.  There was also a strong 
association between improved TTR and physician case load which could reflect better 
organization for warfarin management and drug familiarity [R15-0778]. Warfarin efficacy is 
directly related to the time spent in the therapeutic window.  Therefore risk of recurrence and 
the risk of bleeding is highly dependent on patient adherence and persistence, the ability to
monitor anticoagulant activity (i.e., INR monitoring) and managing the dose effectively. 
NOAC therapy including Factor Xa inhibitors (e.g., apixaban, rivaroxaban or edoxaban) and 
direct thrombin inhibitors (e.g., DE) have been used more recently for prevention and 
treatment of VTE.  In general these agents have fewer drug-drug or dietary interactions and 
do not require rigorous INR monitoring compared with VKA.  Although lower bleeding rates 
were observed with NOACs compared to VKA in clinical trials, bleeding remains a major
side effect. Unlike VKA, regulatory approved reversal agents are not yet available in cases of 

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life-threatening bleeding. The effects of VKA may be reversed through I.V. administration of 
Vitamin K or a prothrombin complex concentrate (Kcentra® in the U.S. or Beriplex® in 
other countries), which can reduce the INR to ≤1.3 within 30 minutes [R15-1423].
The efficacy and safety of dabigatran etexilate versus (vs) warfarin has been tested in 4 
pivotal, randomized, double-blind, clinical trials. A dose of 150 mg b.i.d. of dabigatran 
etexilate was tested in all 4 trials.  Two trials (RE-COVER and RE-COVER II) demonstrated 
that dabigatran etexilate was non-inferior to warfarin for treatment of acute VTE [U09-1400, 
U11-2298].  Two other trials focused on secondary prevention in high-risk (RE-MEDY) 
[U10-2533] and lower risk (RE-SONATE) patients [U11-2267-02].  Dabigatran etexilate was 
non-inferior to warfarin in secondary prevention of recurrent VTE events in high-risk patients
and superior to placebo in lower risk patients.  The safety profile of dabigatran etexilate from 
the pivotal studies is consistent with the available safety data from other indications.  The 
most common related adverse events (AE) for dabigatran etexilate included bleeding and GI 
AEs (e.g., dyspepsia and gastritis) however, dabigatran etexilate had fewer major or clinically 
relevant bleeding events compared to warfarin.  
The safety of dabigatran etexilate vs warfarin in VTE patients has not been assessed in 
routine clinical practice.  However, dabigatran etexilate safety has been assessed in patients 
being treated for nonvalvular AF in a study of elderly Medicare patients [P14-15648].  A total 
of 67,494 dabigatran etexilate patients and 273,920 warfarin patients were eligible for the 
study.  Compared with warfarin, dabigatran etexilate use was associated with a reduced risk 
of ischemic stroke, intracranial hemorrhage, and mortality but with an increased risk of 
gastrointestinal bleeding. The increased risk of gastrointestinal bleeding occurred in women 
aged ≥75 years and to men aged ≥85 years.  
7.3
RATIONALE FOR THE STUDY
The collection of data under conditions of routine clinical practice is important for studying 
large patient numbers that include a broad spectrum of co-morbidities and co-medication use 
with the use of a new drug.  Observational studies can provide supplementary data, including 
safety data with available doses of NOACs (e.g., 75 mg, 110 mg and 150 mg dabigatran 
etexilate) and health care resource utilization.  This can complement previously collected data 
from randomized clinical trials, which generally have stricter entry criteria and structured 
monitoring schemes. This can lead to the exclusion of significant patient segments. But even 
patients theoretically eligible might often not be included in clinical trials, especially older, 
frail, and presumably non adherent/persistent patients. These facts make it desirable to 
generate high-quality non-trial data to complement the evidence obtained from clinical trials. 
With the recent approval of NOACs for the treatment and prevention of recurrent VTE, the 
use of older, traditional treatments, such as VKA, may change, and it is therefore important to 
understand how patients with different characteristics are treated under conditions of routine 
clinical practice.  In addition, there may be geographical or regional differences in treatment 
patterns based on a number of factors, including patient co-morbidities and co-medication use 
or cost and access to newer therapies.
Dabigatran etexilate safety and efficacy with the 150 mg b.i.d. dose has been demonstrated in 
large randomized clinical trials for several indications (e.g., VTE, stroke prevention in AF). 
However, the safety and effectiveness of 110 mg b.i.d. dabigatran etexilate compared with 
VKA for treatment of VTE has not been investigated in randomized clinical trials.  Health 

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authorities, however, have requested the lower dose (110 mg b.i.d) for use in the treatment of 
VTE in special populations (e.g., elderly or patients concomitantly taking verapamil).  This 
observational study provides an opportunity to collect clinical data in a broader patient 
population including all available dosages of dabigatran etexilate.  

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8.
RESEARCH QUESTION AND OBJECTIVES
There are two primary objectives in this study:
Objective 1:
To characterize the DVT / PE patient population including the initial 
acute event phase.  All patients with a DVT and/or PE will be 
enrolled for cross-sectional characterization of the VTE patient 
population and descriptions of current treatment patterns, and 
stratified by geographical location.
Objective 2:
To analyze the safety and effectiveness of dabigatran etexilate
regimens in the treatment of DVT and PE over 1 year of follow-up 
in comparison to a VKA regimen.  
Additional further exploratory objectives are:

To evaluate geographical variations in health care resource utilization and patient 
satisfaction with their treatment in routine clinical practice.

To conduct stratified analysis for the safety and effectiveness of dabigatran etexilate
according to dose. 
The following research questions will be investigated:

With the approval of dabigatran etexilate and other NOACs, what treatments are 
being administered for acute VTE in routine clinical practice in the different regions 
of the world?    

When presenting with an acute VTE event, what factors influence the choice of 
treatment for the event?

What is the safety and effectiveness of dabigatran etexilate versus VKA under 
conditions of routine clinical practice?

What health care resources are utilized in patients who are treated with dabigatran 
etexilate or VKA for an acute VTE under conditions of routine clinical practice?  

For patients who are treated with either dabigatran etexilate or VKA, what is patients’
satisfaction with their treatment under conditions of routine clinical practice?

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
RE-COVERY is a large, multi-national, multi-center observational study based on new data 
collection.  The study will enroll and characterize all patients diagnosed with an acute DVT 
and/or PE. Patients treated with dabigatran etexilate or VKA will be followed up for the 
occurrence of outcome events for up to one year.  The design is outlined in Figure 9.1:1.
To investigate Objective 1, a cross sectional design is selected to characterize the DVT/PE 
patient population at the time of an acute VTE event.  The goal is to consecutively enroll 
approximately 6000 patients, who suffer from a DVT/PE independent of initial treatment 
choice and to allow for characterization of treatment patterns under conditions of routine 
clinical practice.  Sites should utilize consecutive unselected enrollment (i.e., each patient 
who is seen with a VTE should be enrolled regardless of what treatment was provided) to 
avoid bias associated with preferential selection by physicians / site staff for the first 
objective (characterization of patient population).  Patients should be enrolled ideally within 
14 days of their acute VTE however sites will have up to 6 months to enroll the patient.
For Objective 2, that will compare patients who are being treated with dabigatran etexilate or 
VKA, a cohort design was selected to allow for comparisons between the two groups of 
patients regarding major and clinically relevant non-major bleeding events (primary safety 
outcome measure), and symptomatic recurrent DVT and PE events, including VTE-related 
mortality (primary effectiveness outcome measure). For the second objective, a balanced 
enrollment approach should be used so that the number of VKA patients does not vastly 
outnumber the dabigatran etexilate patients and both patient groups are collected at similar 
time points (i.e., for each dabigatran etexilate patient enrolled, the next VKA patient with the 
same index event (DVT/PE) should be recruited ideally at the same study site).  Since the 
severity of the disease, treatment patterns and patient characteristics may differ considerably 
between patients with a DVT versus a PE, the treatment arms should have roughly equal 
numbers of patients with DVT and PE.  To ensure global representation, regional recruitment 
caps will be employed to minimize under-or over-representation from a particular region.  
Patients should be enrolled ideally within 14 days but not more than 30 days of their acute 
VTE.
Figure 9.1:1
Study design

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9.2
SETTING
It is planned that approximately 6000 patients will be enrolled for Objective 1 and up to 5000 
patients will be enrolled for Objective 2 from approximately 300 sites around the world.  
Figure 9.2:1
Enrollment of patients into the study
Participating countries require the approval of dabigatran etexilate for the VTE indication 
prior to study initiation within that country.  Selected sites should include those physicians 
(e.g., specialists and general practitioners) and facilities (e.g., general practice offices, 
specialist offices, hospitals, outpatient-care centers and anticoagulation clinics) that reflect 
the clinical practice within that country. A robust site feasibility process will be undertaken to 
ensure that the participating sites represent the standard of care within that country.  A pre-
screening log will record minimal information about all potential patients (e.g., all patients 
who present with a VTE, age and gender will be collected if permissible by local law and if 
patient provided consent to participate in the study).  This log will be maintained in the 
Investigator site file (ISF).

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9.2.1
Inclusion criteria
1. Written informed consent provided by the patient or the patient’s legal representative
in accordance with local regulations
2. Diagnosis of an acute DVT irrespective of location and/or PE (For objective 1, 
assessment of patient for study participation should be done ideally within 14 days but 
not more than 6 months after diagnosis of the acute VTE.  For Objective 2, patient 
assessment should occur ideally within 14 days but not more than 30 days from 
diagnosis)
3. Age ≥ 18 years
4. For Objective 2, the planned anticoagulation therapy should be for at least 3 months
5. For Objective 2, dabigatran etexilate and VKA patients should be available for 
follow-up data collection (clinic or via phone) at the specified timeframes 
9.2.2
Exclusion criteria
1. On active or prophylactic anticoagulation therapy for conditions other than VTE.
Ongoing anticoagulation treatment due to history of previous VTE is not considered 
an exclusion criterion. Anticoagulation therapy given for planned surgery is not 
considered an exclusion criterion.
2. Current participation in a clinical trial for VTE indication or current use of an 
unapproved (i.e., investigational) drug
The exclusion criteria were chosen for safety reasons and the number of patients thus
excluded should be minimal.  
9.2.3
Removal of subjects from the study
A patient can be withdrawn from the study for the following reasons:
1. A patient withdraws consent, without the need to justify the decision.
2. The patient was erroneously included in the study.
Boehringer Ingelheim (BI) 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 enrollment goals overall or at a particular study site
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the study,  
3. Violation of applicable sections of Good Clinical Practice (GCP), Good 
Pharmacoepidemiology Practice (GEP), the study protocol, or the contract by a study 
site or investigator.
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).

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9.2.4
Visit schedule
Collection of data in the study should be managed during routine practice visits or through 
telephone contacts with the patient, and follow the schedule in Table 9.2.4:1 as closely as 
possible.  
Table 9.2.4:1
Schedule of data collection time-points
Baseline At hospital 
discharge
(or 14 
days)1
3 
months
6 
months
12 
months
All patients
X
X
DE or VKA 
patients 
followed for 
1 year
(objective 2 
only)
X
X
X
X
X
1. Data will be collected at the date of hospital discharge or at 14 days post diagnosis, 
whichever is later.
Baseline
The “baseline” procedures and data to be collected may be done in one visit or over a series 
of contacts occurring after the acute VTE event based on information in the patient’s medical 
record and/or information that is reported by the patient. Treatment with some NOACs (e.g., 
dabigatran etexilate or edoxaban) requires 5 to 10 days of pre-treatment with parenteral 
therapy; therefore, additional data will be collected according to the flowcharts (Table 9.3.1:1
and 9.3.1:2) at hospital discharge or 14 days after baseline, whichever is later.    
Follow-up 
Only patients who are treated with dabigatran etexilate or VKA are eligible to participate in 
the second objective that will include follow-up for up to 12 months after the index event. 
Balanced enrollment should be followed with regards to the treatment (i.e., dabigatran 
etexilate or VKA) and the type of index event (e.g., DVT or PE or DVT and PE).  The 
decision to enroll a dabigatran etexilate or VKA patient for follow-up should be made as soon 
as the dabigatran etexilate or VKA has been prescribed and the patient has signed the study
informed consent form (in accordance with local regulations).  Patients should not be 
excluded from participation due to early outcome events (e.g., bleeding events). Data from all 
visits conducted under usual practice should be recorded in the electronic data capture (EDC) 
system at each data collection time-point even if the patient stops or changes treatment for the 
VTE event.  Follow-up should be conducted by in-person clinic visits ideally.  However, if no 
follow-up clinic visit occurs as part of clinical practice within one month of the planned data 
collection time-point (refer to Table 9.3.1:2), then follow-up contact with patient will be done 
by telephone, and email, if available.   

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If a patient discontinues the study for any reason, a follow-up assessment should be 
performed at the time of study discontinuation, if possible.
If the treatment for a patient changes during the study the following guidance should be 
followed:

An objective 1 patient whose anticoagulation treatment is switched to DE or VKA can 
be enrolled into objective 2 as long as inclusion criteria 2 and 4 are met

An objective 2 patient whose anticoagulant treatment is switched will be followed-up 
per protocol, including ePROs

An objective 2 patient who stops taking anticoagulation treatment will be followed-up 
per protocol but will discontinue ePROs.
9.3
VARIABLES
9.3.1
Data points
Table 9.3.1:1
Flowchart for Objective 1 
Data collection time point
Baseline
At hospital 
discharge 
(or 14 
days)1
Informed consent 
X
Review of in- / exclusion 
criteria
X
Demographics
X
Medical history
X
VTE disease characteristics
X
X
Treatment for VTE 
X
X
Height 
X
Weight
X
Blood pressure and heart rate
X
Collect Laboratory data (if 
available)
X
Adverse drug reactions
(ADR)2
X
X
Adverse events with fatal 
outcomes2
X
X
Concomitant therapy
X
Completion of patient 
participation 
X 
1. Data will be collected at the date of hospital discharge or at 14 days post diagnosis, 
whichever is later.
2. For collection and reporting of ADRs and AEs with fatal outcome please refer to Section 
11.2.

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Table 9.3.1:2
Flowchart for Objective 2 
Data collection time point
Baseline
At hospital 
discharge 
(or 14 
days)1
3 months
6 months
1 year
Informed consent 
X
Review of in- / exclusion 
criteria
X
Demographics
X
Medical history
X
VTE disease characteristics
X
X
Treatment for VTE 
X
X
X
X
X
Concomitant diseases
X
X
X
X
Height 
X
Weight
X
X
X
X
Blood pressure and heart rate
X
Collect Laboratory data (if 
available)
X
X
X
X
X
Adverse drug reactions
(ADR)2
X
X
X
X
X
Adverse events with fatal 
outcomes2
X
X
X
X
X
Outcome events
X
X
X
X
X
Morisky Medication 
Adherence Scale
X
X
X
Health resource utilization
X
X
X
PACT-Q2
X
X
X
Concomitant therapy
X
X
X
X
X
Completion of patient 
participation 
X
Vital status collection3
X
X
X
1.
Data will be collected at the date of hospital discharge or at 14 days post diagnosis, 
whichever is later
2. For collection and reporting of ADRs and AEs with fatal outcome please refer to 
Section 11.2. 
3. Vital status will be collected if the patient declines further clinic visits.  See also 9.3.3.
9.3.1.1
Baseline visit data points
The Flowchart (Table 9.3.1:1 and Table 9.3.1:2) outlines all of the data points to be collected.  
No study procedures or data recorded in the EDC system should be performed unless the 
patient has consented to participate in the study or a waiver has been obtained in accordance 
with local regulations. As in any observational study, patients will be managed according to 
local clinical practice. The choice of treatment is solely at the discretion of the participating 
physicians. This means there are no additional medical or procedural risks to patients by 

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participating in this study. No additional medical procedures are required, over and above 
those that the patient would receive if not enrolled.

Review of in- and exclusion criteria

Demographic data will include year of birth, gender, race (as allowed by local 
regulations), insurance status 

Height, weight, blood pressure, and heart rate

Available laboratory data (e.g., serum creatinine, hemoglobin, and INR)

Information regarding the index VTE event including: 
o
date of diagnosis, 
o
risk factors for VTE (i.e., if the VTE was provoked or unprovoked), 
o
clinical signs and symptoms and
o
the following variables based on objective testing (e.g. Venous compression 
ultrasonography, venography for DVT CT, MRI and any other examination 
that is deemed relevant per routine clinical practice for DVT diagnosis
or ventilation-perfusion (V-Q) lung scan, pulmonary angiography or spiral  
(helical) computed tomography scan for PE):

Date of diagnostic testing

Location, extent and severity of venous thrombus

Impression or findings

Treatment for VTE should include all treatment details including specific therapies
provided for the event, start date(s) and stop dates (if applicable), dosage, planned 
treatment duration, and rationale for treatment choice.

Medical history including current concomitant diseases, history of previous VTE (if 
any) risk factors (i.e., if the VTE was provoked or unprovoked) for VTE re-
occurrence and risk factors for bleeding.

Concomitant therapies that are being currently used by the patient including the name 
of the therapy and indication.
9.3.1.2
Hospital discharge or at 14 days after diagnosis of VTE event (whichever occurs 
later)
For Objective 1, the additional data points will include:

Any changes to the treatment for the VTE event

Date of hospital discharge, if patient was admitted to hospital
For Objective 2, the additional data points will include: 

Any changes in VTE disease characteristics and/or treatment for the VTE event

Concomitant diseases (current, any changes)

Available laboratory data that is associated with outcome events (e.g., complete blood 
count (CBC) for major and clinically relevant non major bleeding events)

INR for VKA patients

Date of hospital discharge, if patient was admitted to hospital.  

Changes in concomitant therapies

Information on any outcome events that may have occurred since study enrollment

Adverse drug reactions

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9.3.1.3
Follow-up visit data points
The flowchart (Table 9.3.1:2) outlines all of the data points to be collected for patients who 
are followed.

Type of data collection (i.e., based on routine clinic visit or telephone contact)

Concomitant diseases (current, any changes)

Available laboratory data that is associated with outcome events (e.g., CBC for major 
and clinically relevant non major bleeding events)

INR for VKA patients

Anticoagulation treatment (current, any changes (start or stop dates) including 
adherence, reasons for dose change).  Adherence will be assessed using the Morisky 
Medication Adherence Scale (refer to the Annex 3.1).

Changes in concomitant therapies

Information on any outcome events that may have occurred since the previous visit.  
If the specific reversal agent for dabigatran is given, information surrounding the 
clinical circumstances, treatment, and clinical outcome will be collected on the CRF.

Adverse drug reactions

PACT-Q2 to be completed by the patient (collection of the PACT-Q2 should occur as 
close to the data collection time-point as possible).  Refer to the Annex 3.2.

Details of health care resources utilization including:
o
Date, reason and duration of hospitalization occurring 
o
Date and reason for visit to ER
o
Need to visit treating physician due to recurrent VTE event, bleeding event or 
for dose adjustment of anticoagulant therapy
o
For patients treated with VKA only:

The number of INR measurements and where the INR blood samples
were drawn (e.g., physician’s office, anticoagulation clinic, hospital, 
outpatient laboratory, self-monitoring) 

At the 3 month data collection time-point only, the following details 
should be collected:

The distance traveled to have the INR measured

The time spent traveling to have the INR measured

If public transportation was used 

If private transportation was used
9.3.2
Outcome measures
For Objective 1: 
The following primary outcome measures will be analyzed on data that is collected at the 
time of the acute VTE event:

Demographic information (age and gender)

VTE event information (event type and treatment for event)
The following further outcome measures will be analyzed on the collected baseline data:

co-medication

co-morbidities,

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
basic physical examination data

laboratory information 

VTE event information including location, extent and severity of the thrombus 

VTE risk factors

history of VTE event 

bleeding risk
For Objective 2:
The following primary outcomes will be analyzed from time of diagnosis of the index event 
to 12 months post diagnosis:

Primary safety outcome measure: ISTH Major bleeding and ISTH clinically relevant 
non major bleeding (CRNMB)

Primary effectiveness outcome measure:  symptomatic recurrent VTE including VTE-
related mortality
The following secondary outcomes will be analyzed from the time of diagnosis of the index 
event to 12 months post diagnosis:

Recurrent DVT and/or PE 

VTE-related mortality

All-cause mortality
The following further outcomes will be analyzed from time of diagnosis of the index event to 
12 months post diagnosis:

Life-threatening bleeding events

Acute coronary syndrome (ACS)

Serious adverse drug reactions

Net clinical benefit (NCB)

Satisfaction with anticoagulation treatment (PACT-Q2)

Health care resource utilization
9.3.3
Assessment of outcome measures
Major bleeding, defined as meeting one or more of the following ISTH criteria [R05-0344, 
P11-05406]:

Overt bleeding associated with a reduction in hemoglobin of at least 20 grams per liter 
or leading to a transfusion of at least 2 units of blood or packed cells

Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal, 
or intramuscular with compartmental syndrome, retroperitoneal bleeding, intra-
articular bleeding or pericardial bleeding
Life-threatening bleeding, as defined as meeting one or more of the following criteria:

Symptomatic intracranial bleed

Reduction in hemoglobin of at least 50 grams per liter

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
Transfusion of at least 4 units of packed cells, associated with hypotension requiring 
the use of intravenous inotropic agents

Necessitated surgical intervention

Fatal bleeding
Clinically relevant, non-major bleeding, defined as meeting one or more of the following 
ISTH criteria [P15-12889]  

Any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit the 
criteria for the ISTH definition of major bleeding but does meet at least one of the 
following criteria:
o
requiring medical intervention by a healthcare professional
o
leading to hospitalization or increased level of care
o
prompting a face to face (i.e., not just a telephone or electronic 
communication) evaluation
Recurrent DVT and/or PE:  All recurrent VTE require objective verification by definitive 
diagnostic evaluation:

any suspected DVT must be confirmed by venous compression ultrasonography 
conventional venography, CT or MRI to be entered as recurrent DVT in the CRF 

any suspected PE must be confirmed by one of the following:  V-Q lung scan, 
pulmonary angiography, or spiral (helical) CT to be entered as recurrent DVT in the 
CRF
Deaths:  Deaths will be classified as being: 

bleeding related (including bleeding events that contributed to deaths), 

VTE related (including VTE events that contributed to death based on investigator 
clinical judgment) and 

other.
ACS: will include ST elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and 
unstable angina (UA) [P13-10618].

STEMI:  must have cardiac marker evidence of myocardial necrosis (e.g. positive
cardiac troponin (Tn) or creatinine kinase isoenzymes CKM and CKB (CK-MB)) and 
new (or presumably new, if no prior electrocardiogram (ECG) is available) ST 
segment elevation or left bundle branch block on admission ECG.

NSTEMI: will have cardiac marker evidence of myocardial necrosis (positive Tn or 
CK-MB) without new ST segment elevation.

UA: is angina pectoris with any 1 of the 3 following features:
o
Angina occurring at rest and prolonged (usually ≥10 min)
o
New-onset angina of at least Canadian Cardiovascular Society (CCS)
classification III severity
o
Recent acceleration of angina reflected by an increase in severity of at least 1 
CCS class to at least CCS class III.  The patient must also not have any 
biochemical evidence of necrosis.
Serious adverse drug reactions:  refer to Section 11.1 and 11.2 for serious criteria and 
reporting requirements.

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NCB: the event rate of recurrent symptomatic VTE or VTE-related mortality plus the major 
bleeding event rate will be compared for dabigatran etexilate versus VKA. [P14-17361]
Treatment adherence:  adherence will be assessed using the Morisky Medication Adherence 
Scale.
Treatment persistence:  will be assessed as time from treatment onset until permanent 
treatment discontinuation.
Exposure:  will be assessed based on the anticoagulation treatment start date, dosage and the 
reported end date.
Perception of anticoagulation treatment satisfaction will be assessed using the PACT-Q2 
(administered at follow-up time-points for those patients followed under Objective 2).
Health care resource utilization will be assessed as number of hospital admissions, 
emergency room visits, and physician’s office visits calculated per-patient-per-month to 
account for variable follow-up time. 
Vital status:  if a patient is enrolled for follow-up (Objective 2) and then declines to return for 
clinic visits, the patient’s vital status should be collected and reported after one year.  If any 
outcome events (e.g., bleeding events, recurrent VTEs or other adverse drug reactions 
(ADRs)) occur, details should be recorded in the electronic Case Report Form (eCRF) and 
reported as appropriate.  If the patient died, available data (e.g. date of death, cause of death) 
should be reported.
9.4
DATA SOURCES
RE-COVERY is a study based on new data collection. Data will be collected based on 
assessment of the patient (e.g., physical examination and patient interview), review of 
hospital / medical records and available laboratory and diagnostic test reports.  Patient 
reported outcomes will be assessed using validated questionnaires.  Refer to Section 9.10.2.1
for details regarding source documents.
9.5
STUDY SIZE
For Objective 1:
It is planned that a total of approximately 6000 patients will be enrolled. This is not based on
formal sample size calculations as there are no hypotheses to be tested. If eligible, patients 
included in the cross-sectional assessment (Objective 1) who are treated with dabigatran 
etexilate and a similar number of those treated with VKA will be followed (Objective 2).
Baseline demographics and characteristics of the patient population will be described by 
estimates and confidence intervals (CI) overall and by relevant categories as specified in 
Section 9.7 and the statistical and epidemiological analysis plan SEAP. Categorical attributes 
will be estimated with the precision (i.e., width of descriptive 95% CI) described in Table 
9.5:1, according to sample size and prevalence of the attribute.

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Table 9.5:1
Width of 95% CI by sample size and prevalence of attribute
Prevalence of attribute
Sample size (overall or per subgroup)
500
1000
2000
3000
4000
6000
5%
Expected n
25
50
100
150
200
300
95% CI width
4.03
2.81
1.96
1.59
1.38
1.12
10% Expected n
50
100
200
300
400
600
95% CI width
5.46
3.82
2.68
2.18
1.88
1.54
20% Expected n
100
200
400
600
800
1200
95% CI width
7.20
5.05
3.55
2.90
2.50
2.04
30% Expected n
150
300
600
900
1200
1800
95% CI width
8.21
5.77
4.06
3.28
2.86
2.34
40% Expected n
200
400
800
1200
1600
2400
95% CI width
8.77
6.17
4.34
3.54
3.06
2.49
50% Expected n
250
500
1000
1500
2000
3000
95% CI width
8.94
6.29
4.43
3.61
3.12
2.54
* Calculations are based on the Clopper-Pearson method.
For example, if an attribute has a prevalence of 40% in the population of acute VTE patients, 
with a sample size of 2000 patients, this proportion can be estimated with a precision of 
4.34% (i.e. width of 95% CI). Furthermore, in a subgroup that consists of 1000 patients, this 
same proportion can be estimated with a precision of 6.17%.
For Objective 2:
Baseline data will be summarized descriptively for eligible patients using a similar approach 
as described above for Objective 1. Categorical attributes will be estimated with the precision 
described in Table 9.5:1. For example, a sample size of 2000 patients allows a population 
attribute with a 30% prevalence to be estimated with a precision of 4.06%.
The primary and further outcomes will be analyzed for dabigatran etexilate patients in 
comparison to VKA patients over 1 year. To support the sample size determination, 
assessments were performed for the primary safety outcome of major and clinically relevant 
non-major bleeding based on the observed event rate for VKA in the pooled analysis of the 
RE-COVER and RE-COVER II trials, and additional assumptions including a 1:1 ratio of 
dabigatran etexilate and VKA patients, one-year fixed follow-up, one-sided alpha of 0.025, 
and 15% loss to follow-up (Table 9.5:2). With these assumptions, a total sample size of 5000 

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patients would provide 90% power to detect a hazard ratio of 0.69 between dabigatran 
etexilate and VKA.
Table 9.5:2
Sample size assessments for the primary safety outcome of major and 
clinically relevant non-major bleeding
Event rates
Hazard 
ratio
Power
Loss to 
follow-up
Total N
Dabigatran
etexilate
VKA*
5.3%
7.7%
0.69
90%
15%
5000
5.2%
7.7%
0.67
4500
5.1%
7.7%
0.65
4000
4.9%
7.7%
0.63
3500
4.7%
7.7%
0.60
3000
* The VKA event rate is based on the pooled RE-COVER and RE-COVER II analysis of the 
oral treatment period [P13-09153, U12-3306-01]. The Freedman formula was used for the 
calculations.
In combination with additional non-statistical considerations, a total sample size of up to 
5000 patients (i.e., 2,500 patients per group) is deemed appropriate for the planned analyses 
for Objective 2 on an exploratory basis. The actual power of the analysis will be dependent 
upon the actual rates of major bleeding and loss to follow-up in the current study, the 
covariates included in the statistical model, their degree of imbalance between the treatment 
groups, their strength of association with the outcome, and the use of propensity score 
matching, and may therefore be different.
9.6
DATA MANAGEMENT
A study specific Data Operations Plan will be created to describe the software, functions, 
processes and specifications used for data collection, cleaning and validation.  The eCRF will 
include programmable edit checks to obtain feedback if data is missing, out of range, illogical 
or potentially erroneous. These rules may encompass simple checks such as range validation 
or presence/absence of data, or complex cross-form verifications such as lab result deviations 
across visits. Concurrent manual data review may be performed based on parameters outlined 
in the Data Operations Plan.  Ad hoc queries to sites may be generated and followed up for 
resolution.  
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 ICH
guideline E6R1 regarding electronic study data handling.  Patient confidentiality will be 
strictly maintained.

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9.7
DATA ANALYSIS
9.7.1
Study design
For Objective 1, the population of acute VTE patients will be described using cross-sectional 
data collected at baseline. No follow-up data will be collected or analyzed. 
For Objective 2, both cross-sectional data at baseline and longitudinal follow-up data up to 1 
year will be collected for acute VTE patients treated with either dabigatran etexilate or VKA. 
Baseline data will be described using a cross-sectional approach. Data from the longitudinal 
follow-up will be summarized descriptively, and dabigatran etexilate patients will be 
analyzed in comparison to VKA patients using multivariable regression, as well as analytical
methods based on propensity scores.
Due to the nature of this observational study, there is no (confirmatory) hypothesis testing 
foreseen in a strict statistical sense. Analyses are descriptive in nature and CIs and p-values 
from statistical models are used for explorative purposes.
9.7.2
Planned analyses
Analyses will be performed by BI or BI’s designees.
The main analysis population will consist of all eligible patients (i.e., all patients who provide 
informed consent and fulfill all inclusion criteria and no exclusion criteria).
Summary statistics for continuous variables will include the N, mean, standard deviation, 
minimum, Q1 (lower quartile), median, Q2 (upper quartile), and maximum value; tabulations 
of categorical variables will include all possible categories and will display the number of 
observations per category as well as percentages based on the relevant denominators. 
Estimates from statistical models will be presented with 95% CIs.
Additional details of the planned analysis will be provided in the statistical and 
epidemiological analysis plan (SEAP).
9.7.2.1
Main analyses
For Objective 1:
Baseline patient demographics and disease characteristics, including information regarding 
the index VTE event, medical history, concomitant therapies, and laboratory data as specified
in Section 9.3.1, will be summarized descriptively for all eligible patients overall and by 
anticoagulation treatment at baseline. The analysis will be repeated by region and by 
additional relevant patient attributes.
Patterns of anticoagulation treatment at baseline will be described overall, by region, and by 
additional relevant patient attributes.
For Objective 2:
Patient demographics and disease characteristics at baseline as described above for Objective 
1 will be summarized descriptively for all eligible patients by their initial anticoagulation
treatment (i.e. dabigatran etexilate or VKA). This analysis will be repeated by region and by 
additional relevant patient attributes.

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Given the observational nature of this study, patients in the dabigatran etexilate and VKA 
groups may differ with regard to important baseline demographics and disease characteristics. 
When the target sample size is reached, propensity scores that estimate the probabilities that 
patients would be initiated on dabigatran etexilate will be calculated using a logistic 
regression model that considers variables that are risk factors for the occurrence of VTE or 
bleeding events or affect the choice of anticoagulation treatment (details of the model will be 
provided in the SEAP). Overlap of propensity scores between the dabigatran etexilate and 
VKA groups will be examined to assess the comparability of the two patient populations, and 
to estimate the loss of patients from the comparative analysis if trimming or matching is to be 
performed.
The primary safety and effectiveness outcomes will be analyzed for dabigatran etexilate
patients in comparison to VKA patients using Cox proportional hazards models. Confounding 
will be controlled for using appropriate methods, including adjustment of covariates in the 
Cox regression model, trimming of extreme observations, and/or propensity score matching, 
based on the evaluation of the comparability of dabigatran etexilate and VKA patients (i.e. 
overlap of propensity scores) as described above. Details of the analytical methods and the 
selection rules of the appropriate analysis strategy will be provided in the SEAP.
The primary comparative analyses will be based on the actual anticoagulation treatment the 
patients receive (i.e. “as treated” analysis). Patients who complete the planned 
anticoagulation treatment prior to one year or discontinue initial anticoagulation treatment 
permanently will be censored at date of last drug intake + 6 days for both dabigatran etexilate
and VKA or at first intake of another relevant anticoagulation treatment, whichever occurs 
first. A patient is considered to have permanently stopped initial anticoagulation treatment if 
other relevant anticoagulation treatment is initiated or otherwise dependent on the duration of 
treatment interruption. Details of the censoring rules will be described in the SEAP.

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9.7.2.3
Safety analyses
Statistical analysis and reporting of safety data will be descriptive in nature, will be based on 
BI standards, and will focus on ADRs to dabigatran etexilate or VKA. No hypothesis testing 
is planned.
Occurrences of ADRs will be analyzed relative to the number of patients treated as well as 
observed person-years (i.e., time at risk). Safety analysis will be based on the concept of 
treatment emergent ADRs. Patients will be analyzed according to the anticoagulation
treatment received at the time of the event. If no concurrent anticoagulation treatment is 
administered, then events occurring within a washout period of 6 days after discontinuation 
of anticoagulation treatment will be assigned to the last treatment given. This washout period 
will also be included as time at risk for derivation of total person-years. ADRs that deteriorate 
under treatment will also be considered as “treatment emergent”. Events occurring prior to 
first intake of anticoagulation treatment prescribed at baseline, during periods without any 
anticoagulation treatment (excluding washout periods), or after the end of the 1 year follow-
up (excluding washout periods) will not be considered treatment emergent events and will not 
be included in the summary tables.
The following parameters will be included in the safety analyses:

Adverse drug reactions 

Adverse drug reactions leading to discontinuation of anticoagulation treatment

Serious adverse drug reactions

Adverse drug reactions leading to deaths
9.7.2.4
Schedule of planned analyses
For Objective 1:
It is planned that one interim analysis will be performed when approximately 3,000 patients 
have been enrolled. The final analysis as specified in Section 9.7.2 will be performed once 
the data collection is completed, the data sets are cleaned, and the database is locked for 
Objective 1.
For Objective 2:
It is planned that an interim analysis that assesses the comparability of patients in the 
dabigatran etexilate and VKA groups based on propensity scores will be performed when the 
target sample size is reached (see details in Section 9.7.2.1). The final analysis as specified in 
Section 9.7.2 will be performed once the data collection is completed for Objective 2.
Additional reports (e.g. for region/country-specific analyses) may be prepared if deemed 
appropriate and will be specified in the SEAP.

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9.7.3
Handling of missing data
Every reasonable attempt will be undertaken to ensure completeness of data collection.
Imputation will be permitted, if deemed appropriate and on a case-by-case basis, depending
on the extent and distribution of missing values, and will be described in the SEAP.
For Objective 1, the presence of missing data is expected to be low, since the variables are 
expected to be collected in routine clinical practice and should therefore be available in the 
patient’s medical record.
For Objective 2, the percentage of and reason for loss to follow-up will be summarized by 
treatment and by other relevant factors (e.g., region). In addition, if the proportion of loss to 
follow-up is large enough to warrant further investigation, baseline characteristics will be 
described for patients who were lost to follow-up in comparison to patients who have 
completed follow-up.
9.8
QUALITY CONTROL
The Clinical Research Associate (CRA) or on-site monitor may review the eCRFs and 
written informed consents.  Approximately 15% of sites will have a routine on-site visit by 
the CRA.  All sites will receive remote monitoring phone calls throughout the study.  The 
accuracy of the data will be verified by reviewing the source documents with the entered 
data.  Details of the monitoring activities will be outlined in the Site Management Plan.
9.9
LIMITATIONS OF THE RESEARCH METHODS
For Objective 1, a cross sectional design will be used to characterize the VTE patient 
population.  Consecutive unselected enrollment will be employed to ensure that specific types 
of patients are not selected by site staff to participate. It is expected that accrual for this 
objective will occur rapidly as there are no requirements to ensure balance between the types 
of anticoagulation treatments prescribed.  To ensure global representation, regional 
recruitment caps will be employed to minimize over- or under-representation from a 
particular region.  There is also the potential that prescribing patterns may change for a 
variety of reasons such as antidotes for NOACs are approved for use.
For Objective 2, two cohorts of patients (dabigatran etexilate vs VKA) will be followed for 
12 months.  VKA has been the mainstay of treatment of VTE for many years.  It is widely 
available, affordable, but does require regular INR monitoring.  Dabigatran etexilate is more 
expensive, may or may not be reimbursed, but does not require the continual INR monitoring.  
There are a number of different types of bias that could influence the analysis from these 
cohorts such as selection bias and recall bias.
The study is designed to collect new data.  The entry criteria are non-restrictive which will 
permit the enrollment of a broad patient population.  The choice of treatment is at the 
discretion of the investigator.  Therefore the data collected in this study should reflect the 
treatment patterns and patient characteristics under conditions of routine clinical practice.   
The primary safety outcome measure is major bleeding and clinically relevant non-major 
bleeding events (CRNMB) according to the ISTH definition.  Clinically relevant non-major 
bleeding events and major bleeding events were combined in the phase III clinical trial safety 
analysis, and, although it is probable that clinically relevant non-major bleeding events may 

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be harder to detect, new recommendations for the ISTH are now available for reporting them 
in a consistent manner in a routine clinical practice setting. The enlargement of the main 
variable, in a validated and consistent manner, will maximize the efficiency of the clinical 
trial in order to not prolong excessively the study duration. As a result, the primary safety 
outcome measure will include major bleeding and CRNMB events and the sample size 
calculations have been adjusted accordingly.
Selection bias:
Selection bias could occur at both the site level and the patient level. If sites where dabigatran 
etexilate is used frequently differ systematically with respect to patient or the routine 
procedures from sites that use dabigatran etexilate less frequently, the between site difference 
could lead to non-comparability between the dabigatran etexilate patients. To minimize the 
site level selection bias, a robust site feasibility process will be performed to ensure that the 
participating centers that have access to all available treatment options for VTE that are 
approved for use in that country and that those physicians follow the standard of care that is 
accepted within the country.  
Selection bias at the patient level could occur if sites preferentially enroll specific patients 
into the study.  To minimize selection bias at the patient level, at a minimum, dabigatran 
etexilate and VKA treatment options must be available.  Consecutive unselected enrollment 
of patients will be used for the recruitment of patients into Objective 1 which will address 
issues associated with preferential patient selection by the site staff however; this could 
potentially create other sources of bias.  A balanced approach for enrollment will be used for 
Objective 2. The balanced approach will also minimize effects of potential temporal changes 
in prescribing patients, as dabigatran etexilate and VKA patients are enrolled in similar time 
periods.
Survivor bias:
Survivor bias can occur if patients who have had an early outcome event (e.g. major 
bleeding) are not enrolled into the study due to the early outcome event.  To minimize 
survivor bias, sites will receive training to ensure that they understand the importance of not 
selectively excluding patients who may have had an early outcome event.  Sites will also be 
encouraged to enroll patients as soon as possible after the patient’s VTE has been diagnosed
so that early outcome events will be captured as part of follow-up.  
Channelling bias:
Channelling bias is a type of selection bias that can occur due to preferential prescribing in 
relation to different risks for events of interest. For example, if dabigatran etexilate is 
prescribed more frequently to high risk patients than to other treatments, a high rate of 
outcome events could be expected in the dabigatran etexilate group.  In order to control for 
potential channelling bias, an interim assessment will be conducted to monitor the 
comparability of important patient baseline characteristics. The use of estimated propensity 
score methods can further address bias.
Loss to follow-up:
All efforts will be made to minimize loss to follow-up in patients who are enrolled into the 
follow-up cohort (Objective 2).  Patients who are lost to follow-up will be characterized and 
compared to the remaining patients and the reason and time point of lost to follow-up will be 
evaluated.

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Recall bias:
Recall bias refers to the phenomenon when the outcomes of treatment (either good or bad) 
may influence the patient’s recollection of events prior to, or during, the treatment.  To 
minimize recall bias, patient reported outcomes and adherence will be assessed using 
validated scales that are administered at regular time intervals so that the time intervals from 
event to collection of the PRO will be limited.  
Confounding:
Confounding occurs when an observed association is due to three factors:  the exposure, the 
outcome of interest and a third factor which is independently associated with both the 
outcome of interest and the exposure.  Statistical techniques, such as adjustment for 
covariates, stratified analysis, matching, etc. can be used to correct for identified 
confounders.  However, as only major confounders for selected research questions can be 
captured, residual (unmeasured) confounding may remain.  The employed methods are 
described in the data analysis section.
In addition, sites will be encouraged to enroll patients as soon as possible after the acute 
index event.
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
All of the clinical data and site/investigator characteristics will be captured via a web-based 
EDC system.  The site staff will enter and edit the data via a secure network, with secure 
access features (username, password and secure identification – an electronic password 
system). A complete electronic audit trail will be maintained.  The Investigator will approve 
the data using an electronic signature that is 21 CFR Part 11 compliant.
Patients must not be identified on the eCRF by name.  Appropriately coded identification (i.e. 
Patient numbers) must be used. The Investigator must make a separate confidential record of 
these details (Patient enrollment log) to permit the identification of all patients enrolled in the 
study in case follow-up is required.  Any supporting documentation must be redacted of any 
patient identifying information and the patient ID number must be clearly written on the 
documents.
9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.  Data 
entered into 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 

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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. The approved clinical data entered into the EDC system will be made available to 
the investigator at the end of the study.  The investigator will be responsible for retaining all 
records pertaining to the study as specified in the contract and per local regulations.
9.10.2.2
Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all informed consent forms and related 
source data / documents. CRFs/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. Food 
and Drug Administration). The CRA/ on site monitor and auditor may review all 
CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 9.10.2.1.
9.10.3
Completion of study
The EC/competent authority (CA) in each participating EU member state needs to be notified 
about the end of the study (last patient/patient out) or early termination of the study.

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the applicable sections of GCP, guidelines for 
Good Epidemiological Practice (GEP) [R10-4560], Good Pharmacoepidemiology Practice 
(GPP) [R09-0182], relevant BI Standard Operating Procedures and local regulations. 
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/International Conference on Harmonization (ICH) GCP / GPP if applicable.
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.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required documentation has been reviewed and 
approved by the respective IRB / IEC and 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 BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorized 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by BI, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 IRB / IEC and the regulatory 
authorities i.e. the Competent Authority (CA).

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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 unfavorable 
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 drug reaction
An adverse drug 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 drug 
reactions may arise from use of the product within or outside the terms of the marketing 
authorization or from occupational exposure. Conditions of use outside the marketing 
authorization include off-label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalization, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for safety monitoring and safety assessment within this study, e.g. the 
potential for AEs based on knowledge from other compounds in the same class.

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The following are considered as AESIs:
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files.
Collection and reporting of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
For Objective 1 
Data collected on the eCRF once informed consent or waiver is obtained
•
Serious and non-serious ADRs to DE from the time of VTE until the end of the study for 
a patient 
•
ALL serious and non-serious ADRs other than DE from time of informed consent/ waiver
until the end of the study for a patient 
•
All AEs with fatal outcome 
Data reported on the NIS AE form once informed consent or waiver is obtained
•
Serious and non-serious ADRs to DE from the time of VTE until the end of the study for 
a patient
•
All AEs with fatal outcome in patients exposed to DE
For Objective 2
Data collected on the eCRF once informed consent is obtained
•
Serious and non-serious ADRs to DE and VKA from the time of VTE until the end of the 
study for a patient. 
Data reported on the NIS AE form once informed consent is obtained
•
Serious and non-serious ADRs to DE form time of VTE until the end of the study for 
a patient
•
All AEs with fatal outcome in patients exposed to DE
All ADRs, including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event

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The definition of an adverse drug reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse drug 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities

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Pregnancy
In rare cases, pregnancy might occur in a study. Once a female subject has been enrolled into 
the study, after having taken dabigatran etexilate, the investigator must report any drug 
exposure during pregnancy 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. 
Timelines for Expedited Reporting of AEs on the NIS AE form and Drug Exposure During 
Pregnancy
Type of Report
Timeline
All Serious ADRs associated with 
dabigatran etexilate (DE)
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to dabigatran etexilate (DE)
immediately within 24 hours
All non-serious ADRs associated with 
dabigatran etexilate (DE)
7 calendar days
All pregnancy monitoring forms
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor or the Sponsor’s 
designee (i.e., the CRO) upfront via telephone. This does not replace the requirement to 
complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form if applicable.
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 
dabigatran etexilate 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 marketing authorization 
holder (MAH) according to local and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Any publication must be consistent with the BI publication policy and guided by the current 
version of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals: 
Writing and Editing for Biomedical Publication of the International Committee of Medical 
Journals.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P08-08095 
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, 
Comerota AJ. Antithrombotic therapy for venous thromboembolic 
disease: American College of Chest Physicians evidence-based 
clinical practice guidelines (8th edition). Chest 2008; 133 (6) 
(Suppl), 454S - 545S.
P11-05406
Lip GYH, Andreotti F, Fauchier L, Huber K, Hylek E, Knight E, 
Lane DA, Levi M, Marin F, Palareti G, Kirchhof P.  Bleeding risk 
assessment and management in atrial fibrillation patients: a 
position document from the European Heart Rhythm Association, 
endorsed by the European Society of Cardiology Working Group 
on Thrombosis. Europace 2011;13, 723 – 746.
P11-07302
Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, 
Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite 
P, Vedantham S, White RJ, Zierler BK, American Heart 
Association Council on Cardiopulmonary, Critical Care, 
Perioperative and Resuscitation, Council on Peripheral Vascular 
Disease, and Council on Arteriosclerosis, Thrombosis and 
Vascular Biology
Management of massive and submassive pulmonary embolism, 
iliofemoral deep vein thrombosis, and chronic thromboembolic 
pulmonary hypertension: a scientific statement from the American 
Heart Association. Circulation 2011; 123 (16), 1788 – 1830.
P12-01518
Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann 
HJ.
Executive summary: antithrombotic therapy and prevention of 
thrombosis, 9th ed: American College of Chest Physicians 
evidence-based clinical practice guidelines. Chest 2012; 141 (2) 
(Suppl), 7S - 47S.
P12-04560
Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep 
vein thrombosis. Lancet 2012; 379 (9828), 1835 – 1854.
P13-09153
Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, 
Mismetti P, Schellong S, Feuring M, Peter N, Friedman J
Safety of dabigatran etexilate versus warfarin for acute venous 
thromboembolism: pooled analyses of RE-COVER and RE-
COVERII. ISTH 2013, 24th Cong of the International Society on 
Thrombosis and Haemostasis (ISTH) and 59th Ann Mtg of the 
Scientific and Standardization Committee (SSC), Amsterdam, 29 
Jun - 4 Jul 2013 (Oral Presentation).

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P13-10618
Cannon CP, et al. 2013 ACCF/AHA key data elements and 
definitions for measuring the clinical management and outcomes of 
patients with acute coronary syndromes and coronary artery 
disease: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Clinical 
Data Standards (Writing Committee to Develop Acute Coronary 
Syndromes and Coronary Artery Disease Clinical Data Standards): 
developed in collaboration with American College of Emergency 
Physicians, Emergency Nurses Association, National Association 
of Emergency Medical Technicians, National Association of EMS 
Physicians, Preventive Cardiovascular Nurses Association, Society 
for Cardiovascular Angiography and Interventions, Society of 
Cardiovascular Patient Care, and Society of Thoracic Surgeons. J 
Am Coll Cardiol 2013;61 (9), 992 – 1025.
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 KA.  Cardiovascular, bleeding, 
and mortality risks in elderly Medicare patients treated with 
dabigatran etexilate or warfarin for non-valvular atrial fibrillation.
Circulation 2015; 131 (2), 157 – 164.
P14-16368
Konstantinides SV, et al. 2014 ESC guidelines on the diagnosis 
and management of acute pulmonary embolism: the Task Force for 
the Diagnosis and Management of Acute Pulmonary Embolism of 
the European Society of Cardiology (ESC), endorsed by the 
European Respiratory Society (ERS). Eur Heart J 2014; 35 (43), 
3033 – 3080.
P14-17361
P15-12889
Amin A, Jing Y, Trocio J, Lin J, Lingohr-Smith M, Graham J.
Evaluation of net clinical benefits of new oral anticoagulants used 
for acute venous thromboembolism treatment vs. standard therapy.
AHA QCOR 2014, American Heart Association's Sci Sess on 
Quality of Care and Outcomes Research, Baltimore, 2 - 4 Jun 2014
Circ Cardiovasc Qual Outcomes 2014: 7 (Suppl 1), Abstr 301.
Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, for the 
Subcommittee on Control of Anticoagulation. Definition of
clinically relevant non-major bleeding in studies of anticoagulants 
in atrial fibrillation and venous thromboembolic disease in non-
surgical patients: communication from the SSC of the ISTH. J 
Thromb Haemost 2015; 13: 2119–26
R04-2883
European Agency for the Evaluation of Medicinal Products 
(EMEA)
Committee for Proprietary Medicinal Products (CPMP): note for 
guidance on clinical investigation of medicinal products for the 
treatment of venous thromboembolic disease (London, 16 
December 1999, CPMP/EWP/563/98). In: London: The European 

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Agency for the Evaluation of Medicinal Products, Evaluation of 
Medicines for Human Use , 1 - 6 (1999).
R05-0300
Diehm C, Stammler F, Amendt K. Die tiefe Venenthrombose: 
Diagnostik und Therapie. Dtsch Aerztebl 1997; 94 (6), A301 -
A311.
R05-0344
Schulman S, Kearon C. Subcommittee on Control of 
Anticoagulation of the Scientific and Standardization Committee 
of the International Society on Thrombosis and Haemostasis.  
Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J 
Thromb Haemost. 2005: 3, 692 – 694.
R09-0182
Guidelines for good pharmacoepidemiology practices (GPP).
Pharmacoepidemiol Drug Saf 2008;17, 200 – 208.
R09-0200
Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, 
Brecht JG, Greer IA, Heit JA, Hutchinson JL, Kakkar AK, Mottier 
D, Oger E, Samama MM, Spannagl M. VTE Impact Assessment 
Group In Europe (VITAE).  Venous thromboembolism (VTE) in 
Europe: the number of VTE events and associated morbidity and 
mortality. Thromb Haemost 2007; 98, 756 – 764.
R09-4888
Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, 
Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A.
The risk of recurrent venous thromboembolism after discontinuing 
anticoagulation in patients with acute proximal deep vein 
thrombosis or pulmonary embolism. A prospective cohort study in 
1,626 patients.
Haematologica 2007; 92 (2), 199 – 205.
R10-4560
International Epidemiological Association (IEA) Good 
epidemiological practice (GEP): IEA guidelines for proper conduct 
of epidemiological research. http://www.ieaweb.org/iea/ (2007).
R12-2550
Gallagher AM, Vries F de, Plumb JM, Hass B, Clemens A, Staa 
TP van. Quality of INR control and outcomes following venous 
thromboembolism. Clin Appl Thromb Hemost 2012; 18(4) 370-
378.
R12-2781
Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk 
factors for venous thromboembolism. Arterioscler Thromb Vasc 
Biol 2012; 32 (3), 563 – 568.
R13-4066
Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom 
J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, 
Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff 
MW, Ohman EM, Steg PG, White H. Standardized bleeding
definitions for cardiovascular clinical trials: a consensus report 
from the Bleeding Academic Research Consortium. Circulation 
2011: 123 (23), 2736 – 2747.

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R15-0778
Dlott JS, George RA, Huang X, Odeh M, Kaufman HW, Ansell J, 
Hylek EM. National assessment of warfarin anticoagulation 
therapy for stroke prevention in atrial fibrillation.  Circulation 
2014; 129 (13), 1407 – 1414.
R15-1423
Kcentra (prothrombin complex concentrate (human)) (CSL 
Behring) (U.S. prescribing information, revised: March 2014R). 
13.2
UNPUBLISHED REFERENCES
U09-1400
A phase III, randomised, double blind, parallel-group study of the 
efficacy and safety of oral dabigatran etexilate (150 mg bid) compared 
to warfarin (INR 2.0-3.0) for 6 month treatment of acute symptomatic 
venous thromboembolism, following initial treatment (5-10 days) with 
a parenteral anticoagulant approved for this indication. BI trial 
1160.53. 21 October 2009.
U10-2533
 A phase III,
randomised, multicenter, double-blind, parallel-group, active 
controlled study to evaluate the efficacy and safety of oral dabigatran 
etexilate (150 mg bid) compared to warfarin (INR 2.0-3.0) for the 
secondary prevention of venous thromboembolism. BI trial 1160.47. 
12 July 2011.
U11-2267-02
 Twice-daily oral direct thrombin 
inhibitor dabigatran etexilate in the long-term prevention of recurrent 
symptomatic venous thromboembolism in patients with symptomatic 
deep-vein thrombosis or pulmonary embolism. BI trial 1160.63. 29 
May 2012.
U11-2298
A phase III randomised, double 
blind, parallel-group study of the efficacy and safety of oral dabigatran 
etexilate (150 mg bid) compared to warfarin (INR 2.0-3.0) for 6 month 
treatment of acute symptomatic venous thromboembolism, following 
initial treatment for at least 5 days with a parenteral anticoagulant 
approved for this indication
(RE-COVER II). BI trial 1160.46. 22 September 2011.
U12-3306-01
  Clinical safety summary.  23 
April 2013.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents have not been finalized at the time of protocol finalization.  The 
final version of these documents will be archived in the study master file.
Number
Document 
Reference Number
Date
Title
1
Site Management Plan
2
Data Operations Plan
3
Statistical and Epidemiological 
Analysis Plan
4
List of Investigators

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS

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Doc.Ref. EMEA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended)
Adopted by the ENCePP Steering Group on 14/01/2013
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 page number(s) of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). Note, the Checklist is a supporting document and does not replace 
the format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP). 
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Study title:
ChaRactErization of patients following aCute venous thrOmboembolism (VTE) and assessment of 
safety and effectiveness of dabigatran etexilate(DE) in the tReatment and secondarY prevention of 
acute deep vein thrombosis (DVT) and pulmonary embolism (PE) in comparison to vitamin K 
antagonist (VKA) in routine clinical practice  - RE-COVERY DVT/PE
Study reference number:
1160.188
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1
Does the protocol specify timelines for
1.1.1 Start of data collection1
15
1.1.2 End of data collection2
15
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
15
1.1.6 Final report of study results
15
Comments:
Status reports will be generated on a regular basis and are dependent on recruitment, strategic 
decisions and regulatory requests, if applicable.
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
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)
18-19
2.1.2 The objectives of the study?
20
2.1.3 The target population? (i.e. population or subgroup 
to whom the study results are intended to be generalised)
21
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested? 
2.1.5 If applicable, that there is no a priori hypothesis?
Comments:
No formal hypothesis are being tested. The research questions, study objectives and analysis are 
defined in the protocol.
Section 3: Study design 
Yes
No
N/A
Page 
Number(s)
3.1
Is the study design described? (e.g. cohort, case-control, 
randomised controlled trial, new or alternative design) 
21
                                                
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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Section 3: Study design 
Yes
No
N/A
Page 
Number(s)
3.2
Does the protocol specify the primary and secondary 
(if applicable) endpoint(s) to be investigated? 
28-29
3.3
Does the protocol describe the measure(s) of effect? 
(e.g. relative risk, odds ratio, deaths per 1000 person-years, 
absolute risk, excess risk, incidence rate ratio, hazard ratio, 
number needed to harm (NNH) per year) 
32-34
Comments:
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1
Is the source population described?
21
4.2
Is the planned study population defined in terms of: 
4.2.1 Study time period? 
15 & 21
4.2.2 Age and sex? 
23
4.2.3 Country of origin? 
2
4.2.4 Disease/indication? 
23
4.2.5 Co-morbidity? 
4.2.6 Seasonality? 
4.3
Does the protocol define how the study population will 
be sampled from the source population? (e.g. event or 
inclusion/exclusion criteria) 
23
Comments:
Patient recruitment is not restricted. Therefore co-morbitities are not part of the entry criteria. The 
planned recruitment period is over 2 years with no reference to seasonality.
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1
Does the protocol describe how exposure is defined 
and measured? (e.g. operational details for defining and 
categorising exposure)
32
5.2
Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study)
35
5.3
Is exposure classified according to time windows? (e.g. 
current user, former user, non-use)
35
5.4
Is exposure classified based on biological mechanism of 
action and taking into account the pharmacokinetics 
and pharmacodynamics of the drug? 
5.5
Does the protocol specify whether a dose-dependent or 
duration-dependent response is measured? 
23
Comments:
No pharmacokinetic information will be collected in this study. 

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Section 6: Endpoint definition and measurement 
Yes
No
N/A
Page 
Number(s)
6.1
Does the protocol describe how the endpoints are 
defined and measured? 
30-32
6.2
Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study) 
32-34
Comments:
Section 7: Confounders and effect modifiers 
Yes
No
N/A
Page 
Number(s)
7.1
Does the protocol address known confounders? (e.g. 
collection of data on known confounders, methods of 
controlling for known confounders) 
38-40
7.2
Does the protocol address known effect modifiers? 
(e.g. collection of data on known effect modifiers, anticipated 
direction of effect) 
38-40
Comments:
Section 8: Data sources 
Yes
No
N/A
Page 
Number(s)
8.1
Does the protocol describe the data source(s) used in 
the study for the ascertainment of: 
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
32
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
or values, claims data, self report, patient interview including 
scales and questionnaires, vital statistics, etc.)
29-30
8.1.3 Covariates?
27-29
8.2
Does the protocol describe the information available 
from the data source(s) on: 
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily dosage, 
prescriber)
30
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)
27-29
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.) 
27-29
8.3
Is a coding system described for: 
8.3.1 Diseases? (e.g. International Classification of Diseases 
(ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities(MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
8.4
Is the linkage method between data sources described? 
(e.g. based on a unique identifier or other) 
40

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Comments:
Coding system will be described in detail in the data management plan.
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
31-33
Comments:
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of excess risks? 
34-36
10.2 Is the choice of statistical techniques described? 
34-36
10.3 Are descriptive analyses included? 
34-36
10.4 Are stratified analyses included? 
34-36
10.5 Does the plan describe the methods for adjusting for 
confounding?
34-36
10.6 Does the plan describe methods addressing effect 
modification?
34-36
Comments:
Additional information will be included in the SEAP.
Section 11: Data management and quality control
Yes
No
N/A
Page 
Number(s)
11.1 Is information provided on the management of missing 
data?
37
11.2 Does the protocol provide information on data storage? 
(e.g. software and IT environment, database maintenance 
and anti-fraud protection, archiving)
33
11.3 Are methods of quality assurance described?
37
11.4 Does the protocol describe possible quality issues 
related to the data source(s)?
37-39
11.5 Is there a system in place for independent review of 
study results? 
Comments:
There are no plans for an independent adjudication or data monitoring committee at time of 
protocol finalization.
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1 Does the protocol discuss:
12.1.1 Selection biases?
37-39
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
37-39

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Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.2 Does the protocol discuss study feasibility? (e.g. sample 
size, anticipated exposure, duration of follow-up in a cohort 
study, patient recruitment)
19-20
12.3 Does the protocol address other limitations? 
37-39
Comments:
Section 13: Ethical issues 
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics Committee/ Institutional 
Review Board approval been described? 
39
13.2 Has any outcome of an ethical review procedure been 
addressed? 
13.3 Have data protection requirements been described? 
39
Comments:
The protocol has not yet been submitted to an ethics review board.
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1 Does the protocol include a section to document future 
amendments and deviations? 
12
Comments:
Section 15: Plans for communication of study results
Yes
No
N/A
Page 
Number(s)
15.1 Are plans described for communicating study results 
(e.g. to regulatory authorities)? 
46
15.2 Are plans described for disseminating study results 
externally, including publication?
Comments:
Publication plan to be developed as a separate document.
Name of the main author of the protocol:
Date: dd/mm/year
Signature: 

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ANNEX 3. ADDITIONAL INFORMATION

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ANNEX 3.1
MORISKY MEDICATION ADHERENCE SCALE

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ANNEX 3.2
PERCEPTION OF ANTICOAGULANT TREATMENT 
QUESTIONNAIRE 2

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BI Study Number 1160.188
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