A Description of Warfarin and NOAC Utilization Patterns Including Initiation, Switching, and Discontinuation
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD 
TITLE PAGE
Protocol for observational studies based on existing data
Doc. No.: c02790280-01
BI Study No.:
1160.177
Products:
PRADAXA (dabigatran)
Title:
A description of warfarin and NOAC utilization 
patterns including initiation, switching, and 
discontinuation
(Phase 3 of the BI/BWH Pradaxa study program)
Team Member Epidemiology:
Status, Version:
Final Protocol, Version 2.0
Date of Protocol:
31 July 2014
Study Sponsor:
Boehringer Ingelheim GmbH
Planned Dates of Study:
Jun 2012 – Jun 2017
Page 1 of 67
Proprietary confidential information
Developed by the Division of Pharmacoepidemiology of the Brigham and Women’s Hospital in collaboration with 
Boehringer Ingelheim
© 2014 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
Page 2 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
TABLE OF CONTENTS ........................................................................................................2
LIST OF TABLES...................................................................................................................3
LIST OF FIGURES.................................................................................................................4
OBSERVATIONAL STUDY PROTOCOL SYNOPSIS .....................................................5
PROTOCOL CHANGES........................................................................................................8
1.
BACKGROUND1 .....................................................................................................10
2.
OBJECTIVES...........................................................................................................11
3.
STUDY DESIGN ......................................................................................................11
3.1
DATA SOURCES.....................................................................................................11
3.2
STUDY POPULATION...........................................................................................12
3.2.1
Study size ........................................................................................................14
3.3
EXPOSURES............................................................................................................15
3.4
OUTCOMES.............................................................................................................15
3.6
DATA ANALYSIS....................................................................................................27
3.6.1
Main analyses .................................................................................................27
4.
STUDY LIMITATIONS..........................................................................................30
6.
QUALITY ASSURANCE AND CONTROL.........................................................31
7.
ETHICAL/SCIENTIFIC APPROVAL..................................................................31
8.
STUDY MILESTONES AND RESPONSIBILITIES...........................................32
9.
DISTRIBUTION OF RESULTS.............................................................................33
10.
FUNDING .................................................................................................................33
11.
APPENDICES...........................................................................................................34
11.1 APPENDIX 1: LIST OF FIGURES AND TABLES .............................................34
11.2 APPENDIX 2: STUDY FIGURES..........................................................................38
 
11.4 APPENDIX 4: LIST OF ALL ABBREVIATIONS INCLUDED IN THE 
PROTOCOL .............................................................................................................53
12.
REFERENCES .........................................................................................................64

Boehringer Ingelheim
Page 3 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF TABLES
Table 1
Precision of estimates for proportion measures ...............................................14
Table 2
Precision of estimates for continuous measures...............................................15
Table 3
Definition of utilization measures....................................................................16

Boehringer Ingelheim
Page 4 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF FIGURES
Figure 1
Patient selection flow chart for initial cohort...................................................13
Figure 2
Illustration of cohort entry and subsequent treatment patterns ........................17
Figure A1
Patient selection flow diagram (CONSORT Style)..........................................38

Boehringer Ingelheim
Page 5 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
OBSERVATIONAL STUDY PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim GmbH
Name of product: PRADAXA®
Name of active ingredient: dabigatran
Protocol date
Study number
Planned study period
Jun 2012 – Jun 2017
31 July 2014
1160.177
Title of study:
A description of warfarin and NOAC utilization patterns including 
initiation, switching, and discontinuation
Team Member 
Epidemiology:
Project Team:
 
Study data source:
UnitedHealth 2009 through 2015
MarketScan 2009 through 2015
Objectives:
The objective of this study is to provide a description of patients with 
non-valvular atrial fibrillation at risk for stroke initiating oral 
anticoagulants and a description of existing utilization patterns for 
warfarin and for the new oral anticoagulant (NOAC) medications as 
they become available over time.
Methodology/Study 
design:
Observational cohort study
Expected number of 
patients: 
~ 200,000 (estimated size of the unmatched cohort including 
warfarin, dabigatran, and other NOACs)

Boehringer Ingelheim
Page 6 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Main
criteria for inclusion:
A recorded diagnosis of atrial fibrillation.
Initiation of oral anticoagulant medication.
At least 18 years of age on the date of anticoagulant initiation
CHA2DS2-VASc score ≥ 1
Name of company:
Boehringer Ingelheim GmbH
Name of product: PRADAXA®
Name of active ingredient: dabigatran
Protocol date
Study number
Planned study period
Jun 2012 – Jun 2017
31 July 2014
1160.177
Main
criteria for exclusion:
Patients with less than 12 months enrolment in the UnitedHealth 
Research Database or MarketScan database preceding the date of first 
dispensing will be excluded.  Also excluded will be patients with 
missing or ambiguous age or sex information.
Patients with documented evidence of valvular disease.
Patients with prior use of any oral anticoagulant
Study product:
PRADAXA (dabigatran) 
Comparison group:
Warfarin, and other new oral anticoagulants as they become available
Expected duration of 
exposure:
Until treatment discontinuation as observed in the data source; the 
study objective is to describe observed utilization
Outcomes:
This study will describe the patient population with non-valvular 
atrial fibrillation initiating oral anticoagulants and anticoagulants 
utilization patterns. Utilization measures include:

Number/proportion of patients initiated on specific 
anticoagulants and anticoagulant doses 

Time until treatment discontinuation (gap > 30 days)

Time until treatment switch

Boehringer Ingelheim
Page 7 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Data Analysis 
Methods:
Analyses are inherently descriptive in nature. Utilization patterns will 
be examined overall 
 
.
The initial analyses will be based on currently available data from Jan 
2009 – Jun 2012. Subsequent analyses will include additional data in 
6-month increments (Jul 2012 – Dec 2015).

Boehringer Ingelheim
Page 8 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
PROTOCOL CHANGES
Informed by the first two analyses (Interim Report 1 and 2), the analyses were streamlined to 
remove redundant information and focus on the main outcomes of interest.  The specific 
changes are documented in the table below.
Date
Versi
on
Type of Change
Comments
31 July 2014
V 2.0
Addition of 
MarketScan data 
throughout the 
document
Added to increase the population size
(Synopsis, Study design, Data Sources 3.1)
31 July 2014
V 2.0
Treatment gap to 
define end of 
follow-up changed 
from 6 months to 
30 days
Many patients will be censored for 
administrative reasons before they reach a 
6-month treatment gap, reducing the 
opportunity to observe between-treatment 
differences.  Treatment discontinuation 
will therefore be evaluated using a 30 day 
treatment gap instead in the main analysis, 
 
 
31 July 2014
V 2.0
Prevalence of use 
was changed to 
treatment 
initiation rates
Change implemented to streamline the 
analyses and focus on the main outcomes 
of interest
(Main analyses 3.6.1)
31 July 2014
V 2.0
 
 
 
 
 
 
 
31 July 2014
V 2.0
Persistence over 
time is considered 
a secondary 
outcome
Informed by the first analyses, persistence 
over time is considered of high importance 
to describe anticoagulant utilization
(Outcomes 3.4 and Main analyses 3.6.1)
31 July 2014
V 2.0
12-month 
covariate 
The covariate assessment period was 
changed from 6 months to one year for 

Boehringer Ingelheim
Page 9 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
assessment period
consistency with the comparative safety 
protocol (Covariates 3.5)
31 July 2014
V 2.0
Utilization 
measures are 
examined in a 
propensity-
matched cohort
To ensure a valid comparison of utilization 
measures, these measures are examined in 
a propensity-score matched cohort, rather 
than in the overall study population
(Main analyses 3.6.1)
31 July 2014
V 2.0
 
 
 
 
 
31 July 2014
V 2.0
 
 
 
 
 
 
 

Boehringer Ingelheim
Page 10 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
BACKGROUND1
A number of new oral anticoagulants are being developed and marketed to replace vitamin K 
antagonists (e.g., warfarin), one of the most important drugs in modern medicine.[P12-08021]
Unlike vitamin K antagonists, these new drugs do not require dose titration involving 
intensive therapeutic monitoring of prothrombin time to achieve target anticoagulation within 
a narrow therapeutic range. In Phase III studies, these drugs were found to be therapeutically 
advantageous or non-inferior over warfarin; however, little is known about their efficacy 
relative to one another.[R11-4190; P09-11669; R11-4223] In the coming years, as many as 
six new anticoagulants could be on the market and a lack of valid comparative evidence will 
hinder prescriber and payor decision-making.
To date, these drugs have been studied in pre-marketing clinical trials for three separate 
indications: (1) prevention of stroke and systemic embolism among patients with atrial 
fibrillation; (2) prevention of deep venous thromboembolism (DVT) among patients 
undergoing hip or knee replacement therapy; and (3) treatment of venous thromboembolism 
(VTE). Phase III clinical trials comparing dabigatran, rivaroxaban, and apixaban to warfarin 
in patients with non-valvular atrial fibrillation (NVAF) have been completed. [R11-4190; 
P09-11669; R11-4223] 
It was hypothesized that the effectiveness and safety of oral anticoagulants in stroke 
prevention will strongly depend on their use patterns. [P12-08021] A thorough understanding 
of (1) the existing utilization patterns for warfarin, and changes in this utilization that occur 
after the introduction of NOACs; (2) differences in utilization patterns between warfarin and 
NOACs; and (3) differences between specific NOACs, will help with the design, analysis and 
interpretation of comparative effectiveness and safety studies for the NOAC. 
This protocol is for a series of descriptive analyses starting with the cohort of patients with 
non-valvular atrial fibrillation identified in the currently available Jan 2009- Jun 2012 data, 
followed by inclusion of additional cohorts identified in 6-month data increments. Such 
sequential approach will extend initial analyses by allowing (1) examination of shifts in 
utilization patterns over time, and (2) inclusion of additional NOACs at they become 
available.  
1 A complete list of all abbreviations used in the protocol is provided in Appendix 4

Boehringer Ingelheim
Page 11 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
OBJECTIVES
To provide an overview of existing utilization patterns for warfarin and the NOAC 
medications as they become available in patients with non-valvular atrial fibrillation at risk 
for stroke. Specifically:

 

Examine treatment initiation, switching and discontinuation.

 

Update initial analyses on a 6-month basis. 
3.
STUDY DESIGN
This study will use a cohort design with descriptive analyses, using data from 2009-2015. It 
will be conducted within two US-based longitudinal healthcare claims databases (MarketScan 
and UnitedHealth Research Database, see also section 3.1 for more details). Cohort selection 
and all analyses will be conducted separately within each data source.
3.1
DATA SOURCES
The data source for this project is a combination of claims data from UnitedHealth, a 
commercial health insurer, and MarketScan, a research claims database from commercial 
employer-sponsored health plans both of which provide comprehensive medical coverage for 
members with active policies.  
 
 
 
 
 
 
 
 
 

Boehringer Ingelheim
Page 12 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.2
STUDY POPULATION
From the UnitedHealth Research Database and MarketScan source data, we will identify 
patients with a recorded diagnosis of non-valvular atrial fibrillation at risk for stroke who 
initiated anticoagulant medications between January 2009 and June 2012. Additional 
increments of data will be added as they become available (in 6 month intervals). Data from 
the time period before dabigatran was launched will be used to describe the characteristics of 
warfarin patients before the availability of NOAC, and to evaluate a potential shift in 
characteristics of warfarin patient over time as NOAC enter the market.
Inclusion criteria2: 

Any person within the source data who had a diagnosis of atrial fibrillation recorded 
(ICD-9 Dx code of 427.31, atrial fibrillation) and received a dispensing of an 
anticoagulant medication (warfarin and dabigatran for the initial analysis; with others 
to be added as they become available for stroke prevention in later time intervals) in 
the timeframe of the study.

The first dispensing is preceded by at least 12 months continuous enrollment in the 
study database, defined as <32 days enrollment gap using enrollment and 
disenrollment dates. The study will thus focus on ‘new initiators’ defined 
operationally as no dispensing of any anticoagulant in the prior 12 months. Note that 
new initiators will turn into prevalent users over time.

Patients’ follow-up will end when there is a treatment gap of ≥30 days. If the same 
patient re-initiates treatment later on – after a treatment gap of ≥12 months –, (s)he
may re-enter the cohort at that time (an indicator variable will be created to identify 
such patients, known as former users).

18 years or older at the time of treatment initiation

CHA2DS2-VASc score3 ≥ 1
Exclusion criteria: 

patients with less than 12 months continuous enrollment in the study database without 
anticoagulant use before the first dispensing of anticoagulant medication.

Patients with missing or ambiguous age or sex information.

Patients with documented evidence of valvular disease defined as at least 1 inpatient 
or outpatient ICD-9 Dx code of [R11-4334]
394.x (diseases of mitral valve)
395.x (diseases of aortic valve)
396.x (diseases of mitral and aortic valve)
397.x (diseases of other endocardial structures)
398.9x (other and unspecified rheumatic heart diseases)
V42.2 (heart valve replaced by transplant)
V43.3 (heart valve replaced  by a mechanical device/prosthesis)
OR
2 A full description of all diagnostic and procedure codes included in this protocol is provided in Appendix 3.
3 See Table 7 in section 3.5 for CHA2DS2-VASc components and calculation

Boehringer Ingelheim
Page 13 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ICD-9 procedure code 35.1x (open heart valvuloplasty without replacement), 35.2x 
(replacement of heart valve) [R03-1232]
OR 
one of the following CPT codes:
33660-33665 (atrioventricular valve repair)
33400-33403 (aortic valve valvuloplasty)
33405 (Replacement, aortic valve, with cardiopulmonary bypass; with prosthetic 
valve other than homograft or stentless valve)
33420-33430 (mitral valve repair/valvuloplasty/replacement)
33460 (valvectomy, tricuspid valve, with cardiopulmonary bypass)
33463-33468 (tricuspid valve repair/valvuloplasty/replacement)
33475 (replacement, pulmonary valve)
33496 (prosthetic valve dysfunction repair)
0257T (implantation of catheter-delivered prosthetic aortic heart valve; open thoracic 
approach)
0258T (transthoracic cardiac exposure for catheter-delivered aortic valve replacement; 
without cardiopulmonary bypass)
0259T (transthoracic cardiac exposure for catheter-delivered aortic valve replacement; 
with cardiopulmonary bypass)
0262T (implantation of catheter-delivered prosthetic pulmonary valve, endovascular 
approach)
Figure 1
Patient selection flow chart for initial cohort
United and MarketScan Data:
Jan 2009 - June 2012 (initial cohort)
July 2012 - Dec2015 (subsequent cohorts)
Include:
• Atrial fibrillation
• Initiation of anticoagulant 
medication
Exclude:
• <12 Months enrollment before 
1st dispensing
• Missing or ambiguous age or sex
• Valvulardisease
Follow for:
Refills (same anticoagulant)
Switch (different anticoagulant)
Discontinuation (30 day gap)
Disenrollment
Label as re-entry
Re-initiate treatment after ≥12 months?
End follow-up
Y
N

Boehringer Ingelheim
Page 14 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.2.1
Study size
This study will be estimating anticoagulant utilization parameters within a sampled 
population.  The precision of these estimates will depend on the numbers of patients on which 
the estimate is made, and features of the estimate itself. The number of patients receiving
anticoagulant medication and meeting study selection criteria is unknown at this stage.  
However, we assume that between 10,000 and 15,000 patients per year will meet selection 
criteria as having used warfarin or a newer anticoagulant so that by the end of the study (data 
from 2009-2015), there will be a total of at least 100,000 patients in each data source. 
(source: These are projections based on preliminary counts in the available UnitedHealth 
data)
The precision of proportion estimates (e.g. prevalence) is a function of the proportion and the 
number of patients contributing to the proportion (precision = standard error = square 
root[p(1-p)/n]).  As indicated in the table below, across a range of estimates provided, the 
precision for a prevalence estimate of 10% or 20% is less than 5% even for sample sizes that 
will likely be present in subgroups described in this study.
Table 1
Precision of estimates for proportion measures
Numerator
Denominator
Prevalence
95% CI
Precision (s.e.)
10
100
10%
4.9%-17.6%
3.0%
100
1,000
10%
8.2%-12.0%
0.9%
1,000
10,000
10%
9.4%-10.6%
0.3%
10,000
100,000
10%
9.8%-10.2%
0.1%
20
100
20%
12.7%-29.2%
4.0%
200
1,000
20%
17.6%-22.6%
1.3%
2,000
10,000
20%
19.2%-20.8%
0.4%
20,000
100,000
20%
19.8%-20.2%
0.1%
For continuous measures such as medication possession ratio ((MPR), see Table 3), the 
precision depends on the number of subjects on whom the estimate is made and the 
variability of the measures (precision = standard error = square root[standard deviation2/n]).
As indicated in the table, the precision for a continuous measure is 5% or less even for 
measures that apply to strata that represent subgroups to be defined in this study.

Boehringer Ingelheim
Page 15 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 2
Precision of estimates for continuous measures
Sample Size
Mean
SD
Precision (s.e.)
100
1
0.5
5.0%
1,000
1
0.5
1.6%
10,000
1
0.5
0.5%
100,000
1
0.5
0.2%
By the end of the study, with a projected 100,000 patients meeting selection criteria, the 
various adherence measures will be estimated with a precision of 1% or less, except within
fairly small strata.
3.3
EXPOSURES

Initiation of oral anticoagulant medication (i.e., no use in the prior 12 months) 
represents the primary exposure.  

Utilization patterns will be defined by individual oral anticoagulant: warfarin and 
dabigatran for the initial cohort (Jan 2009-June 2012), as well as rivaroxaban and 
other NOACs as they enter the market within the study time horizon for subsequent 
cohorts (July 2012- Dec 2015).
3.4
OUTCOMES
Patterns of anticoagulant medication use will be identified on the basis of a pharmacy 
dispensing. Pharmacy dispensing is considered the most accurate utilization measure short of 
electronic pillcounting caps. [R13-0543] 
The primary outcomes considered include the proportion of patients dispensed specific 
anticoagulants and anticoagulant doses (for NOAC), as well as a description of the 
characteristics of these patients.
In addition, a variety of measures will be derived from features of the dispensing data, 
including: number of dispensings, characteristics of dispensings (dose, and days supplied),
 along with persistence 
measures (e.g., proportion with a single dispensing, proportion remaining on therapy over 
time, time until treatment switch or discontinuation). [R13-0542; R12-3689; P06-11504]
Treatment persistence over time constitutes the secondary outcome,
 

Boehringer Ingelheim
Page 16 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 3
Definition of utilization measures
Measure
Definition 
Days supplied*
Number of days supplied by a dispensing
Dose**
Presumed dose based on # tablets, mg per tablet, and number of days
One dispensing only
Number (and fraction) of first anticoagulant recipients with no second 
dispensing
Persistence 
Fraction of anticoagulant users with continued dispensings. Patients 
will be classified as persistent if they possess medication at the 
specified time point. Grace period of 14 days will be allowed to obtain 
an additional refill.
Anticoagulant switch
Dispensing of another anticoagulant within <30 days of the end of 
days supplied of the previous medication
Anticoagulant discontinuation
Treatment gap of ≥30 days (i.e., no dispensing of anticoagulant 
medication within 30 days of the end of days supplied)
*: 
Days supply likely reflects use patterns in a commercial insurer such as United Health or MarketScan.
**: 
Estimation of dose will be challenging during the dose titration period for warfarin. We explore warfarin dose over 
time and assess the feasibility of estimating average dose, seeking to identify maintenance dose (i.e., dose needed for 
consistent therapeutic INR). 
***: 

Boehringer Ingelheim
Page 17 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Notes: 
Incident user: Patient with no dispensing of an oral anticoagulant in the prior 12 months
(potential) prevalent user: Patients with <12 months enrollment before first observed dispensing. Since these patients could 
have been treated in the prior 12 months (treatment status during the unobserved time period is unknown), they are 
considered ‘potential’ prevalent patients.
Figure 2
Illustration of cohort entry and subsequent treatment patterns
Rx 
Drug A
Day supply
Runs out
Rx 
Drug B
12 month 
enrollment
12 month 
enrollment
Rx 
Drug A
Rx 
Drug A
Rx 
Drug B
Rx 
Drug B
Cohort 
entry
End 
FU
Cohort
Re-entry
Tmt
switch
30 day 
gap
Day supply
runs out
SCENARIO A: Incident user with re-entry
SCENARIO B: Potential prevalent user with later entry as incident user
<12 month
enrollment
12 month
enrollment
Cohort 
entry
Excluded

Boehringer Ingelheim
Page 18 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 19 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 20 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 21 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 22 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 23 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 24 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 25 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 26 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 27 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.6
DATA ANALYSIS
All analyses will be conducted separately within each database.
3.6.1
Main analyses
Analyses in this protocol are inherently descriptive in nature.  The analyses described below 
will initially be conducted for the base cohort (Jan 2009- June 2012 data).   Analyses will be 
updated at 6-month intervals as more data become available for the existing cohort(s) and 
new users are identified within the additional time period (July 2012- Dec 2015 data).  As 
new data become available, we will characterize the patients newly initiated on treatment 
during that time period separately, in order to enable characterization of the shift in patient 
characteristics and use over time. In addition, short and long-term outcomes for the already 
existing cohorts (i.e., patients identified in previous time periods) will be updated with the 
newly available information in terms of switches, discontinuations, adherence and 
persistence. 
A 12-month time window of no treatment is used to define a “new” treatment episode (i.e., 
incident user). Patients who re-initiate treatment after a treatment gap of ≥ 12 months will re-
enter the cohort as former users.
Primary outcomes:
Treatment initiation over time:
The yearly anticoagulation initiation rate will be estimated as the proportion of patients who 
initiated treatment among the source cohort of patients with non-valvular atrial fibrillation 
who met the study inclusion criteria and were not already on treatment.  To identify the 

Boehringer Ingelheim
Page 28 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
source cohort of treatment candidates in a given calendar time window (i.e., the denominator 
for the rate), all patients with at least one day eligibility will be identified.  A random date 
within the first eligibility period (if more than one) within the calendar time window will be
selected and set as the index date.  The cohort inclusion and exclusion criteria will be
evaluated using this index date. Patients who were dispensed an anticoagulant before the 
assigned index date (prevalent users) will be removed from the denominator, unless they are
identified as new initiators (i.e., included in the numerator) for that particular time period.
Characteristics of anticoagulant users:
The analyses will describe the proportion of patients treated with various oral anticoagulants, 
as well as the characteristics of these patients.  For the NOACs, the starting dose will also be 
considered. Analyses will be conducted 
 
as well for the combined cohort of 
incident and former users. Characteristics for the combined cohort will be presented in the 
core set of tables; 
 
 
 
 
 
 
 
  
 
Data prior to the launch of dabigatran in October 2010 will be used to characterize warfarin 
patients before the NOACs became available, and to evaluate the potential shift in patient 
characteristics over time. A comparison of patient characteristics across treatment groups will 
only be conducted within a common time window.
Secondary outcomes:
Utilization measures: Non-persistence
To ensure a valid comparison of utilization measures (Table 3), patients exposed to the 
various NOACs will be matched to warfarin on an exposure propensity score (PS) in a 1:1 
fixed ratio using a nearest neighbor technique and a caliper of 0.05.   In addition, the patients 

Boehringer Ingelheim
Page 29 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
will be matched within calendar quarters (3 month periods). 
 
  
Briefly, all covariates listed in 
will be included in a logistic regression propensity 
score (PS) model without further variable selection. In addition to demographic information, 
variables included in the PS were identified based on the a-priori expectation that they might 
be both associated with choice of anticoagulant and risk factors for study outcomes so that 
they represent likely confounding variables in a comparative safety and effectiveness 
analysis. The underlying assumption is that these variables capture the most important 
predictors of treatment persistence.
Balance of baseline characteristics in the matched cohorts will be evaluated.  The utilization 
measures included in Table 3 will be described for the PS-matched cohort.  To properly 
account for differential follow-up, survival type analyses (i.e., Kaplan-Meier) will be used to 
describe time from treatment initiation to non-persistence (discontinuation or switch).  
Number of patients at risk for this treatment outcome will be provided at 3-month intervals.  
 
 
 
 
 
 
The various analyses are summarized below:
Analysis
Population
Outcome measure
Outcome 
type
Treatment initiation 
over time
Source population
Yearly initiation rate
Primary
Characteristics of 
anticoagulant users
Treatment cohort
-
Unmatched
-
Matched
 
Baseline characteristics
Primary
Utilization measures
Matched treatment 
cohort
-
Treatment non-
persistence (KM)
Secondary

Boehringer Ingelheim
Page 30 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.
STUDY LIMITATIONS
As an observational study, there are inherent limitations with respect to potential for alternate 
explanations for any observed association.
The source claims data include limitations with respect to certainty of the capture of 
exposure, covariates, and outcomes.  As a comprehensive insurance database, essentially all
billable medical services will result in claims for reimbursement, so that the certainty of 
capture is tied to likelihood of a claim being submitted to the insurer.
Although duration of atrial fibrillation may represent a risk factor for study outcomes, this 
covariate will be incompletely captured since the patient history in the dataset is relatively 
short (at least 12 months, and an average of approximately 2 years), and a first claim within 
the database may not represent atrial fibrillation onset since the condition is typically not 
diagnosed at its onset.
Dosing of warfarin in clinical practice is complicated, and estimating dose and duration of 
exposure based on healthcare utilization data is therefore challenging.  The “days’ supply” 
field is expected to be most meaningful, but the potential for misclassification exists.
New initiators are operationally defined as patients with no use in the prior 12 months. This 
does not ensure, however, that patients have never used anticoagulants; the possibility 
remains that these patients were treated at some prior time point before they enrolled in 
United or insurance plans that are part of the MarketScan database.
Medication use in United Healthcare and MarketScan data - as in all administrative 
healthcare databases - is restricted to prescription drug medication. Consequently, the use of 
over-the-counter (OTC) medications (e.g., OTC aspirin) is not captured. In addition, exposure 
is assessed based on prescription pick-up at a pharmacy and might be misclassified in “as 
treated” analysis if patients do not take their medications. However, misclassification of 
prescription drug exposure is generally considered less than in other exposure assessment 

Boehringer Ingelheim
Page 31 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
approaches, including physician prescribing records and patient self-reporting. [P13-03077; 
P13-03078]
6.
QUALITY ASSURANCE AND CONTROL
All aspects of data analysis will be conducted according to standard procedures of the 
. Programming for this project will be conducted by a 
primary analyst and validated by a separate analyst (validation analyst).  For all data 
processing and analysis steps, the validation analyst will review the program along with input 
and output data sets, and for select steps of the project will employ double programming 
techniques to reduce the potential for programming errors.
7.
ETHICAL/SCIENTIFIC APPROVAL
This study will be submitted to the Institutional Review Board (IRB) 
 

Boehringer Ingelheim
Page 32 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
STUDY MILESTONES AND RESPONSIBILITIES
Date
Phase 3
Data Source
Milestone
Month
United
Claims and lab data are 
released 
every 6 months in Jan 
and Jul 
(6-month lag time)
MarketScan
Claims data are released quarterly
in Mar, Jun, Sept, and Dec 
(9-month lag time) 
Lab data are released yearly 
in Dec (12-month lag time)  
Year 1
Jun, 2012
Contract
0
Jul, 2012
Draft Protocol
1
Mar, 2013
Protocol 
finalization
9
Year 2
Jun, 2013
Draft Interim 
Report* 
12
Jun, 2012
Aug, 2013
Interim Report
14
Jun, 2012
Dec, 2013
Interim Report
15
Dec, 2012
Oct, 2014
Interim Report
20
Jun, 2013
Claims through Mar 2013
Labs through Dec 2012
Year 3
Mar,2015
Interim Report
27
Dec, 2013
Claims through Sep 2013
Labs through Dec 2012
Aug, 2015
Interim Report
32
Jun, 2014
Claims through Mar 2014
Labs through Dec 2013
Year 4
Mar, 2016
Interim Report
39
Dec, 2014
Claims through Sep 2014
Labs through Dec 2013
Aug, 2016
Interim Report
44
Jun, 2015
Claims through Mar 2015
Labs through Dec 2014
Year 5
Jun, 2017
Final Report
54
Dec, 2015
Claims through Dec 2015
Labs through Dec 2014
 
 

Boehringer Ingelheim
Page 33 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The reports will include a core set of analyses with corresponding tables and figures that 
repeat with updated data in each of the 6 monthly blocks. 
 
The interim reports along with the draft and final reports will consist of a description of the 
methods, including patient selection and variable definitions.  This description will be 
followed by tables for each of the anticoagulant medications, follow-up characteristics 
(including adherence) and the utilization measures of interest.  The tables will be descriptive 
of all included medications and not include explicit comparisons.  The tabular results will be 
followed by an interpretive summary along with a discussion of the findings and 
implications.
9.
DISTRIBUTION OF RESULTS
Manuscripts describing this work will be submitted for publication in peer-review journals. 
Findings may also be submitted for presentation at scientific conferences.
10.
FUNDING
Boehringer Ingelheim GmbH

Boehringer Ingelheim
Page 34 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.
APPENDICES
11.1
APPENDIX 1: LIST OF FIGURES AND TABLES
List of Core Tables 
These tables will be generated separately for United and MarketScan; and will be presented 
only for incident and former users combined, unless meaningful differences between 
characteristics of incident and former users are observed.
Table 1
Treatment initiation over time
Table 2
Characteristics of Anticoagulation Users: all time periods combined 
Table 3
Characteristics of Anticoagulation users: latest time period 
Table 4
Adherence metrics for Anticoagulation users: all time periods combined 
Table 5
Adherence metrics for Anticoagulation users: latest time period 
Table 6
Table 7
Characteristics of continuers, switchers (combined and by treatment switched 
to), and discontinuers at 3 months: characteristics measured during the 12-
months preceding treatment initiation.  
Table 8
Characteristics of continuers, switchers, and discontinuers at 3 months: 
characteristics measured during the 3-months immediately preceding the 
event (day of switch, day of discontinuation, day 90 for continuers).
Table 9
Characteristics of continuers, switchers, and discontinuers at 6 months: 
characteristics measured during the 12-months preceding treatment 
initiation.  
Table 10
Characteristics of continuers, switchers, and discontinuers at 6 months: 
characteristics measured during the 3-months immediately preceding the 
event (day of switch, day of discontinuation, day 180 for continuers).
Table 11
Characteristics of continuers, switchers, and discontinuers at 12 months: 
characteristics measured during the 12-months preceding treatment 
initiation.  
Table 12
Characteristics of continuers, switchers, and discontinuers at 12 months: 
characteristics measured during the 3-months immediately preceding the 
event (day of switch, day of discontinuation, day 360 for continuers).  
List of Core Figures 
These figures will be generated separately for United and MarketScan
Figure 1:
Cumulative incidence of treatment switches - 30 day gap

Boehringer Ingelheim
Page 35 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Figure 2:
Cumulative incidence of treatment discontinuation – 30 day gap
Figure 3:
Cumulative incidence of treatment switches or discontinuation – 30 day gap

Boehringer Ingelheim
Page 36 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 37 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 38 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.2
APPENDIX 2: STUDY FIGURES
NOAC: New Oral Anticoagulant
Figure A1
Patient selection flow diagram (CONSORT Style)
United Health and 
MarketScanData
2009-2011, 
2012-2015
(N= ???)
(N= ???)
Include: 
Patients with non-valvular atrial fibrillation and first 
warfarin or NOAC dispensing
Exclude: 
Patients with <12 months prior enrollment
Patients with missing or ambiguous age or sex
NOAC
(N= ???)
Warfarin
(N= ???)

Boehringer Ingelheim
Page 39 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 40 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 41 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 42 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 43 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 44 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 45 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 46 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 47 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 48 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 49 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 50 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 51 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 52 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 53 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.4
APPENDIX 4: LIST OF ALL ABBREVIATIONS INCLUDED IN THE 
PROTOCOL
ACCP
American College of Chest Physicians
ACEI
Angiotensin-converting Enzyme Inhibitor
AES
Advanced Encryption Standard
AF
Atrial Fibrillation
ARB
Angiotensin Receptor Blocker
ASCVD
Atherosclerotic Cardiovascular Disease
BB
Beta Blocker
BI
Boehringer Ingelheim
BMI
Body Mass Index
CAD
Coronary Artery Disease
CCB
Calcium Channel Blocker
CHA2DS2-VASc
Congestive Heart Failure, Hypertension, Age > 75, Diabetes 
Mellitus, Prior Stroke or Transient Ischemic Attack, Vascular 
Disease, Age 65-74, Sex Category
CHADS2
Congestive Heart Failure, Hypertension, Age> 75, Diabetes 
Mellitus, Prior Stroke or Transient Ischemic Attack
CHF
Congestive Heart Failure
CI
Confidence Interval
CONSORT
Consolidated Standards for Reporting Trials
CPT
Current Procedural Terminology
Cr
Creatinine
DM
Diabetes Mellitus
DVT
Deep Venous Thromboembolism
Dx
Diagnosis-Related Group
ESC
European Society of Cardiology
FU
Follow Up
GFR
Glomerular Filtration Rate
GI
Gastrointestinal
H2 Receptor
Histamine H2 Receptor

Boehringer Ingelheim
Page 54 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
HAS-BLED
Hypertension, Abnormal Liver/Renal function, Stroke, Bleeding 
history or predisposition, Labile INR, Elderly (Age >65), Drugs-
Alcohol usage
HCPC
Healthcare Common Procedure Coding
ICD-9
International Classification of Diseases, Ninth Revision
INR
International Normalized Ratio
ITT
Intent-To-Treat
MI
Myocardial Infarction
MPR
Medication Possession Ratio
NOAC
New Oral Anticoagulant
NSAID
Non-steroidal Anti-inflammatory Drug
NVAF
Non-valvular Atrial Fibrillation
PAD
Peripheral Artery Disease
PDC
Proportion of Days Covered
PE
Pulmonary Embolism
PPI
Proton Pump Inhibitor
PPV
Positive Predictive Value
PS
Propensity Score
PVD
Peripheral Vascular Disease
PY
Person-Year
RE-LY
Randomized Evaluation of Long-Term Anticoagulation Therapy
Rx
Prescription
SCr
Serum Creatinine
SD
Standard Deviation
s.e.
Standard Error
TIA
Trans-Ischemic Attack
US
United States
VTE
Venous Thromboembolism

Boehringer Ingelheim
Page 55 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 56 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 57 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 58 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 59 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 60 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 61 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 62 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 63 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 64 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
12.
REFERENCES
P06-10925
GageBF, WatermanAD, ShannonW, BoechlerM, RichMW, Radford MJ
Validation of clinical classification schemes for predicting stroke:
results from the National Registry of Atrial Fibrillation.
JAMA 285 (22), 2864 - 2870 (2001)
P06-11504
SikkaR, Magauran B, Ulrich A, Shannon M
Bench to bedside: pharmacogenomics, adverse drug interactions, and 
the cytochrome P450 system.
Acad Emerg Med 12 (12), 1227 - 1235 (2005)
P09-11669
ConnollySJ, EzekowitzMD, YusufS, Eikelboom J, Oldgren J, Parekh A, 
Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier 
D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, 
Wallentin L, RE-LY Steering Committee and Investigators
Dabigatran versus warfarin in patients with atrial fibrillation.
N Engl J Med 361 (12), 1139 - 1151 (2009)
P12-01676
YouJJ, SingerDE, HowardPA, Lane DA, Eckman MH, Fang MC, Hylek 
EM, Schulman S, Go AS, Hughes M, Spencer FA, Manning WJ, 
Halperin JL, Lip GYH
Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and 
prevention of thrombosis, 9th ed: American College of Chest Physicians 
Evidence-Based Clinical Practice Guidelines.
Chest 141 (2) (Suppl), e531S - e575S (2012)
P12-05791
U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER)
Guidance for industry: drug interaction studies - study design, data 
analysis, implications for dosing, and labeling recommendations (draft 
guidance, February 2012 (this guidance document is being distributed 
for comment purposes only)).
website: 
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guida nces/ucm292362.pdf (access date: 14 May 2012) ; U.S. 
Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 
(2012)
P12-08021
PotparaTS, Lip GYH, Apostolakis S
New anticoagulant treatments to protect against stroke in atrial 
fibrillation.
Heart (Lond) 98 (18), 1341 - 1347 (2012)
P12-08478
SchneeweissS, Gagne JJ, Patrick AR, Choudhry NK, AvornJ
Comparativeefficacyandsafetyofneworalanticoagulantsinpatientswithatri
alfibrillation.
Circ Cardiovasc Qual Outcomes 5 (4), 480 - 486 (2012)

Boehringer Ingelheim
Page 65 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
P12-11192
CammAJ, Lip GYH, CaterinaRde, Savelieva I, Atar D, Hohnloser SH, 
Hindricks G, Kirchhof P
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 33 (21), 2719 - 2747 (2012)
P13-03077
West SL, Strom BL, Freundlich B, Normand E, Koch G, Savitz DA. 
Completeness of prescription recording in outpatient medical records 
from a health maintenance organization. J Clin Epidemiol 1994;47:165-
71
P13-03078
West SL, Savitz DA, Koch G, Strom BL, Guess HA, Hartzema A. 
Recall accuracy for prescription medications: self-report compared with 
database information. Am J Epidemiol 1995;142:1103-12
R03-1232
GoAS, HylekEM, BorowskyLH, PhillipsKA, SelbyJV, Singer DE
Warfarin use among ambulatory patients with nonvalvular atrial 
fibrillation: the AnTicoagulation and Risk Factors in Atrial Fibrillation 
(ATRIA) study.
Ann Intern Med 131 (12), 927 - 934 (1999)
R10-5332
Lip GYH, NieuwlaatR, PistersR, LaneDA, Crijns HJGM
Refining clinical risk stratification for predicting stroke and 
thromboembolism in atrial fibrillation using a novel risk factor-based 
approach: the Euro Heart Survey on Atrial Fibrillation.
Chest 137 (2), 263 - 272 (2010)
R10-6394
PistersR, LaneDA, NieuwlaatR, VosCBde, Crijns HJGM, Lip GYH
A novel user-friendly score (HAS-BLED) to assess 1-year risk of major 
bleeding in patients with atrial fibrillation: the Euro Heart Survey.
Chest 138 (5), 1093 - 1100 (2010)
R11-4190
GrangerCB, et al, ARISTOTLE Committees and Investigators
Apixaban versus warfarin in patients with atrial fibrillation.
N Engl J Med 365 (11), 981 - 992 (2011)
R11-4223
PatelMR, MahaffeyKW, GargJ, Pan G, Singer DE, Hacke W, Breithardt 
G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini 
JF, Berkovitz SD, Fox KAA, Califf RM, ROCKET AF Steering 
Committee, ROCKET AF Investigators
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
N Engl J Med 365 (10), 883 - 891 (2011)
R11-4329
WinkelmayerWC, SchneeweissS, MogunH, PatrickAR, AvornJ, 
Solomon DH
Identification of individuals with CKD from Medicare claims data: a 
validation study.
Am J Kidney Dis 46 (2), 225 - 232 (2005)
R11-4334
Birman-DeychE, WatermanAD, YanY, NilasenaDS, RadfordMJ, Gage 

Boehringer Ingelheim
Page 66 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BF
Accuracy of ICD-9-CM codes for identifying cardiovascular and stroke 
risk factors.
Med Care 43 (5), 480 - 485 (2005)
R12-0541
FribergL, RosenqvistM, Lip GYH
Evaluation of risk stratification schemes for ischaemic stroke and 
bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial 
Fibrillation cohort study.
Eur Heart J, (2012)
R12-3661
OlesenJB, Lip GYH, Kamper AL, Hommel K, Kober L, Lane DA, 
Lindhardsen J, Gislason GH, Torp-Pedersen C
Stroke and bleeding in atrial fibrillation with chronic kidney disease.
N Engl J Med 367 (7), 625 - 635 (2012)
R12-3689
CramerJA, RoyA, BurrellA, Fairchild CJ, Fuldeore MJ, Ollendorf DA, 
Wong PK
Medication compliance and persistence: terminology and definitions.
Value Health 11 (1), 44 - 47 (2008)
R13-0521
Molnar AO, Coca SG, Devereaux PJ, Jain AK, Kitchlu A, Luo J, Parikh 
CR, Paterson JM, Siddiqui N, Wald R, Walsh M, Garg AX
Statin use associates with a lower incidence of acute kidney injury after 
major elective surgery.
J Am Soc Nephrol 22, 939 - 946 (2011)
R13-0540
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Coso FG
Using serum creatinine to estimate glomerular filtration rate: accuracy 
in good health and in chronic kidney disease.
Ann Intern Med 141 (12), 929 - 937 (2004)
R13-0541
Fitzmaurice GM, Laird NM, Ware JH
Applied longitudinal analysis.
website: hsph.harvard.edu/fitzmaur/ala/ (access date: 7 February 2013) 
(Wiley Series in Probability and Statistics) 2nd ed. Hoboken: John 
Wiley & Sons (2004)
R13-0542
Karve S, Cleves MA, Helm M, Hudson TJ, West DS, Martin BC
An empirical basis for standardizing adherence measures derived from 
administrative claims data among diabetic patients.
Med Care 46 (11), 1125 - 1133 (2008)
R13-0543
Schneeweiss S, Avorn J
A review of uses of health care utilization databases for epidemiologic 
research on therapeutics.
J Clin Epidemiol 58, 323 - 337 (2005)
R13-4176
Olesen JB, Lip GYH, Hansen PR, Lindhardsen J, Ahlehoff O, 
Andersson C, Weeke P, Hansen ML, Gislason GH, Torp-Pedersen C
Bleeding risk in 'real world' patients with atrial fibrillation: comparison 
of two established bleeding prediction schemes in a nationwide cohort.

Boehringer Ingelheim
Page 67 of 67
Protocol for observational studies based on existing data
Study No.: 1160.177
c02790280-01
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
J Thromb Haemost 9, 1460 - 1467 (2011)
R13-5082
Giugliano RP, et al, ENGAGE AF-TIMI 48 Investigators
Edoxaban versus warfarin in patients with atrial fibrillation.
N Engl J Med 369 (22), 2093 - 2104 (2013)
R96-0690
CockcroftDW, Gault MH
Prediction of creatinine clearance from serum creatinine.
Nephron 16 (1), 31 - 41 (1976)

 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Version Number:
Document Name: 
 
 
 
                                                                                                                      
 
Title: 
 
 
 
 
                                                                                                                     
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02790280
1.0
1160-177--protocol
A description of warfarin and NOAC utilization patterns including initiation,
switching, and discontinuation. (Phase 3 of the BI/BWH Pradaxa study program)
Approval-Pharmacovigilance
Representative
31 Jul 2014 16:12 CEST
Approval-Team Member Medical
Affairs
31 Jul 2014 21:40 CEST
Author-Other
01 Aug 2014 10:06 CEST
Approval-Therapeutic Area 
01 Aug 2014 13:41 CEST
Approval-
 Pharmacovigilance
03 Aug 2014 21:12 CEST
Verification-Paper Signature
Completion
05 Aug 2014 16:20 CEST
Approval-Other
05 Aug 2014 17:18 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 
Version Number:
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02790280
1.0