Drug Persistence/Adherence in Patients Being Treated With Dabigatran Etexilate or VKA for Stroke Prevention in Non-valvular Atrial Fibrillation (SPAF)
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

024-MLW-90-118-01_RD-01; V1
Boehringer Ingelheim Pharma 
GmbH & Co. KG
ABCD
Observational plan
Non-interventional study
Boehringer Ingelheim Pharma 
GmbH & Co. KG
BI No.:
1160.218
Product:
Pradaxa® (dabigatran etexilate)
Title:
Drug persistence/adherence in patients being treated with 
Pradaxa® (dabigatran etexilate) or vitamin K antagonists (VKA) 
for stroke prevention in non-valvular atrial fibrillation (AF)
Clinical
monitor:
Scientific co-
ordinator:
Date of
observational plan:
Final version: 04.06.2014
Version 1.0
Scheduled time
frame of the NIS:
FPI September 2014
LPO April 2016
Page 1 of 42
Confidential
Boehringer Ingelheim
This observational plan is the property of Boehringer Ingelheim Pharma GmbH & Co. KG 
and may not be disseminated, copied, published or otherwise used, either in full or in part, 
without express agreement.

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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Signature page 1
SCIENTIFIC CO-ORDINATOR
Study title:
Drug persistence/adherence in patients being treated with Pradaxa®
(dabigatran etexilate) or vitamin K antagonists (VKA) for stroke prevention
in non-valvular atrial fibrillation (AF)
Study number: 1160.218
I hereby declare that I will observe the requirements of the observational plan,
including all the attachments.
Name:
Date:
__________________________
Signature:
__________________________

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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Signature page 2
LOCAL SIGNATURES
Study title:
Drug persistence/adherence in patients being treated with Pradaxa®
(dabigatran etexilate) or vitamin K antagonists (VKA) for stroke prevention
in non-valvular atrial fibrillation (AF)
Study number: 1160.218
Trial Clinical Monitor
Date: _______________
______________________
Trial Statistician
Date: _______________
Global Biometrics and Clinical Applications / BDM (BCA)
_______________________

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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Observational plan – Synopsis
BI OPU
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Trial clinical 
monitor
BI study number
1160.218
Study title
Drug persistence/adherence in patients being treated with Pradaxa®
(dabigatran etexilate) or vitamin K antagonists (VKA) for stroke 
prevention in non-valvular atrial fibrillation (AF)
Study objectives
Primary study objective:

To compare persistence in patients being treated with
dabigatran etexilate or VKA.
Other study objectives:

To compare adherence in patients being treated with 
dabigatran etexilate or VKA

To record the reasons for permanent treatment 
discontinuation
Target group (sites)
1000: about 670 community-based primary care internists or 
general practitioners and 330 cardiologists

Open, prospective, observational study (PMS study) in 
accordance with section 4(23) and section 67(6) AMG: 
all enrolled AF patients will be observed over 12 months 
during treatment with dabigatran etexilate or VKA.

In this NIS, information about dabigatran etexilate/VKA
persistence and adherence will be collected in 4000 AF 
patients.
Visit 1 (start of observation)

Patient data: sociodemographic data (sex, age, height, 
weight, education, marital status, health insurance status)

Case history of non-valvular atrial fibrillation (AF): 
disease onset, data on disease severity (individual 
components of the CHA2DS2-VASc score) and bleeding 
risk (individual components of the HAS-BLED score)

Start of treatment with dabigatran etexilate (110 or 
150 mg hard capsules) or VKA (start date)

Concomitant medication: antiarrhythmics, 
antihypertensives, lipid-lowering agents, other 
prescription-only medicines

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
Number of other prescription-only medicines and
frequency of daily administration (other than dabigatran 
etexilate/VKA)

Other relevant comorbidities
Visit 2 (after about 3 months of use of dabigatran etexilate or 
VKA)

Recording of continuation of treatment with dabigatran 
etexilate (including dosage) or VKA since visit 1

Onset of adverse events since visit 1

Discontinuation (stop date) of treatment with dabigatran 
etexilate or VKA since visit 1
•
Reasons for discontinuation of treatment with
dabigatran etexilate or VKA
•
Antithrombotic therapy after discontinuation of 
treatment with dabigatran etexilate or VKA
•
In the event of treatment discontinuation, all 
emergent adverse events (AE) will be recorded in the 
eCRF up to 30 days after the end of therapy.
Visit 3 (after about 6 months of use of dabigatran etexilate or 
VKA)

Recording of continuation of treatment with dabigatran 
etexilate (including dosage) or VKA since visit 2

Onset of adverse events since visit 2

Discontinuation of treatment (stop date) with dabigatran 
etexilate or VKA since visit 2
•
Reasons for discontinuation of treatment with
dabigatran etexilate or VKA
•
Antithrombotic therapy after discontinuation of 
treatment with dabigatran etexilate or VKA
•
In the event of treatment discontinuation, all 
emergent adverse events (AE) will be recorded in the 
eCRF up to 30 days after the end of therapy.

Regular use of dabigatran etexilate or VKA by means of 
the Morisky score

Number of prescription-only medicines and frequency of 
daily administration

Recording of disease severity (CHA2DS2-VASc score) 
and bleeding risk (HAS-BLED score)

Other relevant comorbidities
Visit 4 (after about 9 months of use of dabigatran etexilate or 
VKA)

Recording of continuation of treatment with dabigatran 
etexilate (including dosage) or VKA since visit 3

Onset of adverse events since visit 3

Discontinuation of treatment (stop date) with dabigatran 

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etexilate or VKA since visit 3
•
Reasons for discontinuation of treatment with
dabigatran etexilate or VKA
•
Antithrombotic therapy after discontinuation of 
treatment with dabigatran etexilate or VKA
•
In the event of treatment discontinuation, all 
emergent adverse events (AE) will be recorded in the 
eCRF up to 30 days after the end of therapy.
End of observation/Visit 5 (after about 12 months of use of
dabigatran etexilate or VKA)

Recording of continuation of treatment with dabigatran 
etexilate or VKA since visit 4

Onset of adverse events since visit 4

Discontinuation of treatment (stop date) with dabigatran 
etexilate or VKA since visit 4
•
Reasons for discontinuation of treatment with
dabigatran etexilate or VKA
•
Antithrombotic therapy after discontinuation of 
treatment with dabigatran etexilate or VKA
•
In the event of treatment discontinuation, all 
emergent adverse events (AE) will be recorded in the 
eCRF up to 30 days after the end of therapy.

Number of prescription-only medicines and frequency of 
daily administration

Recording of disease severity (CHA2DS2-VASc score) 
and bleeding risk (HAS-BLED score)

Other relevant comorbidities
Number of patients:
4000;
2000 on dabigatran etexilate; 2000 on VKA
Control group?
yes ( x )       no ()    
Duration of 
observation / 
number of visits
About 12 months per patient
5 visits (inclusion visit and after about 3, 6, 9, 12 months)
Main inclusion/
exclusion criteria
Inclusion criteria:

Newly prescribed treatment with Pradaxa® (dabigatran 
etexilate)/VKA in the indication “Stroke prevention in non-
valvular atrial fibrillation” (AF) respecting the indication
and contraindications as described in the respective 
Summary of Product Characteristics for Pradaxa® 110 mg or 
150 mg hard capsules or the appropriate VKA (patients are
eligible for both Pradaxa® and VKA therapy).

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
Treatment with dabigatran etexilate or VKA is given in 
accordance with the respective Summaries of Product 
Characteristics. The routine diagnostic procedures and 
treatment that would be undertaken irrespective of the study 
are unaffected.

Only patients who are eligible both for therapy with
Pradaxa® and for therapy with VKA in accordance with the 
respective Summaries of Product Characteristics will be 
documented (patients eligible for VKA and Pradaxa®)

Patients must have signed the patient consent form prior to 
inclusion in the NIS.
Exclusion criteria:

Patients with the general and special contraindications 
mentioned in the packaging leaflet or Summary of Product 
Characteristics must not be included.

Patients participating at the same time or within the last 30 
days in another NIS or an interventional clinical trial must 
not be included.

Patients treated with anticoagulants for a condition other 
than non-valvular atrial fibrillation must not be included.

Pradaxa® and VKA should not be used during pregnancy 
and lactation. Pregnant or breastfeeding women must 
therefore not be included in the NIS.
Target parameters
Primary endpoint:

Proportion of patients still being treated at the time of the 
12-month visit with the initially allocated anticoagulant,
defined as Kaplan Meier estimate at 12 months for
persistence, stratified for dabigatran etexilate and VKA. 
Persistence is defined as the time between initiation and 
permanent termination of therapy. The start of treatment 
(documented in the CRF of visit 1) is documented as the 
start date and the date of discontinuation of treatment with 
Pradaxa® or VKA as the time of permanent termination of 
therapy.
Secondary endpoints:

Proportion of patients with low, medium or high adherence
at the time of the 6-month visit, stratified for dabigatran 
etexilate and VKA; categorisation is done on the basis of the
Morisky questionnaire.

Reasons for permanent treatment discontinuation.
Safety parameters
During this NIS, all emergent adverse events (AE) will be recorded 

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in the eCRF over a period of about 12 months.
In the event of premature treatment discontinuation, all emergent 
adverse events (AE) will be recorded in the eCRF up to 30 days 
after the end of therapy.
Monitoring: source 
data verification?
yes (x)      no ( )   10% SDV
Drug dispensing
Prescription in accordance with the Summary of Product 
Characteristics
Ethics Committee 
approval?
yes (x)
Informed consent 
required?
yes (x)       no ( )
Scheduled study 
duration
Initiation (FPI): 
September 2014
Last patient out (LPO):
April 2016
Report
Report available: 
July 2016

024-MLW-90-118-01_RD-01; V1
Flowchart
Investigations / measure
Visit 1
(first examination)
Visit 2
(after about
3 months)
Visit 3
(after about
6 months)
Visit 4
(after about
9 months)
Visit 5
(after about
12 months)
Sociodemographic data
X
AF history
X
CHA2DS2-VASc -/ HAS-BLED score
X
X
X
Other relevant comorbidities
X
X
X
Recording of the start date of therapy with dabigatran 
etexilate (including dosage) or VKA
X
Concomitant medication including frequency of 
administration
X
X
X
Recording of continuation of initial oral
anticoagulation (dabigatran etexilate including dosage
or VKA)
X
X
X
X
Regular use of dabigatran etexilate or VKA (Morisky
score)
X
Date of discontinuation of treatment with dabigatran 
etexilate or VKA, including reasons for 
discontinuation
X
X
X
X
In the event of discontinuation of the initial
anticoagulation: antithrombotic therapy after
discontinuation
X
X
X
X
Adverse events*
X
X
X
X
* In the event of premature treatment discontinuation, all emergent adverse events (AE) will be recorded in the eCRF up to 30 days after the end of therapy.

024-MLW-90-118-01_RD-01; V1
Contents
Signature page 1........................................................................................................................ 2
Signature page 2........................................................................................................................ 3
Observational plan – Synopsis .................................................................................................. 4
Flowchart................................................................................................................................... 9
Contents................................................................................................................................... 10
List of abbreviations................................................................................................................ 12
1
Introduction ..................................................................................................................... 14
1.1
Medical background ................................................................................................. 14
1.2
Substance profile ...................................................................................................... 15
2
Rationale, objectives and risk-benefit analysis ............................................................... 16
2.1
Rationale for conducting the study........................................................................... 16
2.2
Study objectives........................................................................................................ 16
2.3
Risk-benefit analysis................................................................................................. 17
3
Description of study design and patient population........................................................ 17
3.1
General remarks on the study design and plan......................................................... 17
3.1.1
Administrative structure of the NIS................................................................... 17
3.2
Discussion of the study design ................................................................................. 18
3.3
Choice of patient population..................................................................................... 18
3.3.1
Main diagnosis .................................................................................................. 18
3.3.2
Inclusion criteria:.............................................................................................. 18
3.3.3
Exclusion criteria .............................................................................................. 19
3.3.4
Exclusion of patients from the NIS.................................................................... 19
4
Treatment......................................................................................................................... 20
4.1
Administered medications ........................................................................................ 20
4.1.1
Products............................................................................................................. 20
4.1.2
Allocation of patients and treatment ................................................................. 20
4.1.3
Dosage............................................................................................................... 20
4.1.4
Other.................................................................................................................. 21
4.2
Concomitant medication and restrictions ................................................................. 21
5
Recording and observation parameters ........................................................................... 21
5.1
Target parameters ..................................................................................................... 21
5.1.1
Primary and secondary endpoints..................................................................... 21
5.1.2
Recording of target parameters ........................................................................ 22

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5.2
Safety parameters...................................................................................................... 22
5.2.1
Safety endpoints................................................................................................. 22
5.2.2
Recording of adverse events.............................................................................. 23
5.3
Appropriateness of investigations............................................................................. 25
6
Observational plan........................................................................................................... 25
6.1
Timetable of visits .................................................................................................... 25
6.2
Details of visits ......................................................................................................... 26
7
Statistical analysis ........................................................................................................... 28
7.1
Statistical design model............................................................................................ 28
7.2
Null and alternative hypothesis ................................................................................ 28
7.3
Planned analyses....................................................................................................... 28
7.4
Procedure for missing data ....................................................................................... 31
7.5
Determination of number of patients........................................................................ 31
8
Declaration of consent, data protection, NIS documentation.......................................... 31
8.1
Study approval, patient information and consent ..................................................... 31
8.1.1
Administrative requirements ............................................................................. 31
8.1.2
Patient information and consent ....................................................................... 32
8.2
Data quality and assurance ....................................................................................... 32
8.2.1
Data protection.................................................................................................. 33
8.3
Documentation of the NIS........................................................................................ 33
8.3.1
Source data........................................................................................................ 33
8.3.2
Direct access to source data and documents .................................................... 33
8.3.3
Archiving of documents..................................................................................... 33
8.4
Listing and accelerated reporting procedure of adverse events................................ 34
8.5
Confidentiality statement.......................................................................................... 34
9
References ....................................................................................................................... 35
10
Attachments..................................................................................................................... 37

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List of abbreviations
AF
Atrial Fibrillation
AMG
German Medicines Act [Arzneimittelgesetz]
BfArM
Federal Institute for Drugs and Medical Devices
[Bundesinstitut für Arzneimittel und Medizinprodukte]
BI
Boehringer Ingelheim Pharma GmbH & Co. KG
CHA2DS2-VASc score
Congestive heart failure, Hypertension, Age (> 75), 
Diabetes mellitus, Stroke/TIA, Vascular disease, Age 65-74, 
Sex category
Cmax
Maximum Concentration
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for 
Adverse Events
CTMS
Clinical Trial Management System
eCRF
electronic Case Report Form
ECG
Electrocardiogram
FPI
First Patient In
HAS-BLED
Hypertension, Abnormal renal and liver function, Stroke (1 
point), Bleeding history or predisposition, Labile INR, Elderly 
(>65 years), Drugs and Alcohol
INR
International Normalised Ratio
LÄK
State Medical Association [Landesärztekammer]
LPO
Last Patient Out
MedDRA
Medical Dictionary for Regulatory Activities
Max
Maximum
mg
Milligram
Min
Minimum
N
Number
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for 
Adverse Events
NIS
Non-Interventional Study
OAC
Oral Anticoagulants
OPU
Operating Unit
pdf
Portable Document Format

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pH
Latin: potentia hydrogenii (power of hydrogen)
PMS
Postmarketing Surveillance
PS
Propensity Score
PV
Pharmacovigilance
(S)AE
(Serious) Adverse Event
SD
Standard Deviation
SDV
Source Data Verification
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
VFA
German Association of Research-Based Pharmaceutical 
Companies [Verband forschender Arzneimittelhersteller]
VKA
Vitamin K Antagonists
WHO-DD
World Health Organization Drug Dictionary

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1 Introduction
1.1 Medical background
Atrial fibrillation (AF) is a cardiac rhythm disorder that can occur episodically or 
persistently. During AF, unco-ordinated electromechanical activity of the cardiac atria 
occurs, triggered by rapidly succeeding, disorderly impulses that can in some cases be 
transmitted to the cardiac ventricles. AF is the most common cardiac arrhythmia and is 
associated with considerable morbidity and mortality, due in particular to a 4- to 5-fold 
increase in the risk of thromboembolic strokes (1).
Due to the high thromboembolic risk in atrial fibrillation, it is a fundamental aim of treatment 
to reduce the secondary complications associated with atrial fibrillation and in particular the 
risk of stroke. Oral anticoagulation is usually recommended for this purpose (1;2). In 
Germany, phenprocoumon is most frequently used for anticoagulation with a vitamin K 
antagonist (VKA) (3).
In order to maintain the level of therapeutic anticoagulation within an optimum target range 
during treatment with VKA, the coagulation capacity of the blood must be closely monitored 
(i.e. at least every 3 – 4 weeks) by means of the INR value (4). This usually requires a visit to 
a physician, who can take a blood sample and perform the analysis (where necessary also via 
an external laboratory) and any dosage adjustment necessary.
The use of VKA is associated with various measures that can make it more difficult to use 
these drugs correctly. The narrow therapeutic window of VKA requires routine laboratory 
monitoring of coagulation (INR 2-3). However, optimal INR adjustment is often not obtained 
in everyday patient care in Germany either. The interactions of VKA with a number of 
medicines and foodstuffs require close monitoring and dosage adjustments following a 
change of concomitant medication or dietary habits. A recent analysis of German health 
insurance data came to the conclusion that AF patients with a moderate stroke risk and 
without any observable contraindication to OACs received no OAC on up to half the patient 
days observed (5).

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1.2 Substance profile
Dabigatran etexilate is a synthetic, small-molecule, orally administered, direct inhibitor of the 
coagulation factor thrombin (an endogenous substance involved in the formation of blood 
clots, also known as factor II of the coagulation cascade). It is a medicinal product that 
reduces the risk of developing an obstruction of blood vessels in the brain or body (stroke or 
systemic embolism) as a result of the formation of blood clots in adult patients with certain 
heart rhythm disorders (atrial fibrillation; AF) and additional risk factors.
The prodrug dabigatran etexilate itself exhibits no pharmacological activity and is only 
bioactivated in vivo. Following oral administration, the compound is absorbed and 
hydrolysed by means of catalytic esterases in the liver and plasma to dabigatran. As a 
competitive, reversible direct inhibitor, dabigatran inhibits the serine protease thrombin in 
plasma. As thrombin causes the conversion of fibrinogen to fibrin in the coagulation cascade, 
its inhibition consequently prevents the development of a thrombus. In addition, dabigatran 
inhibits free and fibrin-bound thrombin and thrombin-induced platelet aggregation (6).
Dabigatran etexilate is available in hard capsules. The capsules contain pellets coated with 
dabigatran etexilate with a core of tartaric acid. This produces an acidic medium locally that 
allows absorption of the medicinal product relatively independently of variations in the pH of 
the gastric juice (6).
The absolute bioavailability of dabigatran etexilate after oral administration is approximately 
6.5%. Food does not affect the bioavailability of dabigatran etexilate but does delay the time 
to peak plasma concentration (Cmax) by about 2 hours (7).
Following oral administration of dabigatran etexilate to healthy subjects, the peak plasma 
concentration is reached within 2 hours in the fasting state (6). After repeated doses, a 
terminal half-life of about 12 – 14 hours has been measured (7).
VKA inhibit the hepatic synthesis of active coagulation factors (II, VII, IX and X) and
protein C and S from inactive precursors (precursor proteins). Activation of the precursor 
proteins by gamma-carboxylation requires vitamin K. The regeneration of biologically active 
vitamin K is inhibited by VKA. In addition, further vitamin K-dependent carboxylation 
reactions in other organs are inhibited by VKA (e.g. in bones, kidney, placenta) (8; 9).
Dabigatran etexilate differs from VKA in that it does not intervene in the hepatic synthesis of 
coagulation factors, but indirectly competitively inhibits a specific plasma factor. Routine 
monitoring in the form of coagulation tests is required during therapy with VKA, as opposed 
to with the use of dabigatran etexilate, because the therapeutic margin of VKA is small and 
the anticoagulant effect can be affected by many interactions with other medicinal products, 
but also with certain foodstuffs (9,10).
The pharmacodynamic effect of dabigatran sets in rapidly and also declines rapidly and 
therefore is easily controllable and predictable. That is an essential difference from the VKA,
which only become effective after a few days if the concentration of vitamin K-dependent 
coagulation factors has declined sufficiently and only become ineffective after a few days if 
there is once again sufficient production of these factors in the liver.

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2 Rationale, objectives and risk-benefit analysis
2.1 Rationale for conducting the study
As well as the challenges described above, treatment compliance (persistence and adherence) 
represents a significant factor affecting the success of treatment (11).
Persistence is defined as the time between initiation and termination of therapy (12).
Adherence describes whether patients take their medicine as prescribed. It comprises the 
initiation, implementation and termination of therapy (13). This compliance can be 
determined on the basis of the Morisky questionnaire. This consists of questions relating to 
intake behaviour (14 ). The questionnaire and its further developed version have already been 
used for assessing adherence during warfarin therapy, where it exhibited good validity (15,16).
There are a variety of reasons for poor treatment compliance. These include patient-related 
aspects (e.g. socioeconomic status, personal convictions), but also disease-related (e.g. 
symptom severity) and medication-related (e.g. frequency of intake, side effects) aspects (17).
This also applies particularly to patients with AF who require permanent oral anticoagulation 
(18). In terms of anticoagulation for the prevention of strokes, one important aspect is the fact 
that in the patients’ subjective view it does not improve their condition and only the absence 
of a negative event (e.g. stroke) motivates them to continue treatment. This could limit 
treatment compliance and reduce the acceptance of side effects.
In addition, it has not yet been elucidated whether omission of the routine monitoring of 
coagulation status during treatment with dabigatran etexilate and the associated feedback to 
patients has any effect on treatment adherence in everyday therapeutic use. An analysis of 
Canadian health insurance data shows that drug persistence following the initiation of 
everyday care is higher during treatment with dabigatran etexilate than during VKA therapy
(19).
No studies have yet been undertaken as to whether there are differences in persistence and 
adherence within the German care context between patients treated with Pradaxa® or VKA.
For this reason, a contribution to the resolution of this question constitutes a relevant gain in 
knowledge.
2.2 Study objectives
The objective of this open, prospective, controlled, multicentre, non-interventional cohort 
study (NIS) is to record the treatment compliance (measured as persistence and adherence) of
patients treated with dabigatran etexilate or VKA.
Primary study objective:

To compare persistence in patients treated with dabigatran etexilate or VKA.
Secondary study objectives:

To compare adherence in patients treated with dabigatran etexilate or VKA

To record the reasons for any treatment discontinuation

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2.3 Risk-benefit analysis
Treatment will be administered in accordance with the marketing authorisation of dabigatran 
etexilate or VKA for AF patients requiring permanent oral anticoagulation.
The medicinal products Pradaxa® or VKA used in this NIS are authorised in the Federal 
Republic of Germany.
The medicines under observation are not provided by the marketing authorisation holder but 
are prescribed by the participating physician in accordance with the indication.
The choice of treatment is at the sole discretion of the participating physicians. The NIS has 
no effect on the patient’s treatment. The decision to include a patient in an NIS is distinct 
from the decision to prescribe the medicinal product.
No additional medical procedures are required other than those which the patient would have 
received even if they were not included in the NIS. The treatment, including diagnosis and 
monitoring, follows the standard medical treatment practice.
There is therefore no risk to patients over and above the usual treatment risk for AF patients 
on anticoagulant therapy with dabigatran etexilate or VKA even outside the NIS.
3 Description of study design and patient population
3.1 General remarks on the study design and plan
This is an open, prospective, non-interventional study (NIS) in accordance with sections 4.23 
and 67.6 of the AMG.
The NIS is being conducted by Boehringer Ingelheim Pharma GmbH & Co. KG. The 
scientific co-ordinator i
.
Any changes in the study management in the course of the study will be notified in writing to 
the observing physicians where necessary.
3.1.1 Administrative structure of the NIS
About 10,000 potential sites spread over the whole of Germany (general practitioner and 
primary care internist practices as well as cardiology practices) will be reviewed by members 
of the Boehringer Ingelheim Pharma GmbH & Co. KG pharmaceutical sales force for their 
eligibility for participation in the study.
About 3000 sites interested in participating and able to document four patients treated with 
either dabigatran etexilate or VKA within a period of six months can be selected by 
Boehringer Ingelheim for possible participation. The 1200 sites that actually participate are 
chosen by randomisation. It will be assumed that, following the recruitment of about 1200 
sites, 1000 sites will actually actively document patients.
Of the 1000 active sites, approximately 2/3 (about 670) will be community-based primary 
care internists/general practitioners and approximately 1/3 (about 330) community-based 
cardiologists across Germany.
As a result of the random selection of participants, a high degree of representativeness of the 
collected data can be obtained and a selection bias in the choice of participating practices can 
be avoided.

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All sites and their employees involved in study participation will be trained before the start of 
the study in its content and the documentation process.
Following initiation, each doctor should document alternately the first successive eligible
patients for whom he has decided to prescribe therapy with dabigatran etexilate or VKA.
The rights and duties of the participating doctors and Boehringer Ingelheim Pharma GmbH & 
Co. KG derive from the contract concluded on the conduct of an NIS. The participating 
physicians undertake to conduct the NIS responsibly in accordance with the agreements made 
in the contract.
Boehringer Ingelheim Pharma GmbH & Co. KG will pay participating physicians 
compensation in accordance with the listing in the contract concluded with them.
3.2 Discussion of study design
The intention of this NIS is to collect data on the persistence and adherence to anticoagulant 
therapy of AF patients with dabigatran etexilate or VKA in daily practice.
An NIS appears the most suitable instrument for obtaining information about the use of 
medicines in everyday therapeutic practice and thus for investigating prospectively 
unresolved questions in everyday therapeutic practice as independently as possible.
A sample of 4000 patients offers the opportunity to document and assess the persistence and 
adherence to anticoagulant therapy of AF patients during therapy with dabigatran etexilate or 
VKA in a representative patient population.
3.3 Choice of patient population
The treatment decision is made independently of participation in this NIS and is taken before 
participation is considered.
A list of patients who have given their consent to participate in the NIS will be kept for each 
site. This list will be stored confidentially in the study folder.
3.3.1 Main diagnosis
Four thousand patients with non-valvular atrial fibrillation, in whom anticoagulant treatment
with Pradaxa® or VKA is indicated in accordance with the guidelines and in line with the 
Summary of Product Characteristics, must be observed in about 1000 practices (community-
based cardiologists and primary care internists / general practitioners) in this NIS.
Before the start of therapy with Pradaxa® or VKA, due note must be taken of the 
contraindications. See also the respective current Summaries of Product Characteristics of
Pradaxa® or the VKA used.
Patients treated with VKA must also theoretically be treatable with dabigatran etexilate to 
ensure comparability of the patient populations.
3.3.2
Inclusion criteria:
Patients can be included if all the following criteria are present:

Newly prescribed treatment with Pradaxa® (dabigatran etexilate)/VKA in the 
indication “Stroke prevention in non-valvular atrial fibrillation” (AF) respecting the 
indication and contraindications as described in the respective Summary of Product 

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Characteristics Pradaxa®110 mg or 150 mg hard capsules or the appropriate VKA 
(patients are eligible for both Pradaxa® and VKA therapy).

Only patients who are eligible both for therapy with Pradaxa® and for therapy with 
VKA in accordance with the respective Summaries of Product Characteristics are 
documented (patients eligible for VKA and Pradaxa®)

Treatment with dabigatran etexilate or VKA is given in accordance with the 
respective Summaries of Product Characteristics. The routine diagnostic procedures 
and treatment that would be undertaken irrespective of the study are unaffected.

Only patients on VKA therapy who would also be eligible for therapy with dabigatran 
etexilate in accordance with the Pradaxa® Summary of Product Characteristics are 
documented.

Patients must have signed the patient consent form before inclusion in the NIS.
3.3.3 Exclusion criteria

Patients with the general and special contraindications mentioned in the packaging 
leaflet or Summary of Product Characteristics must not be included.
The Summaries of Product Characteristics for Pradaxa® are contained in the NIS 
study folder in the register "Summaries of Product Characteristics".
For the selected VKA, the observing physician must use the current Summary of 
Product Characteristics of the product concerned for guidance.

Patients participating at the same time or within the last 30 days in another NIS or an 
interventional clinical trial must not be included.

Patients treated with anticoagulants for a condition other than non-valvular atrial
fibrillation must not be included.

Pradaxa® and VKA should not be used during pregnancy and lactation. Pregnant or 
breastfeeding women must therefore not be included in the NIS.
3.3.4 Exclusion of patients from the NIS
3.3.4.1 Exclusion of individual patients from the NIS
The individual patient has the right to withdraw their consent to participate in the NIS at any 
time. Discontinuation of participation in the NIS by the patient has no effect on the patient’s
routine treatment.
3.3.4.2 Termination of the NIS by the sponsor
Following the onset of one or all of the following events, the study can be terminated at the 
sponsor’s discretion:
•
Presence of medical or ethical reasons impacting on the continuation of the study in the
patients’ interests
•
Recruitment problems

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4 Treatment
4.1 Administered medications
4.1.1 Products
Treatment-naive AF patients will be treated with Pradaxa® hard capsules or VKA in 
accordance with the Summary of Product Characteristics:
Direct oral thrombin 
inhibitor:
Pradaxa® 150 mg hard capsules
Pradaxa® 110 mg hard capsules
Vitamin K antagonists
e.g. phenprocoumon
Pradaxa® 150 or 110 mg hard capsules contain dabigatran etexilate (active substance:
dabigatran).
The choice of VKA is at the discretion of the observing physician. There is no set dosage for 
these products.
The Summaries of Product Characteristics for Pradaxa® are contained in the NIS study folder 
in the register "Summaries of Product Characteristics".
For the selected VKA, the observing physician must use the current Summary of Product 
Characteristics of the product concerned for guidance (www.fachinfo.de).
4.1.2 Allocation of patients and treatment
Each physician must include the first 4 successive eligible AF patients to whom he has 
decided to prescribe anticoagulant therapy with either dabigatran etexilate or VKA.
Inclusions must be alternated in a ratio of 1 patient on dabigatran etexilate to 1 patient on 
VKA so as to ensure equal treatment group sizes. The consecutive inclusion of the first 4 
eligible AF patients is intended to prevent a selection bias in the choice of patients. 
To allow comparability of the patients between the cohorts, matched pairs of dabigatran 
etexilate and VKA patients are formed for the analysis.
The decision to treat is made irrespective of participation in this NIS and is taken before any 
consideration of participation.
4.1.3 Dosage
Treatment with dabigatran etexilate or VKA must be given in accordance with the data in the 
respective Summary of Product Characteristics and is based solely on medical therapeutic 
needs.
Pradaxa®
The recommended daily dose of Pradaxa® is 300 mg, taken in the form of one 150 mg 
capsule twice daily. Treatment should be long term.
For the following two patient groups, the recommended daily dose of Pradaxa® is 220 mg, 
taken as one 110 mg capsule twice daily:
• Patients ≥ 80 years

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• Patients receiving verapamil concomitantly.
For the following groups, a daily dose of 300 mg or 220 mg of Pradaxa® will be chosen on 
the basis of an individual assessment of the thromboembolic risk and the bleeding risk:
• Patients between 75 and 80 years old
• Patients with moderate renal impairment
• Patients with gastritis, oesophagitis or gastroesophageal reflux
• Other patients with an increased bleeding risk.
Note: The recommended doses in the Summary of Product Characteristics must not be 
exceeded.
VKA
VKA have no set dosage.
The dosage of VKA (e.g. phenprocoumon) must be monitored by determining the 
thromboplastin time and adapted individually. The outcome of this determination is given as 
INR (International Normalised Ratio).
The target is an effective range of 2.0–3.0 INR.
4.1.4 Other
The medication is supplied on prescription. Patients receive their medicines in the pharmacy. 
These are commercially available products.
The storage conditions described on the pack apply.
A pill count is not undertaken in connection with the NIS as this cannot be expected in 
routine care.
4.2 Concomitant medication and restrictions
Patients can receive any medicines they would also receive in their usual routine treatment.
Patients who have the general and special contraindications mentioned in the respective 
package leaflets or Summaries of Product Characteristics must not be included.
Patients participating at the same time or in the last 30 days in another NIS or interventional 
clinical trial must not be included.
5 Investigations and observation parameters
Data collection must always be done prospectively.
No data on efficacy in the conventional sense are collected. In this NIS, data on the 
persistence and adherence to anticoagulant therapy with dabigatran etexilate or VKA will be 
recorded as target parameters.
5.1 Target parameters
5.1.1 Primary and secondary endpoints
Primary endpoint:

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
Proportion of patients still being treated at the time of the 12-month visit with the 
initially allocated anticoagulant, defined as Kaplan Meier estimate at 12 months for 
persistence, stratified for dabigatran etexilate and VKA. Persistence is defined as the 
time between initiation and permanent termination of therapy (20). The start of 
treatment (documented in the CRF of visit 1) is documented as the start date and the 
date of discontinuation of treatment with Pradaxa® or VKA as the time of permanent 
termination of therapy
Secondary endpoints:

Proportion of patients with low, medium or high adherence at the time of the 6-month 
visit, stratified for dabigatran etexilate and VKA; categorisation is done on the basis 
of the Morisky questionnaire.

Reasons for permanent treatment discontinuation.
5.1.2 Investigation of target parameters
Following information and consenting of the patients, patient data relating to their
sociodemographic factors, AF disease history, initial anticoagulant treatment and prior and 
concomitant medication will be recorded as part of this NIS.
AF patients will use Pradaxa® or VKA in accordance with the respective Summaries of 
Product Characteristics.
The continuation of treatment with Pradaxa® or VKA and any reasons for discontinuation 
will be recorded approximately quarterly over the observation period of 12 months (after 
about 3, 6, 9 and 12 months).
After about 6 months of observation, in addition to the continuation of therapy with Pradaxa®
or VKA, drug adherence will be investigated and documented by means of the Morisky 
questionnaire and the continuation of antithrombotic treatment recorded at a regular follow-
up visit.
After about 12 months of observation, in addition to the continuation or discontinuation of 
treatment with Pradaxa® or VKA, the continuation of antithrombotic treatment will be 
recorded at a regular follow-up visit.
All patient data will be recorded in pseudonymised form and documented in the eCRF.
5.2 Safety parameters
5.2.1 Safety endpoints
In the context of this NIS, all emergent adverse events (S/AE) will be recorded 
approximately quarterly for 12 months in the eCRF.
In the event of treatment discontinuation, all emergent adverse events (S/AE) will be 
recorded in the eCRF up to 30 days after the end of treatment.
In the event of discontinuation of oral anticoagulation, the reasons for discontinuation and the 
subsequent antithrombotic stroke prophylaxis will be recorded.

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5.2.2 Investigation of adverse events
5.2.2.1 Definition of adverse events
Adverse event:
Adverse events (AE) are all harmful, pathological or unintended changes of anatomical, 
physiological or metabolic functions, identifiable by physical signs, symptoms and/or 
changes in laboratory values that occur during the course of the NIS, irrespective of whether 
or not a relationship with a medication is assumed.
Regardless of whether a causal relationship exists with the consumption of the medication, 
adverse events include:

all complaints by patients of a lack of well-being or subjective and objective 
symptoms (including clinically relevant changes in laboratory findings)

new diseases and accidents observed during treatment with the medication

the exacerbation of an existing disease

the lack of efficacy of a medicinal product

resistance formation

abuse

misuse

overdose

habituation, dependence

off-label use

interactions
Serious adverse event:
An adverse event is serious (SAE) if it

results in death,

is immediately life-threatening,

results in permanent or significant disability/incapacity,

requires or prolongs hospital treatment,

involves congenital malformations or a birth defect,

is otherwise medically significant.
Severity of an adverse event
The severity of adverse events must be documented in the (e)CRF and classified in 
accordance with the current version of the NCI-CTCAE criteria.
Causal relationship with an adverse event
The causal relationship must be medically assessed and evaluated and include all relevant 
factors, including the response pattern, time course, outcome after discontinuation of the trial 
medication or re-exposure, other confounding factors such as concomitant medication, 
concurrent diseases and relevant past history. The assessment of the causal relationship must 
be documented in the (e)CRF as follows:

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Yes = There is a plausible causal relationship between the administered medication and the 
adverse event
No = There is no plausible causal relationship between the administered medication and the 
adverse event
Exacerbation of pre-existing diseases and other pre-existing conditions
The exacerbation of pre-existing diseases and other pre-existing conditions is documented as 
an (S)AE in the (e)CRF.
Changes in vital signs, ECG, physical examination results and laboratory values
Changes in vital signs, ECG, physical examination results and laboratory values are 
documented as (S)AE in the (e)CRF if they are classed as clinically relevant by the observing 
physician.
5.2.2.2
Report of (serious) adverse events
All adverse events (SAE and AE) that occur in the course of this NIS (in other words 
between the signature of the informed consent form and the end of the observation phase
after about 12 months or up to 30 days after the end of treatment in the event of premature 
treatment discontinuation) will be collected regardless of whether the trial medication was 
taken or regardless of whether or not there is a causal relationship between trial medication 
and (S)AE.
SAEs and AEs associated with SAEs must be documented in the (e)CRF within 24 hours of 
becoming known so as to be reported promptly to Boehringer Ingelheim Pharmacovigilance 
(see 5.4).
All other AEs must be documented in the (e)CRF within 14 days of becoming known.
Following documentation in the (e)CRF, they are automatically reported to Boehringer 
Ingelheim Pharmacovigilance within 24 hours in the form of a pdf file. The BI SAE/AE form 
is generated from the eCRF at the same time.
If there is no internet access at the time of the report, alternatively a fax must be sent to 
the following address:
Boehringer Ingelheim Pharma GmbH & Co.KG
Pharmacovigilance Germany (PV Germany)
Binger Straße 173
55216 Ingelheim
Fax: +49 (6132) 72 - 141522
Email: PV_local_Germany@boehringer-ingelheim.com
For each (S)AE, the start and end date, severity, any treatment required, outcome of the 
event, severity of the event (serious/non-serious) and any measures in relation to the 
medication being studied must be noted.
The observing physician indicates the causal relationship with the medication being studied 
for all (S)AEs, as defined in section 5.2.2.1.

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In the event of a premature treatment discontinuation, the observing physician must also 
report (S)AEs that occur up to 30 days after the end of treatment. Each (S)AE reported to 
Boehringer Ingelheim during this period must be documented in the safety database.
If new information should be obtained after the initial report of the adverse event, this must 
also be reported in line with the previously mentioned procedure.
The above-mentioned duty of notification to Boehringer Ingelheim extends also to 
documented reports on uses of a Boehringer Ingelheim medicinal product during pregnancy,
irrespective of whether or not an adverse event has occurred.
Pregnancy notifications must be documented on the appropriate forms and faxed to the 
following address:
Boehringer Ingelheim Pharma GmbH & Co.KG
Pharmacovigilance Germany (PV Germany)
Binger Straße 173
55216 Ingelheim
Fax: +49 (6132) 72 - 141522
Email: PV_local_Germany@boehringer-ingelheim.com
5.3 Appropriateness of investigations
Determination of persistence by quarterly recording of the continuation of treatment as a 
parameter for the treatment administered or discontinued. Adherence is recorded using the
Morisky questionnaire. The Morisky questionnaire relates to intake behaviour. The 
questionnaire has already been used to assess adherence to warfarin therapy, where it 
exhibited good validity (16).
6 Observational plan
The arrangement of separate visits to the doctor is not necessary for the NIS.
The Boehringer Ingelheim (BI) GP practice sales force will present the NIS to about 3000 
eligible practices.
Following random selection, about 12,000 eligible doctors will sign a contract on 
participation in the NIS.
Following the decision to use treatment with dabigatran etexilate or VKA in an AF patient 
and before the prescription of treatment with dabigatran etexilate or VKA, the doctor will 
consider whether the patient is eligible for participation in the NIS. If he recommends 
treatment with dabigatran etexilate or VKA to the patient, he can then also propose 
participation in the NIS.
The doctor will explain the nature of the study to the patient and obtain their written consent 
to the processing of patient data for the purpose of this NIS and source data verification. 
Where possible, 4 successive eligible patients will be included in the NIS in a ratio of 1:1 (1 
dabigatran etexilate : 1 VKA, alternately).
6.1 Timetable of visits
Following information and consenting, patient data on sociodemographic factors, previous 
history including risk of stroke and bleeding and the patients’ prior and concomitant 
medication will be recorded at visit 1 as part of this NIS.

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AF patients will use Pradaxa® or VKA in accordance with the respective Summaries of 
Product Characteristics.
Treatment with Pradaxa® or VKA will be recorded approximately quarterly over the 
observation period of 12 months (at a regular visit after about 3, 6, 9 and 12 months).
In addition, any emergent adverse events will be documented at these visits and 
discontinuation and any reasons for discontinuation recorded.
Reasons for discontinuation include intolerable adverse events, intolerability or insufficient 
efficacy of treatment with dabigatran etexilate or VKA.
After about 6 months of observation, in addition to the continuation of therapy, treatment 
adherence will be investigated and documented by means of the Morisky questionnaire at a 
regular follow-up visit.
The patient has the right to end their participation in the NIS at any time without giving a 
reason.
6.2 Details of visits
Visit 1 (start of observation)

Patient data: sociodemographic data (sex, age, height, weight, education, marital 
status, health insurance status)

Case history of non-valvular atrial fibrillation (AF): disease onset, data on disease 
severity (individual components of the CHA2DS2-VASc score) and bleeding risk
(individual components of the HAS-BLED score)

Start of treatment with dabigatran etexilate (110 or 150 mg hard capsules) or VKA
(start date)

Concomitant medication: antiarrhythmics, antihypertensives, lipid-lowering 
agents, other prescription-only medicines

Number of other prescription-only and frequency of daily administration (other 
than dabigatran etexilate/VKA)

Recording of relevant comorbidities (Charlson et al. 1987)21
Visit 2 (after about 3 months of use of dabigatran etexilate or VKA)

Recording of the continuation of therapy with dabigatran etexilate (including dosage)
or VKA since visit 1

Onset of adverse events since visit 1

Discontinuation of treatment with dabigatran etexilate or VKA since visit 1
-
Reasons for the discontinuation of treatment with dabigatran etexilate or VKA
-
Antithrombotic therapy after discontinuation of treatment with dabigatran 
etexilate or VKA
-
In the event of treatment discontinuation, all emergent adverse events (AE) are 
recorded in the eCRF up to 30 days after the end of therapy.
Visit 3 (after about 6 months of use of dabigatran etexilate or VKA)

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
Recording of the continuation of therapy with dabigatran etexilate (including
dosage) or VKA since visit 2

Onset of adverse events since visit 2

Discontinuation of treatment with dabigatran etexilate or VKA since visit 2
-
Reasons for the discontinuation of treatment with dabigatran etexilate or VKA
-
Antithrombotic therapy after discontinuation of treatment with dabigatran 
etexilate or VKA
-
In the event of treatment discontinuation, all emergent adverse events (AE) are 
recorded in the eCRF up to 30 days after the end of therapy.

Regular use of dabigatran etexilate or VKA by means of the Morisky score

Number of prescription-only medicines and frequency of daily administration

Recording of disease severity (individual components of the CHA2DS2-VASc
score) and bleeding risk (individual components of the HAS-BLED score)

Recording of relevant comorbidities (Charlson et al. 1987)21
Visit 4 (after about 9 months of use of dabigatran etexilate or VKA)

Recording of the continuation of therapy with dabigatran etexilate (including dosage) 
or VKA since visit 3

Onset of adverse events since visit 3

Discontinuation of treatment with dabigatran etexilate or VKA since visit 3
-
Reasons for the discontinuation of treatment with dabigatran etexilate or VKA
-
Antithrombotic therapy after discontinuation of treatment with dabigatran 
etexilate or VKA
-
In the event of treatment discontinuation, all emergent adverse events (AE) are 
recorded in the eCRF up to 30 days after the end of therapy.
End of observation/Visit 5 (after about 12 months of use of dabigatran etexilate or 
VKA)

Recording of the continuation of therapy with dabigatran etexilate (including
dosage) or VKA since visit 4

Onset of adverse events since visit 4

Discontinuation of treatment with dabigatran etexilate or VKA since visit 4
-
Reasons for the discontinuation of treatment with dabigatran etexilate or VKA
-
Antithrombotic therapy after discontinuation of treatment with dabigatran 
etexilate or VKA
-
In the event of treatment discontinuation, all emergent adverse events (AE) are 
recorded in the eCRF up to 30 days after the end of therapy.

Number of prescription-only medicines and daily intake

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
Recording of disease severity (individual components of the CHA2DS2-VASc
score) and bleeding risk (individual components of the HAS-BLED score)

Recording of relevant comorbidities (Charlson et al. 1987)21
It is anticipated that anticoagulated patients will be invited for follow-up by the doctor at 
least quarterly. The quarterly recording of prescriptions and patient data therefore appears
compatible with the real-life care situation in Germany.
7 Statistical analysis
All the analyses associated with this observational study are purely descriptive; results are to
be interpreted exploratorily. There are no predefined confirmatory hypotheses and no 
measures are taken to maintain a study-wide 5% significance level or simultaneous 
confidence intervals.
7.1 Statistical design model
This is a non-randomised, open, multicentre, non-interventional cohort study with patients 
who are suffering from non-valvular atrial fibrillation and have recently been prescribed an 
oral anticoagulant (VKA or dabigatran etexilate). As the treatment is attributed by the doctor, 
differences in patient characteristics between the two patient groups receiving VKA or
dabigatran treatment that are to be compared may be expected. To improve the comparability 
of the treatment groups and hence increase the internal validity, the analysis of the primary 
target variable (persistence) is planned using methods such as matching or trimming of the 
population and adjustment.
7.2 Null and alternative hypothesis
As all analyses are performed descriptively, there is no confirmatory null and alternative 
hypothesis formulation.
7.3 Planned analyses
The evaluation is performed using SAS® software. All analyses are descriptive. For end-of-
text tables, N / mean / SD / min / median / max are given as statistical characterisation 
measures for constant variables; for categorial variables, N / % per category are given.
All patients documented in the CRF with at least one prescription for dabigatran etexilate or 
VKA and who meet the inclusion criterion (main diagnosis: non-valvular AF) are included in 
the analyses (i.e. “all eligible patients”). For the analysis of adverse events, all patients 
documented in the CRF with at least one prescription for dabigatran etexilate or VKA will be 
included in the analyses. In order to allow a valid comparison of compliance (persistence and 
adherence), a 1:1 matching of patients prescribed dabigatran or VKA will be performed 
based on the exposure propensity score (PS). The propensity score is calculated on the basis 
of a logistic regression model in which the choice of treatment is included in the model as a 
dependent variable and further relevant baseline characteristics are considered as independent 
variables in the model. The relevant baseline characteristics included in the PS model will be 
predefined in the analysis plan. The choice is based on the premise that all baseline variables 
for which a priori an association with persistence and/or adherence is expected are to be 

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included. These variables correspond to the potential confounder variables for a comparative 
analysis.
Baseline patient characteristics
The cohort resulting from the 1:1 matching as well as the whole cohort of all eligible patients 
will be characterised, stratified by treatment group, in terms of demographic data, concurrent 
diseases, concomitant medication, data on AF severity and other baseline characteristics 
(including risk score for stroke and bleeding, i.e. CHADS-VASc and HAS-BLED).
Persistence and reasons for treatment discontinuation
The analysis is performed on the basis of the patient cohorts resulting from the 1:1 matching. 
Kaplan Meier estimates for the time to discontinuation of treatment (cf. definition in section 
5.1.) will be calculated separately for the dabigatran and the VKA patient group and 
illustrated graphically. In particular, the Kaplan Meier estimates for persistence at time 3, 6, 9 
and 12 months will be reported. The comparison in terms of the persistence of patients on 
treatment with dabigatran versus VKA will be performed by means of the stratified log-
ranked test, which takes account of the dependency of treatment groups resulting from 
matching (cf. Klein, Moeschberger, 1997, 22). Patients who discontinued the study 
prematurely and for whom no treatment discontinuation is documented will be censured at 
the time of study discontinuation. Patients who end the study as planned will be censored on 
the day after the last visit if no previous treatment discontinuation is documented.
The absolute number and proportion of patients discontinuing the initial treatment in the 
course of the study will be summarised overall and according to the reasons for 
discontinuation for the dabigatran and VKA cohorts.
The association of patient characteristics (including treatment allocation) with persistence 
will be investigated by means of Cox regression models (univariate and multivariate models). 
Baseline characteristics will be presented stratified for patients who discontinue the treatment 
in the course of the study and those who do not.
A multivariable Cox regression model (including the factors used for calculating the PS and 
choice of treatment) will be reported as a sensitivity analysis. For this analysis, all patients 
who are within the common supports of the empirical density function of the PS (instead of 
matched pairs) will be included; the common support is determined after excluding patients 
with a propensity score above the 97.5% percentile and below the 2.5% percentile in each 
treatment group in order to avoid a strong influence from patients with extreme PS values.
Adherence
The analysis is performed on the basis of the patient cohort resulting from 1:1 matching. The 
Morisky questionnaire consists of 8 questions and will be presented at the time of the 6-
month visit. The analysis and categorisation of patients into the categories

poor adherence (score >2)

medium adherence (score=1, 2) and

high adherence (score=0)
is performed according to Morisky. For patients who have not answered one or more 
questions, this score is not calculated. If the proportion of patients with missing answers is 
high (e.g. >20%), a sensitivity analysis will be performed, in which the score will also be 

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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BI No.: 1160.218
024-MLW-90-118-01_RD-01; V1
calculated if up to 2 questions per patient are missing23. Patients who at the time of the visit 
are no longer on the initial therapy and those who have already discontinued the study before 
this time will be described separately from those for whom the Morisky score cannot be 
calculated for other reasons. Patients with missing values are analysed in terms of their 
baseline characteristics in comparison with patients with an evaluable Morisky score; patients 
with missing values will be stratified into the above-mentioned groups of study drop-outs, 
treatment drop-outs and patients with missing values for other reasons and the analysis will 
only be performed for strata with at least 200 patients (total and per treatment group).
The number and proportion of patients who fall into the different adherence classes will be 
presented for the dabigatran and VKA patients.
 
Coding
The current version of the Medical Dictionary for Drug Regulatory Activities will be used for 
coding adverse events. Concomitant medication will be coded using the current version of the 
WHO-DD.
Analysis of safety endpoints
For the analysis of adverse events, all patients documented in the CRF with at least one 
prescription for dabigatran etexilate or VKA will be included. Analyses of adverse events are 
descriptive and will be performed in accordance with Boehringer Ingelheim standards. In the 
analysis of adverse events, the focus is on treatment-emergent events. Events that occur in the 
period between the start of treatment and the permanent discontinuation of treatment or the 
end of the study (in patients in whom no permanent discontinuation of the medication is 
documented in the course of the study) + 6 days are categorised as treatment emergent and 
will be presented in frequency tables for dabigatran and VKA patients.
Adverse events that occur before or after this period will be assigned to “screening” or “post-
treatment” and only presented in listings.
Frequency, severity and causal relationship of treatment-emergent adverse events will be 
tabulated in accordance with MedDRA System Organ Class and Preferred Term. Patients 
with treatment-emergent serious adverse events (SAEs) will be presented in tables. In 
addition, significant adverse events and adverse events resulting in treatment discontinuation 
will be investigated.
No interim analyses are planned.

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7.4 Procedure for missing data
All available information will be used in the data analysis. Drop-outs will be duly considered 
in the main analysis by virtue of the methodology used (survival time analysis).
Missing values will be identified as such and no replacement is planned.
7.5 Determination of number of patients
It is planned to include a total of 4000 patients in this non-interventional, controlled, 
observational study (dabigatran etexilate: 2000 patients, VKA: 2000 patients).
Calculation of statistical power:
All analyses are purely exploratory by virtue of the non-interventional study design. On the 
following assumptions:

15% drop-outs /missing values after one year,

2000 dabigatran etexilate patients, 2000 VKA patients, with 66% of VKA patients
with a matching partner in the dabigatran etexilate group
(i.e. total number of patients in the 1:1 matched analysis is 2640)

a persistence rate of 63% in the dabigatran etexilate group (cf. 1-year persistence with 
a 60-day permissible medication gap as reported by Zalesak (19)).
the power for a descriptive p value <=0.05 in a 2-tailed test for the same persistence rates is 
as follows (dependent on the VKA persistence rate):
Assumed VKA 
persistence rate*
51%
53.8%
56.5%
Power
100%
99.7%
91.7%
* The calculations were performed with ADDPLAN6 and are based on survival time analysis test statistics and the endpoint 
variables “Time to permanent treatment discontinuation”.
8 Declaration of consent, data protection, NIS documentation
8.1 Study approval, patient information and consent
8.1.1 Administrative requirements
This NIS will be conducted in accordance with sections 4.23 and 67.6 of the Medicines Act 
of the Federal Republic of Germany (AMG) and the recommendations of the Federal 
Institute for Drugs and Medical Devices and the Paul-Ehrlich Institute for the planning, 
conduct and evaluation of postmarketing surveillance studies, as well as relevant BI standard 
operating procedures (SOPs).
In accordance with section 67.6 AMG, the NIS will be notified by Boehringer Ingelheim 
Pharma GmbH & Co. KG or the duly contracted institute to the Federal Associations for 
Statutory Health Insurance Physicians, National Association of Statutory Health Insurance 
Funds, the Association of Private Health Insurance Funds and the competent Federal 
supervisory authority (BfArM).
The doctors involved will also be designated by name, the nature and amount of the 
compensation paid to them will be reported and a copy of the agreements concluded with 
them will be forwarded to the Federal Associations for Statutory Health Insurance 

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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Physicians, National Association of Statutory Health Insurance Funds and the Association of 
Private Health Insurance Funds.
Copies of the notifications, where these have not been made purely electronically, will be
filed in the appropriate register in the investigator’s folder.
In addition, provision is made for an entry in the publicly accessible clinicaltrials.gov 
database in accordance with the Notification of the Association of Research-Based 
Pharmaceutical Companies (VFA).
The NIS will be assessed by the ethics committee of the Baden-Württemberg LÄK (State 
Medical Association) before the start, and likewise any changes to the observational plan. A 
copy of the approval can be found in the corresponding register in the study folder.
In addition, each participating physician must be advised by his Ethics Committee in 
accordance with the code of professional conduct.
8.1.2 Patient information and consent
The doctor will explain the nature of the study to the patients and obtain their written consent 
to the processing of patient data for the purposes of this NIS and for source data verification 
in accordance with the current data protection guidelines.
The patient will receive one original of his or her written consent. The other original will be 
kept in the study folder.
It is important that this step is performed before the patient is included in the NIS and 
observations entered in the eCRF.
It must be documented in the eCRF that the patient’s consent has been obtained before the 
beginning of the observation.
8.2 Data quality and assurance
This NIS is conducted in accordance with sections 4.23 and 67.6 of the Medicines Act of the 
Federal Republic of Germany (AMG) and the recommendations of the Federal Institute for 
Drugs and Medical Devices and the Paul-Ehrlich Institute for the planning, conduct and 
evaluation of postmarketing surveillance studies, as well as relevant BI standard operating 
procedures (SOPs).
The data from the NIS mentioned under 6.2 will be recorded on internet-based electronic 
documentation forms (eCRF). All documentation forms in the eCRF must be completed in 
full.
All entries in the eCRF and the existing codings will be stored in a database. The structure of 
the database is based on the division into sections and entry fields defined in the eCRF. The 
patient questionnaires are entered directly into the database via entry masks at the CRO.
To improve and ensure data quality, data checks will be performed automatically in the eCRF 
directly on electronic entry at the trial site: plausible value ranges for numerical data entries 
and logical data and list entries will be filed in the eCRF. The tests for consistency and 
completeness based on this will be performed during entry in the eCRF. The validity of the 
recorded data will therefore be ensured by the validations incorporated in the documentation 
system, which highlight incorrect or implausible entries to the data entry clerk/doctor.
If corrections are necessary after the data are input, these will be documented in an audit trail.

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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For the further quality assurance of the documented patient observations, a sample-based
source data comparison will be performed on about 10% of the sites, in the course of which 
the documented data will also be checked on site for completeness and consistency. An 
additional inspection/quality assurance check of this NIS can be performed.
8.2.1 Data protection
Before patients can be included in this NIS, they will be given an explanation of the 
processing of personal data and comprehensively informed about the transmission of their 
data to third parties concerned. They will be asked to give their written consent to this.
Patient data will be recorded in pseudonymous form. A list of patients who have given their 
consent to participate in the NIS will be kept for each site. This list will be kept confidentially 
in the study folder. Patient allocation is done on the basis of year of birth and the patient 
number issued at the participating trial site.
All information collected during the NIS will be treated confidentially at all times. Previous 
history data and data on therapeutic measures, emergent side effects and disease course will 
be obtained from patients in the course of this NIS.
All the recorded data will serve to answer the above-mentioned questions and will be 
recorded at the trial site using an electronic documentation system (eCRF) from
 
.
8.3 Documentation of the NIS
The Morisky questionnaire completed by the patient as part of visit 3 is sent to the attendant 
CRO,
 where it is entered in the database.
All other data from the NIS mentioned under 6.2 will be recorded in an electronic 
documentation system (eCRF).
8.3.1 Source data
All participating doctors are obliged to record patients’ participation in the NIS in the 
patients’ original documents.
In the event of any queries, the participating doctor must be able to identify the observed
patient.
Medical information about patients may only be communicated and analysed under the 
patients’ number.
8.3.2 Direct access to source data and documents
By signing the contract, the participating site has consented to source data verification, which 
will take place at the participating sites.
For quality assurance of the documented patient observations, a source data comparison is 
undertaken sample-based on about 10% of the sites, following which the documented data
are also checked on site for completeness and consistency.
8.3.3 Archiving of documents
The observing physician will keep the original documents in accordance with the statutory 
retention time.

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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All study-specific documents will be archived by Boehringer Ingelheim Pharma GmbH & 
Co. KG for a period of 10 years after the end of this NIS.
8.4 Listing and accelerated reporting procedure of adverse events
As the marketing authorisation holder of Pradaxa®, Boehringer Ingelheim International 
GmbH is responsible for the accelerated reporting of serious adverse events, such as 
SUSARs, in accordance with the currently applicable statutory requirements.
8.5 Confidentiality statement
The observing physician undertakes to observe the confidentiality of all data, information, 
results and findings that he obtains in the course of conducting the NIS or that are disclosed 
to him by BI Pharma directly or indirectly (“confidential information“) and to use them only 
in association with the conduct of the NIS.

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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9 References
                                                
1 Camm, A.J.; Kirchhof, P.; Lip, G.Y.; Schotten, U.; Savelieva, I.; Ernst, S. et al. Guidelines for the 
management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European 
Society of Cardiology (ESC). Eur Heart J 2010; 31(19): 2369-2429
2 Camm, A.J.; Lip, G.Y.; De, C.R.; Savelieva, I.; Atar, D.; Hohnloser, S.H. et al. 2012 focused update of the 
ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the 
management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm 
Association. Eur Heart J 2012; 33(21): 2719-2747.
3 Hein, L., Antithrombotika und Antihämorrhagika. In: U. Schwabe, eds. Arzneiverordnungsreport. 2012. 
Heidelberg: Springer Verlag, S. 425-445.
4 MEDA Pharma GmbH & Co.KG. Marcumar® (phenprocoumon): Summary of Product Characteristics (date 
of last revision: December 2010).
5 Wilke, T.; Groth, A.; Mueller, S.; Pfannkuche, M.; Verheyen, F.; Linder, R. et al. Oral anticoagulation use by 
patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its 
clinical outcomes, based on claims-data of 183 448 patients. Thromb Haemost 2012; 107(6): 1053-1065
6 Stangier, J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran 
etexilate. Clin Pharmacokinet 2008; 47(5): 285-295.
7 Boehringer Ingelheim. Pradaxa® 150 mg hard capsules: Summary of Product Characteristics (date of last 
revision: Januar y2 014).
8 BMS (Bristol-Myers Squibb). Coumadin® 5 mg: Summary of Product Characteristics (date of last revision:
August 2008).
9 MEDA Pharma GmbH & Co.KG. Marcumar® (phenprocoumon): Summary of Product Characteristics (date 
of last revision: December 2010).
10 BMS (Bristol-Myers Squibb). Coumadin® 5 mg: Summary of Product Characteristics (date of last revision:
August 2008).
11 Matthes J, Albus C. Improving adherence with medication: a selective literature review based on the example 
of hypertension treatment. Dtsch Arztebl Int. 2014 Jan 24;111(4):41-7.
12 Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK. Medication compliance 
and persistence: terminology and definitions. Value Health. 2008 Jan-Feb;11(1):44-7.
13 Vrijens B, De Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, Dobbels F, Fargher E, Morrison 
V, Lewek P, Matyjaszczyk M, Mshelia C, Clyne W, Aronson JK, Urquhart J; ABC Project Team. A new 
taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol. 2012 May;73(5):691-705.
14 Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self-reported measure of 
medication adherence. Med Care. 1986 Jan; 24(1):67-74.
15 Davis NJ, Billett HH, Cohen HW, Arnsten JH. Impact of adherence, knowledge, and quality of life on 
anticoagulation control. Ann Pharmacother. 2005 Apr; 39(4):632-6.
16 Wang Y, Kong MC, Ko Y. Psychometric properties of the 8-item Morisky Medication Adherence Scale in 
patients taking warfarin. Thromb Haemost. 2012 Oct; 108(4):789-95.
17 Baroletti S, Dell'Orfano H. Medication adherence in cardiovascular disease. Circulation. 2010 Mar 30;
121(12):1455-8.
18 Brown TM, Siu K, Walker D, Pladevall-Vila M, Sander S, Mordin M. Development of a conceptual model of 
adherence to oral anticoagulants to reduce risk of stroke in patients with atrial fibrillation. J Manag Care Pharm. 
2012 Jun; 18(5):351-62.
19 Zalesak, M.; Siu, K.; Francis, K.; Yu, C.; Alvrtsyan, H.; Rao, Y. et al. Higher Persistence in Newly 
Diagnosed Nonvalvular Atrial Fibrillation Patients Treated With Dabigatran Versus Warfarin. Circ Cardiovasc 
Qual Outcomes 2013
20 Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK. Medication compliance 
and persistence: terminology and definitions. Value Health. 2008 Jan-Feb;11(1):44-7.
21 Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in 
longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83.

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22 P. Moeschberger M. L. Survival analysis: Techniques for censored and truncated data. New York, NY: 
Springer-Verlag; 1997
23 Korb-Savoldelli V, Gillaizeau F, Pouchot J, Lenain E, Postel-Vinay N, Plouin PF, Durieux P, Sabatier B. 
Validation of a French version of the 8-item Morisky medication adherence scale in hypertensive adults. J Clin 
Hypertens (Greenwich). 2012 Jul;14(7):429-34.

024-MLW-90-118-01_RD-01; V1
10 Attachments
Attachment 1: Morisky questionnaire
NIS 1160.xxx:
Drug persistence/adherence in patients being treated with 
Pradaxa® (dabigatran etexilate) or vitamin K antagonists (VKA)
for stroke prevention
in non-valvular atrial fibrillation (AF)
Site number:______
Patient number:________
Visit 3, date:_______
Dear patient,
You have said that you are taking medicine for stroke prevention in atrial fibrillation.
Some patients have experienced various problems associated with their medication-taking behaviour and 
we are interested to find out about your experiences.
There are no right or wrong answers.
Please answer each question on the basis of your personal experience with your medicine for stroke
prevention in atrial fibrillation.
Please tick the answer that applies
No
Yes
1.
Do you sometimes forget to take your stroke prevention tablets?
2.
People sometimes miss taking their medicines for reasons other than 
forgetting.
Thinking over the past 2 weeks, were there any days when you did not take 
your medicine for stroke prevention?
3.
Have you ever cut back or stopped taking your medicine without telling your 
doctor because you felt worse when you took it?
4.
When you travel or leave home, do you sometimes forget to bring along your 
medicine for stroke prevention?
5.
Did you take your medicines for stroke prevention yesterday?
6.
When you feel like your stroke prevention is under control, do you
sometimes stop taking your medicine?
7.
Taking medicine every day is a real inconvenience for some people. Do you 
ever feel hassled about sticking to your treatment plan?
Please tick the answer that applies
Never/rarely
Once in 
a while
Sometimes
Usually
All the 
time
1.
How often do you have 
difficulty remembering to take 
all your medicine?
© Morisky Medication Adherence Scale (MMAS-8-item) German

BOEHRINGER INGELHEIM Pharma GmbH & Co. KG
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BI No.: 1160.218
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Attachment 2: (S)AE form

NIS – reporting form
3/25/2014
                        1 of 2
Please send immediately to Boehringer Ingelheim Pharma GmbH & Co KG on Fax No. 06132-72-141522 or PV_Germany.de@boehringer-ingelheim.com. Leave shaded areas blank.
Abcd
Report of Serious/Non-Serious Adverse Events
in Non-Interventional Study (NIS)
NIS title: 1160.218 / Pradaxa®
OPU case ID number:
Reporter name / telephone and fax number
_____________________________
_____________________________
BI CTMS number: 1160.218
Site number:
|__|__|__|__|
Pat. initials:
|__|__|__|
Pat. No.:
|__|__|
Sex
1 
male
2 
female
Date of birth (Day / Month / Year)
|__|__| |__|__|__| |__|__|    
Age
|__|__|
Height (cm)
|__|__|__|
Weight (kg)
|__|__|__| . |__|
Race        1 White
           2 Black
           3 Asian
Pregnant                0 no
                      1 yes     Week:   |__|__|
Initial report
Follow-up report
Date of the event
(enter date for each event)
Intensity 
of the
event
1= mild
2= 
moderate
3= severe
Therapy 
of the
event
0= no
1= yes
If yes, 
please 
explain 
under 
descrip-
tion
As a result of 
the event, 
adminis-
tration of the 
BI product 
was:
1= continued
2= reduced
3= 
discontinued
4 = increased
5= terminated 
in line with 
observational
plan
6= 
discontinued 
and resumed
7 = not 
applicable
Outcome
of the
event
1= recovered
2= not yet 
recovered
3= permanent 
damage
4= fatal
5= unknown
Was the event serious?
** If fatal, please attach copy 
of death certificate
Causal
relationship
Is there a justified 
suspicion of a causal 
relationship between 
the event and the use 
of Pradaxa®
Is the 
event 
expected
(listed / 
expected)
?
Event:
Describe all observed events, 
symptom(s).
Also all non-serious events 
associated with the serious 
event.
If still ongoing at the end, enter "ongoing" in the 
‘End date’ column
0 = 
no
1 = 
yes
If yes,  enter the 
corresponding code 
number
1= fatal**
2= immediately life-
threatening
3= permanent or 
significant disability/ 
incapacity
4= requires 
hospitalisation
5= prolongs
hospitalisation
6= congenital
abnormality
7= other / further 
comparable medical 
criteria, e.g. drug
dependence, abuse, 
cancer, etc.)
Start
date
Day/Mon/Year
Time in 
hh:mm 
(24-hr
clock)
End
date
Day/Mon/Year
Time in 
hh:mm 
(24-hr
clock)
Reporter
0= no
1= yes
PV 
Ger
0= no
1= 
yes
PV Ger
0= no
1= yes
1.
2.
3.
4.
Description of the events listed above (if necessary, please give the number of the event as in the above table, Event column):
_____________________________________________________________________________________________________________________________

NIS – reporting form
3/25/2014
                      2 of 2
Please send immediately to Boehringer Ingelheim Pharma GmbH & Co KG on Fax No. 06132-72-141522 or PV_Germany.de@boehringer-ingelheim.com. Leave shaded areas blank.
Abcd
Report of Serious/Non-Serious Adverse Events
in Non-Interventional Study (NIS)
NIS title: 1160.218 / Pradaxa®
OPU case ID number:
BI CTMS number:
1160.218
Site number:
|__|__|__| __|
Pat. initials:
|__|__|__|
Pat. No.:
|__|__|
Drug / therapy
If medicinal product, give proprietary and common 
name
Pharma-
ceutical 
form
Total daily 
dose at 
start
(dose, unit)
Route of 
administration
Start 
(date)
Day / Month / Year
End (date)
Day / Month / Year
Given for which 
indication?
Other suspect drug: is there a 
causal relationship between 
event and concomitant therapy?
Boehringer Ingelheim 
medication
Pradaxa®
Reporter:
0= no
If yes, enter 
number of 
event
PV Ger:
0= no
If yes, enter 
number of 
event
Concomitant therapy (relevant)
1.
2.
3.
4.
Comments (surrounding circumstances, alternative explanation of the event, where 
applicable re-exposure, etc.)
_______________________________________________________________________________
_______________________________________________________________________________
Name of reporter:
_______________________________
Signature
Date
____/____ / ____
                                   Day / Month / Year
Concurrent diagnoses (relevant):
1._________________________________________________________________________________________________________
2._________________________________________________________________________________________________________
3._________________________________________________________________________________________________________

ran Boehringer 
i   
Ingelheim 
Observational Plan 
Non-interventional study 
Local Amendment 
Local 
Local Amendment 1 
Amendment 
Number: 
Country Germany 
Date: 
16. APR 2015 
EudraCT No.: 
n.a. 
BI Trial No.: 
1160.218 
0 
To be implemented only after 
documented approval of the IRB / IEC / 
Competent Authorities 
0 
To be implemented immediately in 
order to eliminate hazard — IRB / IEC / 
Competent Authority to be notified of 
change with request for approval 
Investigational 
Pradaxa® 
Product(s): 
X Can be implemented without IRB / IEC / 
Competent Authority approval as 
changes involve logistical or 
administrative aspects only 
Title: 
Drug persistence/adherence in patients being treated with Pradaxa ® 
(dabigatran etexilate) or vitamin K antagonists (VKA) for stroke prevention in 
non-valvular atrial fibrillation (AF) 
Rationale for 
After 6 months of site and patient recruitment it became evident that the 
Local 
targeted patient and site numbers will not be met and that recruitment time 
Amendment: 
should be longer. 
Therefore the planned patient number will be reduced to 1600 and site number 
to 800. 
Recruitment time will be prolonged to 16 months (LPI December 2015), thus 
study duration will also increase. LPO is now planned for December 2016. 
Other timelines will change accordingly. 
New site and patient numbers will be used as calculation basis in the statistical 
analysis plan. 
As this amendment is administrative and does not change the content or the 
nature of this non-interventional study, for readability reasons we refrain from 
changing every sentence in which site numbers, patient numbers or timelines 
are mentioned, except for the front page, study synopsis and statistics section. 
Page 1 of 5 
Proprietary confidential information. 
@ 2015 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. 

SIGNATURE PAGE(S) 
This amendment 
[Zi concerns administrative matters only so that the coordinating investigator's signature 
will not be obtained. 
concerns matters dealing with design elements of the study, in- / exclusion criteria, 
observations, or safety or efficacy related study elements so that the coordinating 
investigator's signature needs to be obtained. 
Trial Clinical Monitor 
Pav e' 2,(f
Trial Statistician 
Team Member Medicine 
Local Clinical Monitor 
Date 
Date 
Boehringer Ingelheim 
Biometrics & Data 
Management 
Date 
Boehringer Ingelheim 
Corporate Medical Affairs 
Boehringer Ingelheim 
Medical Affairs Germany 
irTcl c9C 
Date-) 

Boehringer Ingelbeim 
Biometrics & Data 
Management 
Boehringer Ingelheim 
Corporate Medical Affai 
Date 
SIGNATURE PAGE(S) 
This amendment 
concerns administrative matters only so that the coordinating investigatoes signinure 
will not be obtained. 
El concerns matters dealing with design elements of the study, in- / exclusion criteria, 
observations, or safety or efficacy related study elements so that the coordinating 
investigator's signature needs to be obtained. 
Trial Clinical Monitor 
Date 
Trial Statistician 
Team Member Medicine 
Local Clinical Monitor 
Boehringer Ingelheim 
Medical Affairs Germany 

Boehringer Ingelheirn 
Corporate Medical Affairs 
Date- 
Boehringer Ingelheim 
Biometrics & Data 
Management 
Date 
ate 
SIGNATURE PAGE(S) 
This amendment 
concerns administrative matters only so that the coordinating investigator's signature 
will not be obtained. 
0 concerns matters dealing with design elements of the study, 
observations, or safety or efficacy related study elements so 
investigator's signature needs to be obtained. 
in- / exclusion criteria, 
that the coordinating 
Trial Clinical Monitor 
pcti 
?Pr.
Date 
Trial Statistician 
Team Member Medicine 
Local Clinical Monitor 
Boehringer Ingelheim 
Medical Affairs Germany 

CHANGE 1: ADAPT TIME SCHEDULE, SITE NUMBERS AND PATIENT 
NUMBERS 
Section of the protocol: Front page 
Scheduled time 
FPI September 2014 
LPO April 2016 
frame of the NIS: 
Was changed to: 
Scheduled time 
frame of the NIS: 
FPI September 2014 
LPO December 2016 
Reasons for change 1: 
After 6 months of site and patient recruitment it became evident that the targeted patient and site 
numbers will not be met and that recruitment time should be longer. 
Recruitment time will be prolonged to 16 months (LPI December 2015), thus study duration will 
also increase. LPO is now planned for December 2016. 
CHANGE 2: ADAPT TIME SCHEDULE, SITE NUMBERS AND PATIENT 
NUMBERS 
Section of the protocol: Synopsis 
Target group (sites) 
1000: about 670 community-based primary care internists or general 
practitioners and 330 cardiologists 
• 
In this NIS, information about dabigatran etexilate/VKA 
persistence and adherence will be collected in 4000 AF 
patients. 
Number of patients: 
4000; 
2000 on dabigatran etexilate; 2000 on VKA 
Scheduled study 
duration 
Initiation (FPI): 
September 2014 
Last patient out (LP0): 
April 2016 
Report 
Report available: 
July 2016 

Was changed to: 
Target group (sites) 
800: about 550 community-based primary care internists or general 
practitioners and 250 cardiologists 
•
In this NIS, information about dabigatran etexilate/VKA 
persistence and adherence will be collected in 800 AF 
patients. 
Number of patients: 
Approx. 1600; 
Approx. 800 on dabigatran etexilate; approx. 800 on VKA 
Scheduled study 
duration 
Initiation (FPI): 
September 2014 
Last patient out (LP0): 
December 2016 
Report 
Report available: 
March 2017 
Reasons for change 2: 
After 6 months of site and patient recruitment it became evident that the targeted patient and site 
numbers will not be met and that recruitment time should be longer. 
Therefore the planned patient number will be reduced to 1600 and site number to 800. 
Recruitment time will be prolonged to 16 months (LPI December 2015), thus study duration will 
also increase. LPO is now planned for December 2016. 
Other timelines will change accordingly. 
CHANGE 3: ADAPT TIME SCHEDULE, SITE NUMBERS AND PATIENT 
NUMBERS 
Section of the protocol: Statistics Section Determination of number of patients 
It is planned to include a total of 4000 patients in this non-interventional, controlled, observational 
study (dabigatran etexilate: 2000 patients, VKA: 2000 patients). 
Calculation of statistical power: 
All analyses are purely exploratory by virtue of the non-interventional study design. On the following 
assumptions: 
•
15% drop-outs /missing values after one year, 
•
2000 dabigatran etexilate patients, 2000 VKA patients, with 66% of VKA patients with a 
matching partner in the dabigatran etexilate group 
(i.e. total number of patients in the 1:1 matched analysis is 2640) 
•
a persistence rate of 63% in the dabigatran etexilate group (cf. 1-year persistence with a 60- 
day permissible medication gap as reported by Zalesak ( 19))• 
the power for a descriptive p value <=0.05 in a 2-tailed test for the same persistence rates is as follows 
(dependent on the VKA persistence rate): 
Assumed VKA 
persistence rate* 
51% 
53.8% 
56.5% 
Power 
100% 
99.7% 
91.7% 
* The calculations were performed with ADDPLAN6 and are based on survival time analysis test statistics and the endpoint 
variables "Time to permanent treatment discontinuation". 

Was changed to: 
It is planned to include a total of 1600 patients in this non-interventional, controlled, observational 
study (dabigatran etexilate: 800 patients, VKA: 800 patients). 
Calculation of statistical power: 
All analyses are purely exploratory by virtue of the non-interventional study design. On the following 
assumptions: 
•
15% drop-outs /missing values after one year, 
•
800 dabigatran etexilate patients, 800 VKA patients, with 66% of VKA patients with a 
matching partner in the dabigatran etexilate group 
(i.e. total number of patients in the 1:1 matched analysis is 1056) 
•
a persistence rate of 63% in the dabigatran etexilate group (cf. 1-year persistence with a 60- 
day permissible medication gap as reported by Zalesak ( 19)). 
the power for a descriptive p value <=0.05 in a 2-tailed test for the same persistence rates is as follows 
(dependent on the VKA persistence rate): 
Assumed VKA 
persistence rate* 
51% 
53.8% 
56.5% 
Power 
97.8% 
84.8% 
61.1% 
* The calculations were performed with ADDPLAN6 and are based on survival time analysis test 
statistics and the endpoint variables "Time to permanent treatment discontinuation". 
Reasons for change 3: 
After 6 months of site and patient recruitment it became evident that the targeted patient and site 
numbers will not be met and that recruitment time should be longer. 
Therefore the planned patient number will be reduced to 1600 and site number to 800. 

Boehringer 
\IHIV Ingelheim 
Observational Plan 
Non-interventional study 
Local Amendment 
amanaransavammarmarrom 
Local 
Local Amendment 2 
Amendment 
Number: 
Country Germany 
Date: 
04. JAN 2016 
EudraCT No.: 
n.a. 
BI Trial No.: 
1160.218 
0 To be implemented only after 
documented approval of the IRB / IEC / 
Competent Authorities 
0 To be implemented immediately in 
order to eliminate hazard — IRB / IEC / 
Competent Authority to be notified of 
change with request for approval 
Investigational 
Pradaxa® 
Product(s): 
N Can be implemented without IRB / IEC / 
Competent Authority approval as 
changes involve logistical or 
administrative aspects only 
Title: 
Drug persistence/adherence in patients being treated with Pradaxa ® 
(dabigatran etexilate) or vitamin K antagonists (VKA) for stroke prevention in 
non-valvular atrial fibrillation (AF) 
Rationale for 
After 15 months of patient recruitment 1050 / 1600 patients have been 
Local 
included until December 2015. For a meaningful data analysis and 
Amendment: 
interpretation, the targeted patient number of 1600 patients should be met. 
Therefore, recruitment time will be prolonged for one more year to 27 months 
(LPI December 2016), thus study duration will also increase. LPO is now 
planned for December 2017. 
Other timelines will change accordingly. 
In case 1600 patients will be included earlier, recruitment may be stopped 
before December 2016. 
As this amendment is administrative and does not change the content or the 
nature of this non-interventional study, for readability reasons we refrain from 
changing every sentence in which site numbers, patient numbers or timelines 
are mentioned, except for the front page, study synopsis and statistics section. 
Page 1 of 3 
Proprietary confidential information. 
CD 2016 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. 

Boehringer Ingelheim 
Biometrics & Data 
Management
Date 
Boehringer Ingelheim 
Corpo 
edical 
/Pt 0i, /(‘` 
Date 
SIGNATURE PAGE(S) 
This amendment 
El concerns administrative matters only so that the coordinating investigator's signature 
will not be obtained. 
concerns matters dealing with design elements of the study, in- / exclusion criteria, 
observations, or safety or efficacy related study elements so that the coo
ng 
investigator's signature needs to be obtained. 
Trial Clinical Monitor 
44.04.16 
Date 
Boehringer Ingelheim 
Medical Affairs Germany 
Trial Statistician 
Team Member Medical Affairs 
Local Clinical Monitor 
Date 
Boehringer Ingelheim 
Medical Affairs Germany 

"f 
 
Date 
Trial Statistician 
Team Member Medical Affairs 
Local Clinical Monitor 
Boehringer Ingelheim 
Corporate Nledical 
i   
Boehringer Ingelheim 
Biometrics & Data 
Management 
Ewe 
SIGNATURE PAGE(S) 
This amendment 
El concerns administrative matters only so that the coordinating investigator's signature 
will not be obtained. 
0 concerns matters dealing with design elements of the study, in- / exclusion criteria, 
observations, or safety or efficacy related study elements so that the coordincding 
investigator's signature needs to be obtained. 
Trial Clinical Monitor 
44. 04. 4 
Date 
Boehringer Ingelheim 
Medical Affain Germany 
Boehringer Ingelheim 
Medical Affairs Germany 

CHANGE 1: ADAPT TIME SCHEDULE, SITE NUMBERS AND PATIENT 
NUMBERS 
Section of the protocol: Front page 
Scheduled time 
FPI September 2014 
LPO April 2016 
frame of the NIS: 
Was changed to: 
Scheduled time 
frame of the NIS: 
FPI September 2014 
LPO December 2017 
Reasons for change 1: 
After 15 months of patient recruitment 1050 / 1600 patients have been included until December 
2015. For a meaningful data analysis and interpretation, the targeted patient number of 1600 patients 
should be met. 
Therefore, recruitment time will be prolonged for one more year to 27 months (LPI December 2016), 
thus study duration will also increase. LPO is now planned for December 2017. 
In case 1600 patients will be included earlier, recruitment may be stopped before December 2016. 
CHANGE 2: ADAPT TIME SCHEDULE, SITE NUMBERS AND PATIENT 
NUMBERS 
Section of the protocol: Synopsis 
Scheduled study 
duration 
Initiation (FPI): 
Last patient out (LP0): 
September 2014 
April 2016 
Report 
Report available: 
July 2016 
Was changed to: 
Scheduled study 
duration 
Initiation (FPI): 
Last patient out (LP0): 
September 2014 
December 2017 
Report 
Report available: 
March 2018 
Reasons for change 2: 
After 15 months of patient recruitment 1050 / 1600 patients have been included until December 
2015. For a meaningful data analysis and interpretation, the targeted patient number of 1600 patients 
should be met. 
Therefore, recruitment time will be prolonged for one more year to 27 months (LPI December 2016), 
thus study duration will also increase. LPO is now planned for December 2017. 
Other timelines will change accordingly. 
In case 1600 patients will be included earlier, recruitment may be stopped before December 2016.