Safety and Effectiveness Study Comparing Dabigatran, Rivaroxaban & Apixaban in Non-valvular Atrial Fibrillation Patients Enrolled in the US Department of Defense Military Health System
Conditions: Atrial Fibrillation
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c14336616-01
BI Study Number:
1160.274
BI Investigational
Product(s):
Pradaxa
Title:
The Comparative Safety and Effectiveness of dabigatran, versus 
rivaroxaban, and apixaban Utilized in the Department of Defense 
(DoD) Non-Valvular Atrial Fibrillation Patient Population-A 
Retrospective Database Analysis
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
N/A
PASS:
Yes
EU PAS register 
number:
EUPAS16528
Active substance:
Dabigatran etexilate
Medicinal product:
Pradaxa
Product reference:
N/A
Procedure number:
N/A
Joint PASS:
No
Research question and 
objectives:
To assess the safety and effectiveness of newly initiated dabigatran 
among patients diagnosed with  NVAF in comparison to newly 
initiated rivaroxaban users and newly initiated apixaban users in 
two (2) separate study cohorts 

dabigatran vs. rivaroxaban 

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001-MCS-90-124_RD-01 (4.0)

dabigatran vs. apixaban
Country(-ies) of study:
United States
Author(s):
Marketing 
authorization holder(s):
Boehringer Ingelheim International GmbH
MAH contact person:
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Date:
15Dec2016
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................ 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 8
4.
ABSTRACT........................................................................................................... 9
5.
AMENDMENTS AND UPDATES..................................................................... 16
6.
MILESTONES..................................................................................................... 17
7.
RATIONALE AND BACKGROUND................................................................ 18
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 20
9.
RESEARCH METHODS .................................................................................... 20
9.1
STUDY DESIGN............................................................................................ 20
9.2
SETTING........................................................................................................ 20
9.3
VARIABLES .................................................................................................. 23
9.3.1
Exposures ................................................................................................ 23
9.3.2
Outcomes................................................................................................. 23
........................................................................24
9.3.3
Covariates................................................................................................ 24
9.4
DATA SOURCES........................................................................................... 26
9.5
STUDY SIZE.................................................................................................. 28
9.6
DATA MANAGEMENT................................................................................ 29
9.7
DATA ANALYSIS......................................................................................... 29
9.7.1
Main analysis........................................................................................... 30
....................................................................................... 32
9.8
QUALITY CONTROL................................................................................... 32
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 33
9.10
OTHER ASPECTS ......................................................................................... 33
9.11
BIAS................................................................................................................ 33
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 34
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 35
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 36

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13.
REFERENCES .................................................................................................... 37
13.1
PUBLISHED REFERENCES......................................................................... 37
13.2
UNPUBLISHED REFERENCES................................................................... 37
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 38
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 89
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 90

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2.
LIST OF ABBREVIATIONS
ACE
angiotensin-converting-enzyme inhibitor
AE
Adverse Event
AF
Atrial Fibrillation
ARB
Angiotensin receptor blockers
BIPI
Boehringer Ingelheim Pharmaceuticals Inc
CDR
Clinical data repository
CHA2DS2-VASc
Congestive heart failure, Hypertension, Age ≥75 years (doubled), 
Diabetes mellitus, Stroke (doubled), Vascular disease, Age 65–74 
years, Sex category
CHADS2
Congestive heart failure, Hypertension, Age ≥75 years, Diabetes 
mellitus, Prior Stroke or TIA or Thromboembolism
CCI
Charlson comorbidity index 
CI
Confidence Interval
COPD
Chronic objective pulmonary disease
DEERS
Defense eligibility enrollment reporting system
DoD
Department of Defense
DRG
Diagnosis-related group
EMR
electronic medical record
ER
emergency room
FDA
Federal drug administration
FFS
fee-for-service
GERD
Gastroesophageal reflux disease
GI
Gastrointestinal
GIH
gastrointestinal hemorrhage
HASBLED
Hypertension, Abnormal renal/liver function, Stroke, Bleeding history 
or predisposition, Labile International Normalized Ratio, Elderly, 
Drugs/alcohol concomitantly
HIPAA
health insurance portability and accountability act
HIV
Human immunodeficiency virus

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HMO
health maintenance organization
ICD
International classification of diseases
ICH
intracerebral hemorrhage
IPTW
Inverse probability to weighting
IR
Incidence Rate
IRB
Institutional Review Board
KM
Kaplan-Meier
MB
Major bleed
MDR
Military health system data repository
MHS
Military health system
MTF
military treatment facilities
N
Number
NDC
National drug code
NVAF
Non-valvular Atrial Fibrillation
NOAC
Non-Vitamin K antagonist oral anticoagulant 
NSAID
Non-steroidal anti-inflammatory drug
OV
office visit
PDTS
Pharmacy data transaction system
PPI
Proton pump inhibitor
PPO
preferred provider organization
PSM
Propensity score matching
PS
Propensity Score 
PSTAT
Project Statistician
PY
Person-years at risk

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RCT
Randomized controlled trial
RR
Rate Ratio
SD
Standard deviation
SAS
Statistical analysis software
TIA
transient ischemic attack
Tx
Treatment
VPN
Virtual private network

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3.
RESPONSIBLE PARTIES
Medical Affairs
Email: 
Biostatistics 
Email:
Email: 
Principal Investigator (DoD)
Email: 
Associate Investigator (DoD)
Email:
Senior 
, RWE
Email: 
, Biostatistics Late Stage
Email: 

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Pradaxa
Name of active ingredient:
dabigatran etexilate
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
15Dec2016
1160.274
1.0
N/A
Title of study:
The Comparative Safety and Effectiveness of dabigatran, versus 
rivaroxaban, and apixaban Utilized in the Department of Defense 
(DoD) Non-Valvular Atrial Fibrillation Patient Population-A 
Retrospective Database Analysis
Rationale and 
background:
Due to the emergence of multiple pharmaceutical alternatives to 
warfarin, physicians in the US are faced with many 
anticoagulation options. To help inform their decisions physicians 
want to know the comparative safety and efficacy profiles of 
these new agents.
Now that real world experience with dabigatran for NVAF 
patients has accrued, the safety and effectiveness for dabigatran, 
rivaroxaban, and apixaban may also be assessed and compared in 
this setting.
Boehringer Ingelheim Pharmaceuticals Inc. (BIPI) has an 
opportunity to collaborate with DoD to conduct comparative 
safety and effectiveness studies of dabigatran, rivaroxaban, and 
apixaban using already existing real world data from DoD’s 
claims and EMR data.
Research 
question and 
objectives:
To assess the safety and effectiveness of newly initiated 
dabigatran among patients diagnosed with  NVAF in comparison 
to newly initiated rivaroxaban users and newly initiated apixaban 
users in two (2) separate study cohorts:

dabigatran vs. rivaroxaban 

dabigatran vs. apixaban
Study design:
Non-interventional study based on existing data with propensity 
score matching (PSM)
Population:
NVAF patients, ≥18 years of age, enrolled within the DoD
Military Health System (MHS) who have newly initiated 
dabigatran, rivaroxaban or apixaban. Patients must be treatment 
naïve from OAC use prior to first (index) NOAC.

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Variables:
Covariates

Gender

Age 

Geographic location

Health plan type

Baseline comorbid conditions

Pre-index medication use

NOAC prescribing provider type

Baseline Charlson comorbidity index 

Baseline stroke risk (CHADS2  and CHA2DS2-VASc)

Baseline bleeding risk (modified HAS-BLED) 

Index exposure

Time to index exposure

Duration of follow-up
Primary outcomes

Stroke overall (hemorrhagic, ischemic, uncertain)

Major bleeding, overall
Secondary outcomes

Ischemic stroke

Hemorrhagic stroke

Major intracranial bleeding

Major extracranial bleeding
o
Major GI bleeding
o
Major other bleeding

TIA

All-cause mortality
Data sources:
Military Health System Data Repository (MDR)
Study size:
Initial study feasibility counts show newly initiated dabigatran 
among patients diagnosed with  NVAF in comparison to newly 
initiated rivaroxaban users and newly initiated apixaban users in 
two (2) separate study cohorts:

dabigatran (n= 16,604) vs. rivaroxaban (n=25,215);   July 
1, 2011 to June 30, 2016

dabigatran (n=6,050) vs. apixaban (n=20,930); December 
28, 2012 to June 30, 2016
These numbers are based on initial inclusion/exclusion criteria as 

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specified above.  Additional inclusion/exclusion criteria will 
reduce population sizes further but feasibility estimates provide 
strong support for necessary sample size.
Data analysis:
The target population will include OAC treatment naïve NVAF 
patients with at least one prescription claim for dabigatran, 
rivaroxaban or apixaban. For each patient treated with a NOAC, 
the date of the first NOAC prescription (index exposure) will 
serve as the index date. Only those patients whose index date 
occurs between the respective study periods will be included. The 
12-month period prior to the index date will be defined as the pre-
index period. The patients will be required to have a NVAF 
diagnosis in the pre-index period (including index date).
Study period NOT including pre-index period:

Dabigatran vs. Rivaroxaban: July 1, 2011 to June 30, 
2016 

Dabigatran vs. Apixaban: December 28, 2012 to June 30, 
2016
Study period including pre-index period:

Dabigatran vs. Rivaroxaban: July 1, 2010 to June 30, 2016 

Dabigatran vs. Apixaban: December 28, 2011 to June 30, 
2016
Standard dosing for each NOAC will be used for main analyses.  
All doses for each NOAC will be combined for a sensitivity 
analysis. Standard dose for NOAC’s:

Dabigatran 150 mg, twice daily, total daily dose of 300 
mg

Rivaroxaban 20 mg, once daily, total daily dose of 20 mg

Apixaban 5 mg, twice daily, total daily dose of 10 mg
Length of Follow-up:
The post-index follow-up period will begin the day following the 
NOAC index date and end on whichever of the following occurs 
earliest:

The day of discontinuation of the index NOAC exposure;

The day before a switch to an anticoagulant different from 
the index exposure;

The day before a change in dose for the index NOAC;

The end of continuous eligibility of a patient in the health 
plan (disenrollment);

The end of the study observation period; or

The date of death of the patient.

The last date of calculated days supplied if treatment gap 

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>30 days
Patients need at least two days of exposure to the index NOAC to 
ensure they had at least one day of index NOAC exposure in the 
post-index follow-up period. A sensitivity analysis will also be 
performed using a 14 day treatment gap. 
Both claims-level data, including diagnosis codes, procedure 
codes, pharmacy dispensed drugs, cost information, and 
enrolment data, as well as EHR-level data, including relevant lab 
tests and results, will be extracted for all applicable patients.  
Patient demographics, treatment history, and comorbidities, will 
be derived from the electronic database.  Start and stop dates of 
each course of treatment will be coded from the pharmacy and 
medical claims data using rules to be developed in the study 
protocol.  Comorbidities of interest will be ascertained through 
ICD-9 and ICD-10 diagnosis codes, in combination with 
procedures and medications, as appropriate to the study protocol 
definitions.  
To account for potential selection bias, the study cohorts 
(dabigatran/rivaroxaban and dabigatran/apixaban) will be 
matched on their baseline characteristics using the propensity 
score matching (PSM) method.  The PSM aims to balance the two 
treatment groups on baseline demographics, health plan type and 
clinical characteristics. The feasibility of PSM will be evaluated 
based on available sample size and descriptive results. If patient 
characteristics between dabigatran/rivaroxaban and 
dabigatran/apixaban cohorts are significantly different, i.e., less 
than 50% of patients in the dabigatran group can be matched to
the rivaroxaban or apixaban group based on PSM, then the study 
design will be re-evaluated before proceeding to analysis. The 
Nearest Neighbor method of propensity score matching within a 
caliper of 0.10-0.20 (depending on resulting sample sizes) of the 
standard deviation of the estimated logit will be used to select the 
matched samples.
The propensity score models will include baseline variables 
known to be confounders or factors related to the outcome only,
including age, gender, health plan type, geographic region, month 
and year of index date, Charlson comorbidity index (CCI), stroke 
risk scores (i.e. CHADS2 or CHA2DS2-VASc), bleeding risk 
scores (i.e., modified HAS-BLED), specified comorbid 
conditions and medication use, based on literature and clinical 
relevance, as well as empirical data (top diagnoses, procedures, 
etc.) that may account for possible unforeseen confounding.  

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Descriptive Statistics
Patient characteristics, including demographics, will be reported 
for NVAF patients treated with dabigatran, rivaroxaban, or 
apixaban. Stroke risk will be quantified using the CHADS2, 
CHA2DS2-VASc score and bleeding risk through the HAS-BLED 
score Other descriptive variables may include the following:
Comorbid conditions at baseline:

Cancer 

Rheumatoid arthritis

Coronary artery disease

Acute myocardial infarction

Cardiomyopathy

Ischemic stroke

Stroke (all types)

TIA

Congestive heart failure

Left ventricular heart failure 

Hypertension

Peripheral artery disease

Liver disease

Renal disease

COPD/emphysema

Diabetes

Peptic ulcer (bleeding or non-bleeding)

GERD

Venous thromboembolism 

Hyperlipidemia

HIV infection

Bone marrow disease (thrombocytopenia, chronic anemia, 
myelofibrosis) 

Coagulopathy (hemophilia, Von Willebrand disease)

Chronic kidney disease
Medication History and Concomitant Use:

Non-Oral Anticoagulants: Number of prescription fills 
(normalized to a 30-day supply) will be captured during 
the pre-index period (See Appendix A, Table 8)
o
Argatroban (can be used in procedures in lieu of 
heparin)
o
Unfractionated Heparin (Heparin) 
o
Low Molecular Weight Heparins:

Enoxaparin

Tinzaparin

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
Dalteparin

Fondaparinux

Other medication use: Use of other medications will be 
determined if patients had ever filled a medication in the 
following drug classes during the pre-index period (See 
Appendix A, Table 3, Table 8). 
o
Beta blockers
o
Calcium channel blockers
o
Diuretics
o
Other antihypertensives (i.e., angiotensin-
converting-enzyme (ACE) inhibitors, 
combinations)
o
Antihyperlipidemics
o
Corticosteroids
o
Antidiabetics
o
Antiarrhythmics (Amiodarone HCl, Propafenone 
and Flecainide, Dronedarone, Betapace (Sotalol), 
Tikosyn, Disopyramide (Norpace), Quinidine)
o
Ketoconazole
o
Antiplatelets (e.g., dypridamole, aspirin, etc.)
o
NSAIDs
Outcome Analysis
The follow-up period, which comprises the patient-time 
denominator, will start at index and will be censored at the first 
occurrence of either of the following:

outcome event

switch to another anticoagulant

change in dose of index NOAC

discontinuation of therapy, as defined as a gap in therapy 
exceeding 30 days (a 14 day gap sensitivity analysis will 
also be performed) 

end of DoD eligibility

end of study period
Primary outcomes

Stroke overall (hemorrhagic, ischemic, uncertain)

Major bleeding, overall
Secondary outcomes

Ischemic stroke

Hemorrhagic stroke

Major intracranial bleeding

Major extracranial bleeding
o
Major GI bleeding
o
Major other bleeding

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
TIA

All-cause mortality
The first occurrence of each outcome will be identified, 
separately. For each outcome, event rates and 95% confidence 
intervals (CI) will be calculated using a person-time approach for 
each treatment and further stratified by age and gender.  Time-to-
event analyses (i.e. Kaplan-Meier analysis and Cox proportional 
hazards model analysis) will be performed for each treatment 
comparison. Details will be laid out in the protocol and approved 
by the 
-
-DoD-BIPI study teams.
Sensitivity, subgroup and/or exploratory analyses will be 
performed and may impact changes to the definitions to the 
assigned cohort, covariates, or outcome.  Potential 
sensitivity/subgroup/exploratory analyses are below:
Milestones:
Protocol Completion 
Data Extraction, Preparation, and QA 
Data Analysis 
Develop Final Report 

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone:
Planned date:
Protocol finalization
02 December 2016
BI Approval
05 December 2016
Start of data evaluation and specific 
programming rules development:
19 October 2016
Start of data analysis:
05 December 2016
Completion of ACC data analyses-
Primary analyses with PSM
17 January 2016
Completion of data analyses- Secondary 
analyses with PSM 
31 January 2017
Completion of data analyses-Sensitivity 
analyses (not including IPTW) with PSM
14 February 2017
Completion of data analyses-IPTW 
analyses
10 March 2017
Final report of study results:
March 2017

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7.
RATIONALE AND BACKGROUND
Non-valvular atrial fibrillation (NVAF) is an abnormal heart rhythm characterized by rapid 
and irregular beating. Patients may experience shortness of breath, palpitations, fainting, or 
chest pain. Anticoagulants have long been used to decrease the risk of stroke in NVAF 
patients and the efficacy of blood thinners have been well studied. 
Until recently, warfarin, which was FDA-approved in 1954, was the only drug on the market 
used to prevent stroke in patients with NVAF. In the last few years, the FDA has approved 
three NOACs – dabigatran, rivaroxaban, and apixaban. All three NOACs have shown 
efficacy in reducing the overall risk of stroke, but, can also increase the risk for bleeding.
In several clinical trials that included more than 50,000 patients from around the world, 
studies concluded that all three NOACs were either equivalent to, or more effective than, 
warfarin in preventing strokes, with an acceptable risk of bleeding.1-6  NOACs have some 
advantages, including fewer interactions with food and other drugs, rapid onset, and freedom 
from the need to have periodic blood test monitoring. Additionally the effects of these drugs 
wane within a short time frame after they are stopped, a day or so, while the effects of 
warfarin persist for many days after it is discontinued, potentially causing a slower resolution 
to bleeding events.
There is still an unmet need to truly understand utilization patterns of NOAC and non-NOAC 
therapies, as well as outcomes and safety associated with NOACs when compared to one 
another.  Many traditional insurance plans do not allow for lengthy follow-up periods, as 
patients tend to frequently switch insurance coverage and in some cases providers. Therefore, 
the ability to assess longitudinal real-world data in a large patient population poses an unmet 
need in the medical community.  The DoD patient population is well suited to help tackle 
these real-world issues due to its “closed loop system”.  DoD beneficiaries have much longer 
treatment durations and follow-up periods because beneficiaries tend to have longer coverage 
periods when compared to traditional commercial insurance plans. 
DoD, in collaboration with
 have successfully published prior findings in a reputable 
medical journal comparing dabigatran and warfarin in an NVAF patient population (1).  That 
study aimed to mitigate many of the potential biases and limitations of observational studies 
via vigorous methodology including inclusion of only newly treated patients, propensity 
score matching (PSM) to derive cohorts for comparison, and adjustments of covariates if 
needed based on imbalances left following PSM.  Additionally, rules were pre-specified to 
ensure that PSM analyses of outcomes were only performed if there were enough patients per 
cohort to support a robust analysis.  
The opportunity to expand on our initial study by including additional NOAC usage in a large 
patient population with a relatively long duration of continuous follow-up provides an 
outstanding opportunity to assess safety and outcomes in a real-world setting.  Results from 

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our findings may better inform clinical decisions across the DoD and international medical 
communities.

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8.
RESEARCH QUESTION AND OBJECTIVES
To assess the safety and effectiveness of newly initiated dabigatran among patients diagnosed 
with NVAF in comparison to newly initiated rivaroxaban users and newly initiated apixaban 
users in two (2) separate study cohorts:

dabigatran vs. rivaroxaban 

dabigatran vs. apixaban
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a retrospective database cohort analysis of the DoD population.
9.2
SETTING
A retrospective cohort study will be conducted using the DoD database. The target population 
will include OAC treatment naïve NVAF patients with at least one prescription claim for 
dabigatran, rivaroxaban or apixaban (new oral anticoagulant or NOAC). For each patient 
treated with a NOAC, the date of the first NOAC prescription (index exposure) will serve as 
the index date. Only those patients whose index date occurs between the respective study 
periods will be included. The 12-month period prior to the index date will be defined as the 
pre-index period. The patients will be required to have a NVAF diagnosis in the pre-index 
period (including index date). Inclusion and exclusion codes can be found in Appendix B.
Study period NOT including pre-index period:

Dabigatran vs. Rivaroxaban: July 1, 2011 to June 30, 2016 

Dabigatran vs. Apixaban: December 28, 2012 to June 30, 2016
Study period including pre-index period:

Dabigatran vs. Rivaroxaban: July 1, 2010 to June 30, 2016 

Dabigatran vs. Apixaban: December 28, 2011 to June 30, 2016
NOAC approval dates used for study period determination:

Dabigatran (Pradaxa®) – approved October 11, 2010

Rivaroxaban (Xarelto®) – approved July 1, 2011

Apixaban (Eliquis®) – approved December 28, 2012

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Subject Inclusion Criteria:

Age 18+ on index date 

Patients must have been prescribed either dabigatran, rivaroxaban, or apixaban 
identified by pharmacy claim during the study period. The first dispensing date of 
either study drug will be defined as the index date;

Patients must be treatment naïve from all OAC use prior to the first NOAC 
prescription, during study period.

Patients must have at least 12 months of continuous eligibility prior to the index 
date;

Patients must have at least one diagnosis code of atrial fibrillation, defined as ICD-
9-CM diagnosis of 427.31 or ICD-10-CM diagnosis of I48.0, I48.1, I48.2, I48.91 
on the index date or during the pre-index period.
Subject Exclusion:

Less than 12 months of continuous eligibility in the pre-index period

Any claim for OAC drug (oral use only) in the pre-index period

Diagnosis of hyperthyroidism during the pre-index period

Having at least one claim for alternative indications; orthopedic procedures, VTE
(includes DVT &PE) and the index NOAC prescription at the same time, or, the 
alternative indication for anticoagulant occurring within 3 months prior to index 
date in pre-period Having at least one claim with any of the following diagnoses or 
procedure codes in order to exclude patients with “transient” causes of Afib (3 
months prior to index date in pre-period):
o
Cardiac surgery 
o
Pericarditis 
o
Myocarditis

Having at least one medical claim with any of the following diagnoses or 
procedures codes in order to exclude patients with “valvular” Afib (pre-period): 
o
Mitral stenosis 
o
Mitral stenosis with insufficiency 
o
Mitral valve stenosis and aortic valve stenosis 
o
Mitral valve stenosis and aortic valve insufficiency 
o
Diseases of other endocardial structures 
o
Other and unspecified rheumatic heart diseases 
o
Open heart valvuloplasty without replacement 
o
Open and other replacement of unspecified heart valve 
o
Open and other replacement of aortic valve 

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o
Open and other replacement of mitral valve 
o
Open and other replacement of pulmonary valve
o
Open and other replacement of tricuspid valve 
o
Heart valve replaced by transplant 
o
Heart valve replaced by a mechanical device/prosthesis 
o
Atrioventricular valve repair
o
Aortic valve valvuloplasty 
o
Unlisted procedure, cardiac surgery 
o
Implantation of catheter-delivered prosthetic aortic heart valve; open 
thoracic approach 
o
Transthoracic cardiac exposure (e.g., sternotomy, thoracotomy, subxiphoid) 
for catheter-delivered aortic valve replacement; without cardiopulmonary 
bypass 
o
Transthoracic cardiac exposure (e.g., sternotomy, thoracotomy, subxiphoid) 
for catheter-delivered aortic valve replacement; with cardiopulmonary 
bypass 
o
Replacement, aortic valve, with cardiopulmonary bypass; with prosthetic 
valve other than homograft or stentless valve 
o
Valvuloplasty, mitral valve, with cardiopulmonary bypass 
o
Valvuloplasty, mitral valve, with cardiopulmonary bypass; with prosthetic 
ring 
o
Valvuloplasty, mitral valve, with cardiopulmonary bypass; radical
reconstruction, with or without ring 
o
Replacement, mitral valve, with cardiopulmonary bypass 
o
Implantation of catheter-delivered prosthetic pulmonary valve, 
endovascular approach 
o
Replacement, pulmonary valve 
o
Valvectomy, tricuspid valve, with cardiopulmonary bypass 
o
Valvuloplasty, tricuspid valve; without ring insertion 
o
Valvuloplasty, tricuspid valve; with ring insertion 
o
Replacement, tricuspid valve, with cardiopulmonary bypass 
Standard dosing for each NOAC will be used for main analyses. All doses for each NOAC 
will be combined for a sensitivity analysis. Standard dose for NOAC’s include:

Dabigatran 150 mg, twice daily for total daily dose of 300 mg

Rivaroxaban 20 mg, once daily for total daily dose of 20 mg

Apixaban 5 mg, twice daily for total daily dose of 10 mg
Length of Baseline
The 12-month period prior to and including the NOAC index date will be defined as the 
baseline period. Patients will be required to have an NVAF diagnosis during this baseline 
period.

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The pre-index period will serve as a look-back period to measure baseline covariate data and 
apply other inclusion and exclusion criteria.    
Length of Follow-up:
The post-index follow-up period will begin the day following the NOAC index date and end 
on whichever of the following occurs earliest:

The day of discontinuation of the index NOAC exposure;

The day before a switch to an anticoagulant different from the index exposure;

The day before a change in dose for the index NOAC;

The end of continuous eligibility of a patient in the health plan (disenrollment);

The end of the study observation period; or

The date of death of the patient.
Patients need at least two days of exposure to the index NOAC to ensure they had at least one 
day of index NOAC exposure in the post-index follow-up period.
For patients, index exposure will be considered discontinued if there is a treatment gap longer 
than the 30 day allowable gap specified from the end of the calculated days supplied.  
Patients that have treatment gap longer than the specified allowable gap will be censored at 
that point and follow-up will be discontinued.  A sensitivity analysis will also be performed 
using a 14 day treatment gap. 
9.3
VARIABLES
9.3.1
Exposures
Exposure to NOACs for the purpose of describing the potential study population will be 
identified by the presence of at least one prescription for dabigatran, rivaroxaban or apixaban. 
Please refer to Table 1 in Appendix A for the corresponding codes to identify each therapy. 
As described in Section 9.11 Study Population, the potential study population will be divided 
into the following two cohorts based on NOAC exposure:

Dabigatran vs. Rivaroxaban: July 1, 2011 to June 30, 2016 

Dabigatran vs. Apixaban: December 28, 2012 to June 30, 2016
Standard dosing for each NOAC will be used for main analyses. All doses for each NOAC 
will be combined for a sensitivity analysis.
9.3.2
Outcomes
The outcomes will be assessed during the post-index period for the two cohorts. If a patient 
discontinued the index NOAC or switched to a different NOAC, the outcomes assessment 
would not continue beyond the date of discontinuation or the switch. The primary and 
secondary outcomes assessed will be safety and effectiveness measures as described below in 
in the Outcomes of Interest table. 
The safety and effectiveness analysis will be conducted for the following cohorts:

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
Oral Anticoagulant treatment naive patients: Dabigatran vs. Rivaroxaban

Oral Anticoagulant treatment naive patients: Dabigatran vs. Apixaban
Outcomes of Interest 
Primary
Stroke (hemorrhagic, ischemic, uncertain classification)
Major bleeding
Secondary
Major bleeding, by the following sites

Major intracranial

Major extracranial
o
Major gastrointestinal
o
Other
Stroke by type 

Ischemic stroke

Hemorrhagic stroke
Transient ischemic attack (TIA)
All-cause mortality
Further 
9.3.3
Covariates
The following variables, but not limited to, will be used as covariates in the relevant analysis:

Gender: Gender will be determined from eligibility file. Dichotomous variable 
(male=1, female=0).

Age: Age in years will be determined on the index date. Continuous variable.

Geographic location: Geographic locations of patient residence will be determined 
from eligibility file and will be grouped based on the US census classification (i.e., 
Northeast, Midwest, South, and West regions). South region will be the reference 
location.

Health plan type: Health plan benefit designs such as health maintenance 
organization (HMO), preferred provider organization (PPO), fee-for-service (FFS), 
Medicare Advantage and Part D plan, etc. FFS is the reference plan type.

Baseline comorbid conditions: The comorbid conditions will be captured by any 
inpatient claim, any two physician office visit (OV) or emergency room (ER) visits, 

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or a combination of both (OV+ER) with a diagnosis of the following conditions in 
any position during  baseline (12 month pre-index period) (See Appendix A, Table 2, 
for ICD-9-CM) and ICD-10 codes:
o
Cancer 
o
Rheumatoid arthritis
o
Coronary artery disease
o
Acute myocardial infarction
o
Cardiomyopathy
o
Ischemic stroke
o
Stroke (all types)
o
TIA
o
Congestive heart failure
o
Left ventricular heart failure 
o
Hypertension
o
Peripheral artery disease
o
Liver disease
o
Renal disease
o
COPD/emphysema
o
Diabetes
o
Peptic ulcer (bleeding or non-bleeding)
o
GERD
o
Venous thromboembolism 
o
Hyperlipidemia
o
HIV infection
o
Bone marrow disease (thrombocytopenia, chronic anemia, myelofibrosis) 
o
Coagulopathy (hemophilia, Von Willebrand disease)
o
Chronic kidney disease
o
Baseline (pre-index) medication use
o
Non-Oral Anticoagulants: Number of prescription fills (normalized to a 
30-day supply) will be captured during the pre-index period (See Appendix 
A, Table 8)
•
Argatroban (can be used in procedures in lieu of heparin)
•
Unfractionated Heparin (Heparin) 
•
Low Molecular Weight Heparins:

Enoxaparin

Tinzaparin

Dalteparin

Fondaparinux
o
Other medication use: Use of other medications will be determined if 
patients had ever filled a medication in the following drug classes during 
the pre-index period (See Appendix A, Table 3, Table 8). 
•
Beta blockers
•
Calcium channel blockers
•
Diuretics
•
Other antihypertensives (i.e., angiotensin-converting-enzyme (ACE) 
inhibitors, combinations)

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•
Antihyperlipidemics
•
Corticosteroids
•
Antidiabetics
•
Antiarrhythmics (Amiodarone HCl, Propafenone and Flecainide, 
Dronedarone, Betapace (Sotalol), Tikosyn, Disopyramide (Norpace), 
Quinidine)
•
Ketoconazole
•
Antiplatelets (e.g., dypridamole, aspirin, etc.)
•
NSAIDs

Prescribing provider specialty of NOAC treatment on index date: The prescribing 
specialties will include cardiology, pulmonary medicine, hematology, internal 
medicine, family/general practice, geriatrics, surgery (all types, including vascular 
surgery), gastroenterology, neurology, emergency medicine, other physician types, 
other non-physician specialty, unknown.

Baseline Charlson comorbidity index (CCI) score: Baseline CCI measures specific 
individual comorbidities that are associated with mortality that are observed in the 
pre-index period. A score will be calculated based on CCI criteria. (See Appendix A, 
Table 4). 

Baseline stroke risk: This will be assessed during 12-month pre-index period using 
two alternative risk score schemes: 
(1) the CHADS2 stroke risk score is calculated by adding 1 point each for 
congestive heart failure, hypertension, diabetes, and age >75 years and 2 
points for prior stroke or TIA (See Appendix A, Table 5); 
(2) the CHA2DS2-VASc stroke risk score - calculated by adding 1 point each 
for congestive heart failure/left ventricle dysfunction, hypertension, diabetes,
vascular disease (prior myocardial infarction (MI), peripheral artery disease, 
or aortic plaque), age between 65-74, female gender, and 2 points for and age 
>75 years prior stroke or TIA (See Appendix A, Table 6).

Baseline bleeding risk: This will be assessed during the pre-index period using the 
bleeding score of modified HAS-BLED (See Appendix A, Table 7). 

Index exposure: NOAC on the index date 

Time to index exposure: The time period in days between the first AF diagnosis 
observed in the pre-index period and the index date

Newly vs. Previously AF diagnosed: patients with a claim for AF <3 months before 
the index date will be classified as newly diagnosed. Patients with a claim >3 months 
before the index date will be classified as previously diagnosed. 

Duration of follow-up period: The time period in days between the index date and 
the end of follow-up.
9.4
DATA SOURCES
The study will use the Military Health Systems (MHS) database.
The US DoD operates the largest cradle-to-grave health care database in the US. The military 
database has over 30 billion archived records, including 5 billion online records spanning 

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over 11 years for EMRs, 20 years of ePrescribing, and decades of prescription, inpatient, and 
outpatient data. Its size increases by 230,000 outpatient encounters and 2,700 inpatient 
admissions every day. As a single-payer, fully budgeted $55 billion health care system, there 
are uniform medical coverage and pharmacy benefits for the 10 million active people served. 
The pharmacy benefit in particular has minimal expenses for most patients, thus positioning 
the DOD as a dynamic platform for patient adherence. It is completely free of expense for 
patients utilizing military treatment facilities (MTF) and clinics. These data are commercially 
available only through 
.
The MHS provides 2 types of care to its beneficiaries. It provides direct care through a 
network of over 60 military hospitals and 411 clinics and purchased care provided by civilian 
providers financed through managed care contracts and fee-for-service reimbursements 
globally. Direct care accounts for approximately 40% of the total care provided, with the 
balance being purchased from civilian providers. All the administrative events generated by 
either a direct care or purchased care inpatient or outpatient encounter are centrally processed 
into the MDR. Examples of the data recorded in such encounters include patient demographic 
data, provider information (provider ID, specialty, facility), diagnostic codes (ICD-9 codes 
for outpatient; diagnosis-related group [DRG] codes for inpatient), and Current Procedural 
Terminology (CPT) codes for any procedures. Extensive information regarding the patient, 
including age, race, and gender, is also stored within the MDR via connections with the 
Defense Eligibility Enrollment Reporting System (DEERS). The military utilizes an 
electronic medication system called the Pharmacy Data Transaction System (PDTS). All the 
prescribing details of both direct care and purchased care outpatient medication orders, 
including mail order, are electronically coded, including the prescribed drug name and NDC, 
dose, quantity, refills, and prescribing provider. All PDTS information is fed into the MDR. 
In addition to feeding data into the MDR, direct care encounters conducted at MTFs utilize 
the military’s EMR system, called AHLTA. This robust EMR system stores the entire 
encounter electronically and is powered by the MEDCIN® Engine; AHLTA is therefore 
designed with extensive variables documenting the individual components of an encounter, 
including symptoms, vital signs, history, physical exams, laboratory and radiology results, 
diagnostic codes, procedure codes, pharmacy orders, and other orders such as specialty 
consultation. The AHLTA dataset for each encounter is stored within the Clinical Data 
Repository (CDR). Aspects of the CDR feed into the MDR, including vitals and lab results. 
Administrative information such as ICD-9 diagnoses, CPT codes, and pharmacy orders for all 
direct care encounters are held in common by the CDR and MDR. The CDR is a transactional 
database required to provide millions of interactions every day for hundreds of thousands of 
users. 

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Figure 1
Age distribution among DOD active patients
9.5
STUDY SIZE
Given the non-interventional design, the study’s objective is not to demonstrate superiority of 
dabigatran vs. rivaroxaban or apixaban but rather to provide real-world estimates of the 
comparative effectiveness and safety of dabigatran, rivaroxaban, and apixaban in a large US 
population of NVAF patients. Therefore, the planned analyses are descriptive in nature and 
results of the statistical tests are to be interpreted in an exploratory manner.
For each treatment comparison, the available sample size is determined by feasibility 
assessments of the DoD database according to the pre-specified time window and 
inclusion/exclusion criteria, and not by formal sample size justifications. Therefore, the 
purpose of the power assessments described in this section is to illustrate the precision of the 
effect estimates that can be achieved given the feasible sample size. The primary safety 
outcome of major bleeding was used for the power assessments, for which an annual event 
rate of 3.1% for the dabigatran patients and a mean follow-up duration of 0.82 years for both 
groups were assumed based on the study by Villines et al6. In addition, all calculations are 
based on a two-sided test with α=0.05 and a 10% loss of dabigatran patients during the 1:1 
propensity score matching.
For the analysis of dabigatran vs. rivaroxaban, it is estimated that a total of approximately 
41,000 patients (16,000 dabigatran vs. 25,000 rivaroxaban patients) will be available for this 
study, based on the proposed time window of July 2011 to March 2016. Power calculations 
suggest that such a sample size will allow the study to detect a relative difference in the rate 
of major bleeding of 22% with 80% power, and 25% with 90% power, between the 
rivaroxaban and dabigatran groups.

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For the analysis of dabigatran vs. apixaban, it is estimated that a total of approximately 
27,000 patients (6,000 dabigatran and 21,000 apixaban patients) will be available for this 
study, based on the proposed time window of December 2012 to March 2016. Power 
calculations suggest that such a sample size will allow the study to detect a relative difference 
in the rate of major bleeding of 37% with 80% power, and 43% with 90% power, between the 
apixaban and dabigatran groups. The analysis may therefore have insufficient power to detect 
a smaller treatment difference if the expected sample size is confirmed. 
The actual power of the study will be dependent on the actual event rate in each treatment 
group, the covariates included in the analysis models, and the actual loss of patients during 
matching, and may therefore differ.
9.6
DATA MANAGEMENT
Access to the DoD data will be through a VPN connection. Through this secure connection 
 and 
will construct the study-specific analytic datasets. Data are 
checked for internal consistency within each patient’s claims/records relevant to the study 
analyses and any patients with extreme or unexpected treatment patterns or diagnoses are 
identified. BIPI will not have direct access to the raw data. All data management and 
statistical analyses will be performed using SAS Version 9.4 (or later) in the secured 
environment
9.7
DATA ANALYSIS
All statistical analyses will be performed using SAS version 9.4 (SAS Institute, Cary, NC).
Baseline characteristics will be described for the two cohorts based on the NOAC treatment 
(dabigatran vs. rivaroxaban and dabigatran vs. apixaban) using standard summary statistics. 
Means (±standard deviation, SD) and median (interquartile range) will be reported for 
continuous variables and frequencies (%) for categorical variables. The final study sample 
will be newly initiating cohorts.
To account for potential selection bias, the study cohorts (dabigatran/rivaroxaban and 
dabigatran/apixaban) will be matched on their baseline characteristics using the propensity 
score matching (PSM) method.  The PSM aims to balance the two treatment groups on 
baseline demographics, health plan type and clinical characteristics. The feasibility of PSM 
will be evaluated based on available sample size and descriptive results. If patient 
characteristics between dabigatran/rivaroxaban and dabigatran/apixaban cohorts are 
significantly different, i.e., less than 50% of patients in the dabigatran group can be matched 
to the rivaroxaban or apixaban group based on PSM, then the study design will be re-
evaluated before proceeding to analysis. The Nearest Neighbor method of propensity score 
matching within a caliper of 0.10-0.20 (depending on resulting sample sizes) of the standard 
deviation of the estimated logit will be used to select the matched samples.

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The propensity score will be defined as the probability of being treated with the index NOAC 
based on a set of baseline characteristics. If, for example, two patients, one in the dabigatran 
group and another in the rivaroxaban group, had the same propensity score, they would both 
have the same probability of being treated with dabigatran. The final list of baseline 
characteristics to be utilized in the PSM will be decided in conjunction with BI. The 
following baseline characteristics in the pre-index period will be considered: age, gender, 
health plan type, geographic region, month and year of index date, Charlson comorbidity 
index (CCI), stroke risk scores (i.e. CHADS2 or CHA2DS2-VASc), bleeding risk scores (i.e., 
modified HAS-BLED), relevant baseline comorbid conditions and medication use as defined 
in Section 9.3.3. The distribution of baseline characteristics will be presented before and after 
the matching process. For baseline covariates that are not sufficiently balanced after PSM, the 
covariates will be included in an appropriate multivariate model to adjust for those 
differences.
9.7.1
Main analysis
Patient demographics and clinical characteristics will be reported for NVAF patients by 
treatment groups: dabigatran, rivaroxaban, or apixaban. Stroke risk will be quantified using 
the CHADS2 score, CHA2DS2-VASc score and bleeding risk through the HAS-BLED score. 
In addition, administrative variables of eligibility time and post-index follow-up time will be 
described. Other descriptive variables may include, but are not limited to, the following:
Comorbid conditions at baseline (the 12 month pre-index period), based on diagnosis codes:

Cancer 

Rheumatoid arthritis

Coronary artery disease

Acute myocardial infarction

Cardiomyopathy

Ischemic stroke

Stroke (all types)

TIA

Congestive heart failure

Left ventricular heart failure 

Hypertension

Peripheral artery disease

Liver disease

Renal disease

COPD/emphysema

Diabetes

Peptic ulcer (bleeding or non-bleeding)

GERD

Venous thromboembolism 

Hyperlipidemia

HIV infection

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
Bone marrow disease (thrombocytopenia, chronic anemia, myelofibrosis) 

Coagulopathy (hemophilia, Von Willebrand disease)

Chronic kidney disease
Medication History and Concomitant Use at baseline (the 12 month pre-index period), based 
on prescription information:

Non-Oral Anticoagulants: Number of prescription fills (normalized to a 30-day 
supply) will be captured during the pre-index period (See Appendix A, Table 8)
o
Argatroban (can be used in procedures in lieu of heparin)
o
Unfractionated Heparin (Heparin) 
o
Low Molecular Weight Heparins:
•
Enoxaparin
•
Tinzaparin
•
Dalteparin
•
Fondaparinux

Other medication use: Use of other medications will be determined if patients 
had ever filled a medication in the following drug classes during the pre-index 
period (See Appendix A, Table 3, Table 8). 
o
Beta blockers
o
Calcium channel blockers
o
Diuretics
o
Other antihypertensives (i.e., angiotensin-converting-enzyme (ACE) 
inhibitors, combinations)
o
Antihyperlipidemics
o
Corticosteroids
o
Antidiabetics
o
Antiarrhythmics (Amiodarone HCl, Propafenone and Flecainide, 
Dronedarone, Betapace (Sotalol), Tikosyn, Disopyramide (Norpace), 
Quinidine)
o
Ketoconazole
o
Antiplatelets (e.g., dypridamole, aspirin, etc.
o
NSAIDs
The follow-up period, which comprises the patient-time denominator, will start at index and 
will be censored at the first occurrence of either of the following:

outcome event

therapeutic switch

index NOAC dose change

discontinuation of therapy, as defined as a gap in therapy exceeding 30 days

end of DOD eligibility

end of study period
Patients need at least two days of exposure to the index NOAC to ensure they had at least one 
day of index NOAC exposure in the post-index follow-up period.

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For patients, index exposure will be considered discontinued if there is a treatment gap longer 
than the 30 day allowable gap specified from the end of the calculated days supplied.  
Patients that have treatment gap longer than the specified allowable gap will be censored at 
that point and follow-up will be discontinued.  A sensitivity analysis will be performed on 
patients that have treatment gaps longer than 14 days to determine if an adjustment to the gap 
days is necessary.
The first occurrence of each outcome will be identified, separately. For each outcome, event 
rates and 95% confidence intervals (CI) will be calculated using a person-time approach for 
each treatment and further stratified by age and gender.  To compare the occurrence of each 
outcome between treatments, Kaplan-Meier analysis and Cox proportional hazards model 
analysis will be performed. Additional adjustments will be made for baseline variables that 
are not sufficiently balanced after PSM. 
Standard dosing for each NOAC will be used for main analyses. All doses for each NOAC 
will be combined for a sensitivity analysis as defined below. 
9.8
QUALITY CONTROL
All amendments to the study protocol will be discussed with and agreed upon by the sponsor. 
Actual amendments to the study protocol will be made by the vendor and sent to BIPI for 
review and approval. The date of the amendments will be documented on the cover page of 
the study protocol. Amendments to the protocol will be submitted to the Institutional Review 
Board (IRB) for review and approval prior to implementation in accordance with regulatory 
requirements.
Clinicians from two MTFs, who are well versed in the standard of care for the NVAF 
population in the military setting, will be available to provide oversight and feedback. 

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9.9
LIMITATIONS OF THE RESEARCH METHODS
Similar to other retrospective database studies, this study is subject to limitations including 
coding errors of omission and commission, incomplete claims, unreliable clinical coding, and 
unobservable factors not equally distributed in the treatment groups that may also influence 
the outcomes. In addition, unrecognized confounding due to characteristics not measured or 
included in the PSM.
9.10
OTHER ASPECTS
Ethical Approval:
This study will be conducted using a limited administrative claims database which fully 
complies with HIPAA. Institutional Review Board and Independent Ethics Committee 
approvals will be obtained for this study.
9.11
BIAS
As for any observational study, there are many potential sources of bias, and there may be 
significant sources of bias that are not recognized. To minimize bias, this study will include 
only patients who have not previously been treated with novel oral anticoagulation, and will 
use propensity score IPTW. Further, effort has been made to avoid exclusions that may 
differentially affect the treatment groups, and be a potential bias.

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10.
PROTECTION OF HUMAN SUBJECTS
IRB Review and Approval
Upon contracting and once the final protocol has been agreed upon by the client, 
 will 
submit the protocol to an independent IRB review. All protocols including those for purely 
retrospective studies need to be submitted to the IRB. A request for exemption, expedited or 
full IRB review will be requested depending on the type of study. Only upon receipt of the 
IRB exemption or approval letter can the study be initiated. 
 will inform the study team 
once the letter is received, so the study can begin. 

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Safety Reporting:  
This is a retrospective observational study, in which all patient data will be de-identified and 
analyzed in aggregate. Individual patient safety related information will not be captured 
during this study. Thus, individual safety reporting is not applicable for this study.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Ongoing teleconferences with the project team will be conducted to review the project status 
and results. Ad hoc meetings will be scheduled as needed. A face-to-face meeting to review 
the results of the study is complete can be scheduled at the client’s request.
At the completion of all analyses, 
 will develop a full written report, which 
will describe the research, its results, and the implications of study findings. The report will 
contain an executive summary as well as detailed description of the methodology, results and 
conclusions. Study results will be provided in Microsoft Excel spreadsheet table shells and 
figures as appropriate, with results summarized in a Microsoft Word document. A draft report 
will be delivered to BIPI followed by a final report once feedback from BIPI is received by 
. 
An abstract, poster (given abstract acceptance) and manuscript will be developed based on 
the study results. Abstract(s), poster(s), and/or manuscript(s) related to this study will be 
completed in accordance to the contractual agreement set forth between 
 
 and 
BIPI. Publications resulting from this study will comply with recognized ethical standards 
concerning publications and authorship, including Section II – “Ethical Considerations in the 
Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, established by the International Committee of Medical 
Journal Editors.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1] Lip, Gregory Y.H., Larsen, Torben Bjerregaard, Skjoth, Flemming, Rasmussen, Lars Hvilsted. “Indirect 
Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention 
in Atrial Fibrillation.” J Am Coll Cardiol. 2012; 60(8): 738-746.
[2] Patel, Manesh R. “Rivaroxaban – Once daily, oral, direct factor Xa inhibition compared with vitamin K 
antagonism for prevention of stroke and embolism trial in atrial fibrillation: Rationale and design of the 
ROCKET study.” Am Heart Journal. March 2010; 159 (3): 340-347.
[3] Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel 
E. Singer, M.D., Werner Hacke, M.D., Ph.D., Günter Breithardt, M.D., Jonathan L. Halperin, M.D., 
Graeme J. Hankey, M.D., Jonathan P. Piccini, M.D., Richard C. Becker, M.D., Christopher C. Nessel, 
M.D., John F. Paolini, M.D., Ph.D., Scott D. Berkowitz, M.D., Keith A.A. Fox, M.B., Ch.B., Robert M. 
Califf, M.D., and the ROCKET AF Steering Committee, for the ROCKET AF Investigators “Rivaroxaban 
versus Warfarin in Nonvalvular Atrial Fibrillation” N Engl J Med 2011; 365:883-891.
[4] Stuart J. Connolly, M.D., Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Salim Yusuf, F.R.C.P.C., 
D.Phil., John Eikelboom, M.D., Jonas Oldgren, M.D., Ph.D., Amit Parekh, M.D., Janice Pogue, M.Sc., Paul 
A. Reilly, Ph.D., Ellison Themeles, B.A., Jeanne Varrone, M.D., Susan Wang, Ph.D., Marco Alings, M.D., 
Ph.D., Denis Xavier, M.D., Jun Zhu, M.D., Rafael Diaz, M.D., Basil S. Lewis, M.D., Harald Darius, M.D., 
Hans-Christoph Diener, M.D., Ph.D., Campbell D. Joyner, M.D., Lars Wallentin, M.D., Ph.D., and *the 
RE-LY Steering Committee and Investigators. “Dabigatran versus Warfarin in Patients with Atrial 
Fibrillation.” N Engl J Med 2009; 361:1139-1151
[5] Christopher B. Granger, M.D., John H. Alexander, M.D., M.H.S., John J.V. McMurray, M.D., Renato 
D. Lopes, M.D., Ph.D., Elaine M. Hylek, M.D., M.P.H., Michael Hanna, M.D., Hussein R. Al-Khalidi, 
Ph.D., Jack Ansell, M.D., Dan Atar, M.D., Alvaro Avezum, M.D., Ph.D., M. Cecilia Bahit, M.D., Rafael 
Diaz, M.D., J. Donald Easton, M.D., Justin A. Ezekowitz, M.B., B.Ch., Greg Flaker, M.D., David Garcia, 
M.D., Margarida Geraldes, Ph.D., Bernard J. Gersh, M.D., Sergey Golitsyn, M.D., Ph.D., Shinya Goto, 
M.D., Antonio G. Hermosillo, M.D., Stefan H. Hohnloser, M.D., John Horowitz, M.D., Puneet Mohan, 
M.D., Ph.D., Petr Jansky, M.D., Basil S. Lewis, M.D., Jose Luis Lopez-Sendon, M.D., Prem Pais, M.D., 
Alexander Parkhomenko, M.D., Freek W.A. Verheugt, M.D., Ph.D., Jun Zhu, M.D., and Lars Wallentin, 
M.D., Ph.D., for the ARISTOTLE Committees and Investigators*“Apixaban versus Warfarin in Patients 
with Atrial Fibrillation.” N Engl J Med 2011; 365:981-992.
[6] Thromb Haemost. 2015 Nov 25;114(6):1290-8. doi: 10.1160/TH15-06-0453. Epub 2015 Oct 8
13.2
UNPUBLISHED REFERENCES
Not applicable.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS

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APPENDIX A. VARIABLE CODING LIST
Table 1.  NOACs for Exposure
Class
Description
GPI Code
Direct thrombin inhibitors
Dabigatran 
833370302001
Direct Xa inhibitor
Rivaroxaban
83370060 
Apixaban
83370010
Table 2.  Baseline Comorbid Conditions
Comorbidity
Cancer
140.xx-172.xx, 174.xx-
208.xx, 230.xx-231.xx, 
233.xx-234.xx
C00.xxx-D49.xxx
Rheumatoid arthritis
714.xx
M05.xxx, M06.xxx, M08.xxx, M12.0xx
Multiple sclerosis
340
G35
Coronary artery disease
411.xx, 412.xx, 413.xx, 
414.xx, 429.2
I20.x, I24.x, I25.xxx
Acute myocardial infarction
410.xx
I21.xx
Cardiomyopathy
425.xx
I42.x, I43
Ischemic stroke
433.x1, 434.x1,  436.x
I63.xxx, I67.89
TIA
435.x
G45.0, G45.1, G45.2, G45.8, G45.9, 
G46.0, G46.1, G46.2
Heart failure
402.x1, 404.x1, 404.x3, 
428.xx
I11.0, I13.0, I13.2, I50.1, I50.2x, I50.3x, 
I50.4x, I50.9
Atrial flutter
427.32
I48.92
Hypertension
401.x, 402.x0, 403.xx, 
404.x0, 404.x2, 405.xx
I10, I11.9, I12.x, I13.1x, I15.x, I16.x
Peripheral artery disease
440.xx, 443.xx
I70.xxx, I73.xx, I77.7x, I79.1, I79.8
Liver disease
121.1, 423.2, 570-573.xx, 
751.62
B661, I311. K70.0-K77, Q446
Renal disease
580.xx-588.xx, 
N0x.x, N08, B52.0, E08.2x, E09.2x, 
N14.x, N15.x, N17.x, N18.x, N19, 
N25.0, N25.1, N25.9, N25.81, N25.89, 
N26.x,
590.xx-593.xx
N10, N11.x, N12, N13.0, N13.0, N13.1, 
N13.2, N13.30, N13.39, N13.4, N13.5, 
N13.6, N13.70, N13.71, N13.732, 
N13.729, N13.721, N13.731, N13.722, 
N13.739, N13.8, N13.9, N15.x, N16, 
N20.x, N22, N28.1, N28.0, N28.81, 
N28.83, N28.84, N28.85, N28.86, 
N28.89, N28.9, N29, R80.2
COPD/emphysema
490-492.xx, 496
J40.x-J44.x

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Hypothyroidism
243-244.x
E00.x, E01.8, E02, E03.0, E03.1, E03.2, 
E03.3, E03.4, E03.8, E03.9, E89.0
Diabetes
250.xx
E10.xxxx, E11.xxxx, E13.xxxx
Peptic ulcer/GERD
530.11, 530.81, 536.2, 
536.8, 787.1, 533.xx
K21.x, K27.x, K30, R11.10, R12
Venous thromboembolism
415.11, 415.19, 451.1x, 
451.2, 451.81, 451.83, 
451.84, 451.9,453.4x, 
453.8x, 453.9
I2699, I80.1x-I80.9, I82.4xx, I82.6xx, 
I82.890, I82.90, I82.A1x, I82.B1x, 
I82.C1x
Hyperlipidemia
272.0 – 272.4
E78.0x-E78.5
HIV infection
V08, 042, 079.53
Z21, B20, B97.35
Bone Marrow disease 
     Thrombocytopenia
287.3, 287.4, 287.5
D69.3, D69.4x, D69.5x, D69.6
     Chronic anemia
285.2
D63.x
     Myelofibrosis
289.83
D75.81
Coagulopathy 
286.0-286.9, 287.1, 287.3-
287.5
D65-D68.x, D69.1, D69.3-D69.6
Dyspepsia
536.8
K30
Left ventricular heart failure
428.1
I50.1
Bone marrow disease
289.9
D75.9
Thrombocytopenia
287.5
D69.6
Anemia
285.9
D64.9
Myelofibrosis
289.83
D75.81
Coagulopathy (other and 
unspec)
286.9
D68.8, D68.9
Hemophilia
286.52
D68.311
Von Willebrand Disease
286.4
D68.0
Chronic Kidney Disease (not for 
Renal disease)
585.1
N18.1
585.2
N18.2
585.3
N18.3
585.4
N18.4
585.5
N18.5
585.9
N18.9
Table 3.  Medications of Interest (Include antiplatelets from Table 8)
Description
GPI codes 
starting with:
GPI 10 

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Beta blockers
33
3310004510, 3310004512 
Calcium channel blockers
34
3400000710, 3400000310, 3400001010, 3400001011, 
3400001012,  3400001015, 3400001050, 3400001300, 
3400001500, 3400001810, 3400001812, 3400001814, 
3400002000, 3400002200, 3400002400, 3400003010
Antihypertensives
36
3610000510, 3610001000, 3610002010, 3610002510, 
3610002710, 3610003000, 3610003310, 3610003510, 
3610004010, 3610005000, 3610006000, 3615001020, 
3615002010, 3615002420, 3615003000, 3615004020, 
3615005520, 3615007000, 3615008000, 3617001010, 
3620101010, 3620102510, 3620103000, 3620103010, 
3620200510, 3620203010, 3620204010, 3620304000, 
3625003000, 3630001010, 3630002010, 3630002500, 
3640001010, 3640002000, 3640004010, 3640203010, 
3660002010, 3699150220, 3699150223, 3699150270, 
3699180215, 3699180225, 3699180235, 3699180240, 
3699180255, 3699180260, 3699180265, 3699200210, 
3699200213, 3699200220, 3699200230, 3699200240, 
3699270250, 3699300205, 3699300210, 3699300270, 
3699400210, 3699400220, 3699400225, 3699400230, 
3699400245, 3699400250, 3699400260, 3699400270, 
3699450320, 3699450345, 3699500220, 3699500270, 
3699600215, 3699670210, 3699680320, 3699850250, 
3699880260
Diuretics
37
3710001000, 3710001010, 3710002000, 3710003000, 
3720001000, 3720002000, 3720002010, 3720003000, 
3720008000, 3740001000, 3740003000, 3750001010, 
3750002000, 3750003000, 3760001000, 3760002000, 
3760002010, 3760002500, 3760004000, 3760005000, 
3760005500, 3760006000, 3790003000, 3799000210, 
3799000220, 3799000230, 3799200410
Antihyperlipidemics
39
3910001000, 3910001010, 3910001610, 3910002010, 
3920000600, 3920002400, 3920002500, 3920002510, 
3920003000, 3930003000, 3935001000, 3935002000, 
3940001010, 3940003010, 3940005000, 3940005810, 
3940006010, 3940006510, 3940007500, 3940990225, 
3940990245, 3940990270, 3945005000, 3948005020, 
3950003510, 3950004010, 3950004520, 3950005500, 
3999400220, 3999400230, 3999900250
Corticosteroids
22
2210001000, 2210001020, 2210001200, 2210001510, 
2210002000, 2210002010, 2210002020, 2210002500, 
2210002540, 2210003000, 2210003010, 2210003020, 
2210004000, 2210004010, 2210004020, 2210004500, 
2210005010, 2210005020, 2210005022, 2210005030, 
2210990210, 2210990215, 2210990258, 2210990260, 
2210990262, 2210990263, 2210990265, 2210990285, 
2210990287, 2210990290, 2210990308, 2210990310, 
2210990315, 2210990320, 2210990350, 2210990360, 
2210990370, 2210990373, 2210990420, 2220003010

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Antidiabetics
27
2710400200, 2710400300, 2710400400, 2710400500, 
2710400600, 2710400700, 2710401000, 2710402000, 
2710407000, 2710408000, 2710409000, 2715005010, 
2717001000, 2717001500, 2717002000, 2717005000, 
2720002000, 2720002700, 2720003000, 2720004000, 
2720004010, 2720005000, 2720006000, 2725005000, 
2728004000, 2728006000, 2730001010, 2730001015, 
2730002000, 2730003000, 2730405000, 2730990240, 
2750001000, 2750005000, 2755001010, 2755005000, 
2755006510, 2755007010, 2757402010, 2760705010, 
2760706010, 2770002000, 2770004020, 2770005000, 
2799250210, 2799250240, 2799250260, 2799250270, 
2799300270, 2799400210, 2799500270, 2799600220, 
2799600230, 2799600240, 2799650230, 2799700235, 
2799700240, 2799780240, 2799780260, 2799800240, 
2799800260, 2799900250
Antiarrhythmics:
   Amiodarone HCl
3540000
3540000500
   Propafenone and 
Flecainide
353000
3530005000
   Dronedarone
35400028
3540002810
   Betapace (Sotalol)
33100045
33100045
   Tikosyn 
35400025
3540002500
   Disopyramide 
(Norpace) 
35100010
3510001010
   Quinidine
351000301
3510003010, 3510003030
   Ketoconazole
11404040
1140404000
Table 4. Charlson Comorbidity Index Calculation
Programming algorithm for the Charlson Comorbidity Index (CCI)
1.
Identify all patients who ever had the following conditions during their 
baseline period.
Condition
Myocardial Infarction
410.x, 412.x
I21.xx, I22.x, I25.2
Congestive Heart 
Failure
428.x
I50.xx
Peripheral Vascular 
441.x, 443.9x, 
I71.xx, I73.9, I96, Z95.828

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Disease
785.4x, V43.4x
Cerebrovascular 
Disease
430.x-438.x
G45.0-G45.2, G45.4-G46.8, 
I60.xx-I69.xxx (exclude I67.3, 
I67.83)
Dementia
290.x
F01.5x, F03.90
Rheumatologic Disease
710.0x, 710.1x, 
710.4x, 714.0x, 
714.1x, 714.2x, 
725.x, 714.81
M05.xx-M06.9 (exclude M06.4), 
M32.xx, M33.20, M34.xx, M35.3
Peptic Ulcer Disease
531.4x-531.7x, 
532.4x-532.7x, 
533.4x-533.7x, 
534.4x-534.7x, 
531.0x-531.3x, 
532.0x-532.3x, 
533.0x-533.3x, 
534.0x-534.3x, 
531.9x, 532.9x, 
534.9x
K25.0-K28.9
Mild Liver Disease
571.2x, 571.4x, 
571.5x, 571.6x
K70.2, K70.3x, K73.x, K74.xx, 
K75.4
Diabetes (mild to 
moderate)
250.0x, 250.1x, 
250.2x, 250.3x, 
250.7x
E10.1x, E10.5x, E10.641, E11.0x, 
E11.5x, E11.641, E13.0x, E13.1x, 
E13.5x, E13.641, E13.9
Diabetes with 
Complications
250.4x, 250.5x, 
250.6x
E10.3xxx, E10.4x, E10.610, 
E11.2x, E11.3xxx, E11.4x, 
E11.610, E13.2x, E13.3xxx, 
E13.4x, E13.610
Hemiplegia or 
Paraplegia
342.x, 344.1x
G81.xx, G82.2x
Renal Disease
582.x, 585.x, 586.x, 
588.x
N03.x, N18.x, N19, N25.xx, N27.x
Malignancy
140.x-172.x, 174.x-
195.x, 201.x, 203.x, 
205.x-208.x
C00.x-C43.xx, C45.x-C49.xx, 
C50.xxx-C76.xx, C81.xx, C88.2, 
C88.3, C88.8, C88.9, C90.xx, 
C92.xx-C95.xx, D03.xx, D45
Moderate or Severe 
Liver Disease
572.2x-582.8x, 
456.0x, 456.1x, 
456.2x
I85.xx, K72.1x, K72.9x, K75.0, 
K75.1, K75.2, K75.3, K75.8x, 
K75.9, K76.1, K76.3-K76.9, K77, 
K80.xx-K90.49, K90.89, K90.9, 
K91.2, K91.5, K92.0, K92.1, 
K92.2, N00.0-N03.8, N04.0-N04.9
Metastatic Solid Tumor
196.x-199.x
C77.x-C79.x, C80.x
AIDS
042.x-044.x
B20
Chronic Obstructive 
Pulmonary Disease and 
allied conditions 
490.x
J40
491.x
J41.1, J41.8, J44.x,  J42
492.x
J43.x
493.x
J45.xxx, J44.x
494.x
J47.x

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495.x
J67.x
496.x
J44.9
2.
If a patient had both the milder and more severe form of the condition, only 
count the more severe form of the condition -- Diabetes (mild to moderate) / 
Diabetes with complications; Mild liver disease / Moderate or severe liver 
disease; Malignancy / Metastatic solid tumor.
3.
Weight each of the baseline conditions by the given weights and sum the 
number of conditions the patient has at baseline. This sum is the patient’s CCI 
at baseline.
Table 5.  CHADS2 Stroke Risk Score
CHADS2 Risk 
Criteria
Congestive Heart 
Failure 
428.x
I50.xx
Hypertension
401.x–405.x, 437.2
I10-I16.x, I67.4
Diabetes
250.x
E10.xxxx, E11.xxxx, E13.xxxx
Stroke/ transient 
ischemic attack 
(TIA)
433.x1, 434.x1, 435.x, 436, 
437.1x, 437.9x, 438.x
G45.0-G45.2, G45.8-G46.2, I63.xxx, I67.8xx, I67.9, 
I69.xxx
After assessing the risk factors and adding up the risk score, the stroke risk classifications are 
as below: 
Score 
CHADS2Stroke Risk Classification 
0
Low
1
Intermediate
2–6
High  
Table 6.  CHA2DS2-VASc Stroke Risk Score
CHA2DS2-VASc 
Criteria
Congestive heart 
428.x, 
I50.xx, 

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failure or                     
left ventricle 
dysfunction 
398.91, 402.01, 402.11, 
402.91, 404.01, 404.11, 
404.91, 404.03, 404.13, 
404.93, 425.4, 425.5, 425.7
I09.81, I11.0, I13.0, I13.2, I42.5, I42.6, I42.8, I42.9, 
I43
Hypertension
401.x–405.x, 437.2
I10-I16.x, I67.4
Diabetes Mellitus 
250.x
E10.xxxx, E11.xxxx, E13.xxxx
Stroke/TIA
433.x1, 434.x1, 435.x, 436, 
437.1x, 437.9x, 438.x
G45.0-G45.2, G45.8-G46.2, I63.xxx, I67.8xx, I67.9, 
I69.xxx
Vascular disease 
(prior myocardial 
infarction, 
peripheral artery 
disease, or aortic 
plaque) 
410.xx, 412.xx; 440.2x, 
443.8x, 443.9x;                
ICD-9 proc code: 88.48; 
CPT code: 75710, 75716, 
93922, 93923
I21.xx, I22.xx, I25.2, I70.2xx, I73.8x, I73.9, I79.1, 
I79.8;                          ICD-10 proc code: B40F0ZZ, 
B40F1ZZ, B40FYZZ, B40G0ZZ, B40G1ZZ, 
B40GYZZ, B40J0ZZ, B40J1ZZ, B40JYZZ, 
B41F0ZZ, B41F1ZZ, B41FYZZ, B41G0ZZ, 
B41G1ZZ, B41GYZZ, B41J0ZZ, B41J1ZZ, 
B41JYZZ
After assessing the risk factors and adding up the risk score, the stroke risk classifications are as 
below: 
Score 
CHA2DS2-VASc Stroke Risk Classification 
0
Low
1
Intermediate
2 or greater 
High  
Table 7.  HAS-BLED Bleed Risk Score
HAS-
BLED 
Criteria
Hypertens
ion 
401.x-405.x
I10-I16.x
Drugs used to treat hypertension (GPI 
codes 3300, 3400, 3610, 3615, 3620, 
3625, 3630, 3640, 3660, 3720, 3760)
Abnormal 
renal and 
liver 
function 
Renal: 580.xx-586.xx, V56.0, V56.8; 
ICD-9 procedure codes 39.95, 54.98; 
CPT codes 90935-90993, 99512, 
99559
N00.0-N08, N17.0-N19, Z49.31, Z49.32;                        
ICD-10 procedure code: 3E1M39Z, 5A1D00Z, 
5A1D60Z

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(1 point 
for each)
Liver: 070.x, 155.0x, 155.1x, 155.2x, 
571.x, 572.x, 573.x, 576.8, 456.0x, 
456.1x, 456.2x; ICD-9 procedure 
codes 39.1x, 42.91
B15.x-B19.xx, C22.x, I85.xx, K70.xx, K71.xx, 
K72.01-K76.1, K76.3-K77, K83.5;  ICD10 procedure 
code: 0610xxx, 0611xxx, 0612xxx, 0614xxx, 
0615xxx, 0616xxx, 0617xxx, 0618xxx, 0619xxx, 
061Bxxx, 061Jxxx, 06L30CZ, 06L30DZ, 06L30ZZ, 
06L33CZ, 06L33DZ, 06L33ZZ, 06L34CZ, 06L34DZ, 
06L34ZZ
Stroke
433.xx-437.xx
G45.x, G46.x, I63.xxx-I66.9, I67.1, I67.2, I67.4-
I67.82, I67.84x-I68.8
Bleeding 
(includes 
anemia 
and other 
prior 
hemorrha
ge)
285.0x, 285.1x, 285.9x, 423.0x, 
430.x-432.x, 455.2x, 455.5x, 455.8x, 
459.0x, 531.0x, 531.2x, 531.4x, 
531.6x, 532.0x, 532.2x, 532.4x, 
532.6x, 533.0x, 533.2x, 533.4x, 
533.6x, 534.0x, 534.2x, 534.4x, 
534.6x, 562.02, 562.03, 562.12, 
562.13, 568.81, 569.3, 569.83, 
569.85, 569.86, 578.0, 578.1, 578.9, 
599.7x, 719.1x, 784.7x, 786.3x; ICD-
9 procedure code 44.43; CPT code 
43255 
D62, D64.0, D64.1, D64.2, D64.3, D64.9, I31.2, 
I60.xx, I61.x, I62.xx, K25.0, K25.2, K25.4, K25.6, 
K26.0, K26.2, K26.4, K26.6, K27.0, K27.2, K27.4, 
K27.6, K28.0, K28.2, K28.4, K28.6, K55.21, K57.11, 
K57.13, K57.31, K57.33, K62.5, K63.1, K63.81, 
K64.4, K64.8, K66.1, K92.0, K92.1, K92.2, M25.0xx, 
R04.0, R04.2, R04.81, R04.89, R04.9, R31.0, R31.1, 
R31.21, R31.29, R31.9, R58;                                           
ICD-10 procedure code: 0W3P8ZZ
Labile 
INRs
Elderly 
(Age >65 
years) 
-
Drug or 
alcohol 
abuse (1 
point for 
each)
Drug: NSAIDs (GPI codes 6410, 
6610), Anti-platelets (8515), Other 
aspirin-containing products 
(3940990215, 4399100222, 
4399100223, 4399100232, 
4399100405, 4399400321, 
4399400456, 4399590415, 
4399590419, 6030990225, 
6499000220, 6499000221, 
6499000225, 6499000226, 
6499000232, 6499000320, 
6499000321, 6499000335, 
6499000340, 6499000450, 
6499000460, 6499100220,
6499100222, 6499100228, 
6499100330, 6499100335, 
6599000222, 6599100210, 
6599100220, 6599100325, 
6599100430, 6599100510, 
6599170220, 6599400220, 
7599000210, 7599000240, 
7599000310, 7599000320, 
8515990220, 9990000000)

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Alcohol: 291.xx, 303.xx, 305.0x, 
357.5x, 425.5x, 571.1x, 571.2x, 
571.3x; ICD-9 procedure codes 94.61-
94.63, 94.67-94.69
F10.xxx, G62.1, I42.6, K70.xx;                                        
ICD-10 procedure code: HZ2ZZZZ, HZ30ZZZ, 
HZ31ZZZ, HZ32ZZZ, HZ33ZZZ, HZ34ZZZ, 
HZ35ZZZ, HZ36ZZZ, HZ37ZZZ, HZ38ZZZ, 
HZ39ZZZ, HZ3BZZZ, HZ40ZZZ, HZ41ZZZ, 
HZ42ZZZ, HZ43ZZZ, HZ44ZZZ, HZ45ZZZ, 
HZ46ZZZ, HZ47ZZZ, HZ48ZZZ, HZ49ZZZ, 
HZ4BZZZ, HZ50ZZZ, HZ51ZZZ, HZ52ZZZ, 
HZ53ZZZ, HZ54ZZZ, HZ55ZZZ, HZ56ZZZ, 
HZ57ZZZ, HZ58ZZZ, HZ59ZZZ, HZ5BZZZ, 
HZ5CZZZ, HZ5DZZZ, HZ63ZZZ, HZ83ZZZ, 
HZ86ZZZ, HZ88ZZZ, HZ89ZZZ, HZ93ZZZ, 
HZ96ZZZ, HZ98ZZZ, HZ99ZZZ
*the maximum score will be 8 since we do not have data available for labile INRs
After assessing the risk factors and adding up the score, the bleed risk classifications are as follows:
Score 
HAS-BLED Bleed Risk Classification 
0-1
Low
2
Intermediate
3 or greater 
High  
Table 8.  Atrial Fibrillation Medications
Rate control medications
GPI codes starting 
with:
GPI 10 
       Beta blockers
3300
3310004510, 3310004512 
       Calcium channel 
blockers
3400000710, 3400000310, 3400001010, 
3400001011, 3400001012,  3400001015, 
3400001050, 3400001300, 3400001500, 
3400001810, 3400001812, 3400001814, 
3400002000, 3400002200, 3400002400, 
3400003010
          Verapamil
34000030100
3400003010
          Diltiazem
340000101
3400001010, 3400001011, 3400001012, 
3400001015,  3400001050
       Digoxin/digitoxin
321000
3120001000
       Dronedarone
35400028100320
3540002810
      Amiodarone
3540000500
3540000500
Rhythm control medications
      Disopyramide (Norpace)
35100010
3510001010
      Procainamide
3510002010
3510002010

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      Flecainide
3530001
3530001010
      Propafenone
3530005
3530005000
      Betapace (Sotalol)
33100045
3310004510, 3310004512
      Tikosyn (Dofetilide)
35400025
3540002500
      Quinidine
351000301
3510003010, 3510003030
      Mexiletine  
352000251
not exist 
      Moricizine 
35050301003
not exist 
Other 
      ACE Inhibitors
3610
36100005, 36100010, 36100020, 36100025, 
36100027, 36100030, 36100033, 36100035, 
36100040, 36100050, 36100060
      Angiotensin-II Receptor 
Blockers (ARB)
3615
3615004020, 3615003000, 3615002010, 
3615008000, 3615005520, 3615007000, 
3615002420, 3615001020
      Diuretics (Thiazide, loop)  
3720, 3760
3710001000, 3710001010, 3710002000, 
3710003000, 3720001000, 3720002000, 
3720002010, 3720003000, 3720008000, 
3740001000, 3740003000, 3750001010, 
3750002000, 3750003000, 3760001000, 
3760002000, 3760002010, 3760002500, 
3760004000, 3760005000, 3760005500, 
3760006000, 3790003000, 3799000210, 
3799000220, 3799000230, 3799200410
      Antihypertensives 
(excluding above group)
3620, 3625, 3630, 
3640, 3660
3610000510, 3610001000, 3610002010,
3610002510, 3610002710, 3610003000, 
3610003310, 3610003510, 3610004010, 
3610005000, 3610006000, 3615001020, 
3615002010, 3615002420, 3615003000, 
3615004020, 3615005520, 3615007000, 
3615008000, 3617001010, 3620101010, 
3620102510, 3620103000, 3620103010, 
3620200510, 3620203010, 3620204010, 
3620304000, 3625003000, 3630001010, 
3630002010, 3630002500, 3640001010, 
3640002000, 3640004010, 3640203010, 
3660002010, 3699150220, 3699150223, 
3699150270, 3699180215, 3699180225, 
3699180235, 3699180240, 3699180255, 
3699180260, 3699180265, 3699200210, 
3699200213, 3699200220, 3699200230, 
3699200240, 3699270250, 3699300205, 
3699300210, 3699300270, 3699400210, 
3699400220, 3699400225, 3699400230, 
3699400245, 3699400250, 3699400260, 
3699400270, 3699450320, 3699450345, 
3699500220, 3699500270, 3699600215, 
3699670210, 3699680320, 3699850250, 
3699880260

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      Fondaparinux 
83103030
8310303010  (Also include HCPCS code: 
Injection, fondaparinux sodium, 0.5 mg - J1652)
Anticoagulants
Dabigatran 
833370302001
8333703020
Argatroban
83337015
8333701500, 8333701520
Warfarin
83200030
8320003020
Heparin
83100020
8310002020, 8310002022, 8310002025, 
8310002030,   (Also include HCPCS code: 
Injection, heparin sodium, (heparin lock flush), per 
10 units - J1642, Injection, heparin sodium, per 
1000 units - J1644)
Enoxaparin
83101020
8310102010  (Also include HCPCS code: 
Injection, enoxaparin sodium, 10 mg - J1650)
Tinzaparin
83101080
not exist in GPI database (Include HCPCS code: 
Injection, tinzaparin sodium, 1000 iu - J1655)
Dalteparin
83101010
8310101010  (Also include HCPCS code: 
Injection, dalteparin sodium, per 2500 iu - J1645)
Rivaroxaban
83370060
8337006000
Apixaban
83370010
8337001000
Antiplatelet
Clopidogrel
85158020
8515802010
Brilinta (ticagrelor) 
85158470
8515847000
Prasugrel
85158060100330, 
85158060100320
8515806010
Ticlopidine
85158080100320
8515808010
Cilostazol
85155516000320, 
85155516000330
8515551600
Dipyridamole
85150030000310, 
85150030000320, 
85150030000330
8515003000
NSAIDs
6610
6610007000, 6610003000, 6610002000, 
6610004010, 6610001010, 6610006000, 
6610008000, 6610006010, 6610009010, 
6610001200, 6610005000, 6610006500, 
6610003500, 6610000710, 6610101000, 
6610000720, 6610000800, 6610003710, 
6610990220, 6610052500, 6610005200, 
6610005500, 6610003010, 6610002040, 
6610006050, 6610002050, 6610990328, 
6610990244, 6610005260, 6610990232, 
6610000700, 6610990241, 6610990340, 
6610990435, 6610990337, 6610990217, 
6610990338, 6610990256, 6610990440, 
6610990339, 6610990315, 6610990317, 

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6610990238,
Table 9.  Outcome Codes
Medical 
Conditions
ICD-9 Codes
Description
ICD-10 Codes
Stroke
Inclusive of ischemic stroke and 
hemorrhagic stroke below
Major Bleeding
Inclusive of hemorrhagic stroke, major 
intracranial bleeding and major extracranial 
bleeding below
Ischemic Stroke 
(Primary Only)
433.x1
Occlusion and stenosis of precerebral 
arteries with cerebral infarction
I63.xxx
434.x1
Occlusion of cerebral arteries with cerebral 
infarction
436
Acute, but ill-defined, cerebrovascular 
disease 
I67.89
Exclusion
EXCLUDE above codes if hospitalization 
lasted <48 hours and was accompanied by 
carotid endarterectomy (ICD-9 procedure 
code 38.1)
Hemorrhagic 
Stroke (Primary 
Only)
431
Intracerebral hemorrhage (ICH) 
I61.x
Exclusion
EXCLUDE  above codes if “traumatic brain 
injury” ICD-9-CM code (800 to804, 850 to 
854) or “rehabilitation care” as the primary 
ICD-9-CM code (V57) is present.
S02.xxxA, 
S02.xxxB, 
S06.xxxA, Z51.89
Major 
Intracranial 
Bleeding 
(Primary or 
Secondary)
430
Subarachnoid hemorrhage
I60.xx
431
Intracerebral hemorrhage
I61.x
432.x
Other and unspecified intracranial 
hemorrhage
I62.xx
852.0
Subarachnoid hemorrhage following injury 
without mention of open intracranial wound
S06.36xA
852.2
Subdural hemorrhage following injury 
without mention of open intracranial wound
S06.4XxA
852.4
Extradural hemorrhage following injury 
without mention of open intracranial wound
S06.5XxA
853.0
Other and unspecified intracranial 
hemorrhage following injury without 
mention of open intracranial wound
S06.6XxA

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Exclusion
EXCLUDE – above codes if concomitant 
discharge diagnosis of major trauma was 
present (ICD-9 codes 852.1, 852.3, 852.5, 
and 853.1)
S01.90XA,
S06.36xA, 
S06.4XxA, 
S06.5XxA, 
S06.6XxA
Major Extracranial
Inclusive of major GI bleeding, major 
urogenital bleeding and major other 
bleeding
Major GI Bleeding
Inclusive of major upper GI bleeding and 
major lower GI bleeding
Major upper GI 
bleed (Primary 
Only)
531.0x
Acute gastric ulcer with hemorrhage 
with/without obstruction
K25.0
531.2x
With hemorrhage and perforation 
with/without obstruction
K25.2
531.4x
(chronic or unspecified gastric ulcer with 
hemorrhage with/without obstruction)
K25.4
531.6x
(with hemorrhage and perforation 
with/without obstruction)
K25.6
532.0x
(acute duodenal ulcer with hemorrhage 
with/without obstruction)
K26.0
532.2x
(with hemorrhage and perforation 
with/without obstruction)
K26.2
532.4x
(chronic or unspecified duodenal ulcer with 
hemorrhage with/without obstruction)
K26.4
532.6x
(with hemorrhage and perforation 
with/without obstruction)
K26.6
533.0x
(acute peptic ulcer of unspecified site with 
hemorrhage with/without obstruction)
K27.0
533.2x
(with hemorrhage and perforation 
with/without obstruction)
K27.2
533.4x
(chronic or unspecified peptic ulcer of 
unspecified site with hemorrhage 
with/without obstruction)
K27.4
533.6x
(with hemorrhage and perforation 
with/without obstruction), 
K27.6
534.0x
(acute gastrojejunal ulcer with hemorrhage 
with/without obstruction)
K28.0
534.2x
(with hemorrhage and perforation 
with/without obstruction)
K28.2
534.4x
(chronic or unspecified gastrojejunal ulcer 
with hemorrhage with/without obstruction)
K28.4
534.6x
(with hemorrhage and perforation 
with/without obstruction)
K28.6

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578.0
(hematemesis) 
K92.0
ICD-9 Procedure 
Code 44.43
(endoscopic control of gastric or duodenal 
bleeding)
CPT code 43255
(upper gastrointestinal endoscopy including 
esophagus, stomach, and either the 
duodenum and/or jejunum as appropriate 
with control of bleeding, any method)
Major lower GI 
bleeding
(Primary Only)
562.02
Diverticulosis of small intestine with 
hemorrhage
K55.21
562.03
Diverticulitis of small intestine with 
hemorrhage
K57.11
562.12
Diverticulosis of colon with hemorrhage
K57.13
562.13
Diverticulitis of colon with hemorrhage
K57.31
569.3x
Hemorrhage of rectum and anus
K57.32
569.85
Angiodysplasia of intestine with 
hemorrhage
K62.5
578.1x
Blood in stool
K92.1
578.9
Hemorrhage of GI tract, unspecified
K92.2
Major 
urogenital bleed 
(Primary Only)
599.7
Hematuria 
R31.0 - R31.29 
626.2x and (280.0, 
285.1 or 285.9)
Excessive/frequent menstruation and 
secondary diagnosis indicating acute 
bleeding (anemia)
N92.0 and 
(D50.0, D62, 
D64.9)
Other major 
bleeds (Primary 
Only)
719.1x
Hemathrosis
D62
423.0x
Hemopericardium
I31.2
786.3x
Hemoptysis
M25.0xx
784.7x
Epistaxis
R04.0
459.0x
Hemorrhage not specified 
R04.2
285.1x
Acute posthemorrhagic anemia 
R04.8x, R04.9, 
R58
TIA (Primary 
Only)
435.x
Transient cerebral ischemia as the principal 
(primary) discharge diagnosis
G45.0, G45.1, 
G45.8, G45.9, 
G46.0, G46.1, 
G46.2
 
              
 
 
 
 
 
                     
 

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APPENDIX B: Inclusion and exclusion diagnosis, procedure and CPT codes
Table 1. List of codes for atrial fibrillation 
Study Inclusion DX
ICD9 Diagnosis Codes
ICD10 Diagnosis Codes
Atrial Fibrillation
427.31
I48.0, I48.1, I48.2, I48.91 
Table 2. List of codes and descriptions to identify patients with exclusion diagnoses
Study Exclusion DX
ICD9 Diagnosis Codes
ICD10 Diagnosis Codes
Hyperthyroidism 
242.x
E05.00, E05.01, E05.10, 
E05.11, E05.20, E05.21, 
E05.30, E05.31, E05.40, 
E05.41, E05.80, E05.81, 
E05.90, E05.91
Orthopedic Procedures                   
(See also procedure codes)
V43.64, V43.65
Z9664x, Z9665x
DVT
451.xx, 453.xx
I80.xxx, I82.xxx
PE
415.1x
I26.01, I26.09, I26.90, 
I26.92, I26.99, I27.82
Perocarditis
391.x, 393, 420.x, 423.2, 
036.41, 074.21, 093.81, 
098.83
A39.53, B33.23, I01.0, 
I09.2, I30.0, I30.1, I30.8, 
I30.9, I31.0, I32, M32.12
Myocarditis
391.2, 422.xx, 074.23, 
398.0, 429.0, 032.82, 
036.43, 093.82, 130.3
A36.81, A38.1, A39.52, 
A52.06, A54.83, B26.82, 
B33.22, B58.81, D86.85, 
I01.2, I09.0, I40.0, I40.1, 
I40.8, I41, I511.4, 
J10.82, J11.82
Pulmonary Embolism
415.1x
I26.01, I26.09, I26.90, 
I26.92, I26.99, I27.82
Valvular Afib 
Mitral stenosis 
394.0x
I05.0, I05.1, I05.2, I05.8, 
I05.9, I34.2
Mitral stenosis with 
insufficiency 
394.2
I34.0, I34.2, I34.8, I34.9
Mitral valve stenosis and aortic 
valve stenosis 
396.0
I06.0, I35.0, Q23.0
Mitral valve stenosis and aortic 
valve insufficiency 
396.1
I08.0, I06.1, I25.1, 
Q23.1, Q23.8, Q23.9

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BI Study Number 1160.274
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001-MCS-90-124_RD-01 (4.0)
Diseases of other endocardial 
structures 
397.x
I07.x, I09.89, I08.1, 
I08.2, I08.3, I08.8, I08.9
Other and unspecified rheumatic 
heart diseases 
398.9x
I09.9, I09.81, I09.89
Heart valve replaced by 
transplant 
V42.2
Z95.3, Z95.4
Heart valve replaced by a 
mechanical device/prosthesis 
V43.3
Z95.2
Atrioventricular valve repair
V43.3
Z95.2
Aortic valve 
valvuloplasty/diseases of aortic 
valve
395.x
I06.x
Table 3. List of codes and descriptions to identify patients with exclusion procedures
Subject Exclusion 
Criteria:
ICD9 
Procedure 
Codes
ICD10 Procedure Codes              CPT 
Codes
Valvular Afib 
Procedure/CPT 
codes
Open heart 
valvuloplasty 
without replacement 
35.1x
02QF0ZZ, 02QG0ZZ, 
02QH0ZZ, 02QJ0ZZ, 027F04Z, 
027F0DZ, 027F0ZZ, 02NF0ZZ, 
02QF0ZZ, 027G04Z, 027G0DZ, 
027G0ZZ, 02NG0ZZ, 
02QG0ZZ, 027H04Z, 
027H0DZ, 027H0ZZ, 
02NH0ZZ, 02QH0ZZ, 027J04Z, 
027J0DZ, 027J0ZZ, 02NJ0ZZ, 
02QJ0ZZ

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001-MCS-90-124_RD-01 (4.0)
Open And Other 
Replacement Of 
Heart Valve (This 
includes : Open and 
other replacement of 
unspecified heart 
valve, Open and 
other replacement of 
aortic valve, Open 
and other 
replacement of 
mitral valve , Open 
and other 
replacement of 
mitral valve , Open 
and other 
replacement of 
pulmonary valve, 
Open and other 
replacement of 
tricuspid valve.)
35.2x
02RF07Z, 02RF08Z, 02RF0JZ,
02RF0KZ, 02RF47Z, 02RF48Z, 
02RF4JZ, 02RF4KZ, 02RG07Z, 
02RG08Z, 02RG0JZ, 
02RG0KZ, 02RG47Z, 
02RG48Z, 02RG4JZ, 
02RG4KZ, 02RH07Z, 
02RH08Z, 02RH0JZ, 
02RH0KZ, 02RH47Z, 
02RH48Z, 02RH4JZ, 
02RH4KZ, 02RJ07Z, 02RJ08Z, 
02RJ0JZ, 02RJ0KZ, 02RJ47Z, 
02RJ48Z, 02RJ4JZ, 02RJ4KZ, 
02RF07Z, 02RF08Z, 02RF0KZ, 
02RF47Z, 02RF48Z, 02RF4KZ, 
X2RF032, X2RF432, 02RF0JZ, 
02RF4JZ, 02RG07Z, 02RG08Z, 
02RG0KZ, 02RG37Z, 
02RG38Z, 02RG3KZ, 
02RG47Z, 02RG48Z, 
02RG4KZ, 02RG0JZ, 
02RG3JZ, 02RG4JZ, 02RH07Z, 
02RH08Z, 02RH0KZ, 
02RH47Z, 02RH48Z, 
02RH4KZ, 02RH0JZ, 
02RH4JZ, 02RJ07Z, 02RJ08Z, 
02RJ0KZ, 02RJ47Z, 02RJ48Z, 
02RJ4KZ, 02RJ0JZ, 02RJ4JZ
Closed Heart 
Valvotomy
35.0x
02NF3ZZ, 02NF4ZZ, 
02NG3ZZ, 02NG4ZZ, 
02NH3ZZ, 02NH4ZZ, 
02NJ3ZZ, 02NJ4ZZ, 02NF3ZZ, 
02NF4ZZ, 02NG3ZZ, 
02NG4ZZ, 02NH3ZZ, 
02NH4ZZ, 02NJ3ZZ, 02NJ4ZZ, 
02RF37Z, 02RF38Z, 02RF3JZ, 
02RF3KZ, X2RF332, 02RF37H, 
02RF38H, 02RF3JH, 02RF3KH, 
02RH37Z, 02RH38Z, 02RH3JZ, 
02RH3KZ, 02RH37H, 
02RH38H, 02RH3JH, 
02RH3KH, 02RF37Z, 
02RF38Z, 02RF3JZ, 02RF3KZ, 
02RG37H, 02RG37Z, 
02RG38H, 02RG38Z, 
02RG3JH, 02RG3JZ, 
02RG3KH, 02RG3KZ, 

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001-MCS-90-124_RD-01 (4.0)
02RH37Z, 02RH38Z, 02RH3JZ, 
02RH3KZ
Unlisted procedure, 
cardiac surgery 
33999
Implantation of 
catheter-delivered 
prosthetic aortic 
heart valve; open 
thoracic approach 
0257T
Transthoracic 
cardiac exposure 
(e.g., sternotomy, 
thoracotomy, 
subxiphoid) for 
catheter-delivered 
aortic valve 
replacement; 
without 
cardiopulmonary 
bypass
0258T
Transthoracic 
cardiac exposure 
(e.g., sternotomy, 
thoracotomy, 
subxiphoid) for 
catheter-delivered 
aortic valve 
replacement; with 
cardiopulmonary 
bypass 
0259T
Replacement, aortic 
valve, with 
cardiopulmonary 
bypass; with 
prosthetic valve 
other than 
homograft or 
33405

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001-MCS-90-124_RD-01 (4.0)
stentless valve 
Valvuloplasty, 
mitral valve, with 
cardiopulmonary 
bypass 
33425
Valvuloplasty, 
mitral valve, with 
cardiopulmonary 
bypass; with 
prosthetic ring 
33426
Valvuloplasty, 
mitral valve, with 
cardiopulmonary 
bypass; radical 
reconstruction, with 
or without ring 
33427
Replacement, mitral 
valve, with 
cardiopulmonary 
bypass 
33430
Implantation of 
catheter-delivered 
prosthetic 
pulmonary valve, 
endovascular 
approach 
0262T
Replacement, 
pulmonary valve 
33475
Valvectomy, 
tricuspid valve, with 
cardiopulmonary 
bypass 
33460
Valvuloplasty, 
tricuspid valve; 
without ring 
insertion 
33463
Valvuloplasty, 
tricuspid valve; with 
ring insertion 
33464
Replacement, 
tricuspid valve, with 
33465

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001-MCS-90-124_RD-01 (4.0)
cardiopulmonary 
bypass 
Description for 
CPT=33660-33665
33660
-
33665
Description for 
CPT=33400-33403
33400
-
33403
Orthopedic 
Procedures  
(Hip/Knee)
Total/Partial Hip 
Replacement
81.52
0SRA009,0SRA00A,0SRA00Z,
0SRA019,0SRA01A,0SRA01Z,
0SRA039,0SRA03A,0SRA03Z,
0SRA07Z,0SRA0J9,0SRA0JA,0
SRA0JZ,0SRA0KZ,0SRE009,0
SRE00A,0SRE00Z,0SRE019,0S
RE01A,0SRE01Z,0SRE039,0S
RE03A,0SRE03Z,0SRE07Z,0S
RE0J9,0SRE0JA,0SRE0JZ,0SR
E0KZ,0SRR019,0SRR01A,0SR
R01Z,0SRR039,0SRR03A,0SR
R03Z,0SRR07Z,0SRR0J9,0SRR
0JA,0SRR0JZ,0SRR0KZ,0SRS
019,0SRS01A,0SRS01Z,0SRS0
39,0SRS03A,0SRS03Z,0SRS07
Z,0SRS0J9,0SRS0JA,0SRS0JZ
81.51
0SR90J9,0SR90JA,0SR90JZ,0S
RB0J9,0SRB0JA,0SRB0JZ

Boehringer Ingelheim
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001-MCS-90-124_RD-01 (4.0)
0070,             
0071,             
0072,             
0073,             
8153
0SP908Z,0SP909Z,0SP90BZ,0S
P90JZ,0SPB08Z,0SPB09Z,0SP
B0BZ,0SPB0JZ,0SR9019,0SR9
01A,0SR901Z,0SR9029,0SR90
2A,0SR902Z,0SR9039,0SR903
A,0SR903Z,0SR9049,0SR904A,
0SR904Z,0SR90J9,0SR90JA,0S
R90JZ,0SRB019,0SRB01A,0SR
B01Z,0SRB029,0SRB02A,0SR
B02Z,0SRB039,0SRB03A,0SR
B03Z,0SRB049,0SRB04A,0SR
B04Z,0SRB0J9,0SRB0JA,0SRB
0JZ,0SP908Z,0SP909Z,0SP90B
Z,0SPA0JZ,0SPB08Z,0SPB09Z,
0SPB0BZ,0SPE0JZ,0SRA009,0
SRA00A,0SRA00Z,0SRA019,0
SRA01A,0SRA01Z,0SRA039,0
SRA03A,0SRA03Z,0SRA0J9,0
SRA0JA,0SRA0JZ,0SRE009,0S
RE00A,0SRE00Z,0SRE019,0S
RE01A,0SRE01Z,0SRE039,0S
RE03A,0SRE03Z,0SRE0J9,0SR
E0JA,0SRE0JZ,0SP908Z,0SP90
9Z,0SP90BZ,0SPB08Z,0SPB09
Z,0SPB0BZ,0SPR0JZ,0SPS0JZ,
0SRR019,0SRR01A,0SRR01Z,
0SRR039,0SRR03A,0SRR03Z,
0SRR0J9,0SRR0JA,0SRR0JZ,0
SRS019,0SRS01A,0SRS01Z,0S
RS039,0SRS03A,0SRS03Z,0SR
S0J9,0SRS0JA,0SRS0JZ,0SP90
8Z,0SP909Z,0SP90BZ,0SP90JZ
,0SPB08Z,0SPB09Z,0SPB0BZ,
0SPB0JZ,0SU909Z,0SUA09Z,0
SUB09Z,0SUE09Z,0SUR09Z,0
SUS09Z,0SW90JZ,0SW93JZ,0
SW94JZ,0SWA0JZ,0SWA3JZ,0
SWA4JZ,0SWB0JZ,0SWB3JZ,
0SWB4JZ,0SWE0JZ,0SWE3JZ,
0SWE4JZ,0SWR0JZ,0SWR3JZ,
0SWR4JZ,0SWS0JZ,0SWS3JZ,
0SWS4JZ
27125
, 
27130
, 
27132

Boehringer Ingelheim
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001-MCS-90-124_RD-01 (4.0)
, 
27134
, 
27137
, 
27138 
Total/Partial Knee 
Replacement
81.54
0SRC07Z,0SRC0JZ,0SRC0KZ,
0SRC0LZ,0SRD07Z,0SRD0JZ,
0SRD0KZ,0SRD0LZ,0SRT07Z,
0SRT0JZ,0SRT0KZ,0SRU07Z,
0SRU0JZ,0SRU0KZ,0SRV07Z,
0SRV0JZ,0SRV0KZ,0SRW07Z
,0SRW0JZ,0SRW0KZ
0080,             
0081,             
0082,             
0083,             
0084,             
8155
0SPC08Z,0SPC09Z,0SPC0JZ,0
SPC48Z,0SPC4JZ,0SPD08Z,0S
PD09Z,0SPD0JZ,0SPD48Z,0SP
D4JZ,0SRC0J9,0SRC0JA,0SRC
0JZ,0SRD0J9,0SRD0JA,0SRD0
JZ,0SPC08Z,0SPC09Z,0SPC48
Z,0SPC4JZ,0SPD08Z,0SPD09Z
,0SPD48Z,0SPD4JZ,0SPT0JZ,0
SPU0JZ,0SRV0J9,0SRV0JA,0S
RV0JZ,0SRW0J9,0SRW0JA,0S
RW0JZ,0SPC08Z,0SPC09Z,0S
PC48Z,0SPC4JZ,0SPD08Z,0SP
D09Z,0SPD48Z,0SPD4JZ,0SPV
0JZ,0SPW0JZ,0SRT0J9,0SRT0
JA,0SRT0JZ,0SRU0J9,0SRU0J
A,0SRU0JZ,0QPD0JZ,0QPD3J
Z,0QPD4JZ,0QPF0JZ,0QPF3JZ
,0QPF4JZ,0QRD0JZ,0QRD3JZ,
0QRD4JZ,0QRF0JZ,0QRF3JZ,
0QRF4JZ,0QUD0JZ,0QUD3JZ,
0QUD4JZ,0QUF0JZ,0QUF3JZ,
0QUF4JZ,0SUC09C,0SUD09C,
0SPC09Z,0SPD09Z,0SUV09Z,0
SUW09Z,0SWC0JC,0SWC0JZ,
0SWC3JC,0SWC3JZ,0SWC4JC
,0SWC4JZ,0SWD0JC,0SWD0J
Z,0SWD3JC,0SWD3JZ,0SWD4
JC,0SWD4JZ,0SWT0JZ,0SWT
3JZ,0SWT4JZ,0SWU0JZ,0SW
U3JZ,0SWU4JZ,0SWV0JZ,0S
WV3JZ,0SWV4JZ,0SWW0JZ,0
SWW3JZ,0SWW4JZ

Boehringer Ingelheim
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001-MCS-90-124_RD-01 (4.0)
27447
, 
27486
, 
27487
, 
27437
, 
27438
, 
27440
, 
27441
, 
27442
, 
27443
, 
27445
, 
27446
Cardiac Surgery 
00.5x, 
35.xx, 
36.xx, 
37.xx
0210083,0210088,0210089,021
008C,021008F,021008W,02100
93,0210098,0210099,021009C,0
21009F,021009W,02100A3,021
00A8,02100A9,02100AC,02100
AF,02100AW,02100J3,02100J8,
02100J9,02100JC,02100JF,0210
0JW,02100K3,02100K8,02100
K9,02100KC,02100KF,02100K
W,02100Z3,02100Z8,02100Z9,
02100ZC,02100ZF,0210344,021
03D4,0210444,0210483,021048
8,0210489,021048C,021048F,02
1048W,0210493,0210498,02104
99,021049C,021049F,021049W,
02104A3,02104A8,02104A9,02
104AC,02104AF,02104AW,021
04D4,02104J3,02104J8,02104J9
,02104JC,02104JF,02104JW,02
104K3,02104K8,02104K9,0210
4KC,02104KF,02104KW,02104
Z3,02104Z8,02104Z9,02104ZC,
02104ZF,0211083,0211088,021
1089,021108C,021108F,021108
W,0211093,0211098,0211099,0
21109C,021109F,021109W,021

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
10A3,02110A8,02110A9,02110
AC,02110AF,02110AW,02110J
3,02110J8,02110J9,02110JC,02
110JF,02110JW,02110K3,0211
0K8,02110K9,02110KC,02110
KF,02110KW,02110Z3,02110Z
8,02110Z9,02110ZC,02110ZF,0
211344,
02113D4,0211444,0211483,021
1488,0211489,021148C,021148
F,021148W,0211493,0211498,0
211499,021149C,021149F,0211
49W,02114A3,02114A8,02114
A9,02114AC,02114AF,02114A
W,02114D4,02114J3,02114J8,0
2114J9,02114JC,02114JF,02114
JW,02114K3,02114K8, 
02114K9,02114KC,02114KF,02
114KW,02114Z3,02114Z8,0211
4Z9,02114ZC,02114ZF,021208
3,0212088,0212089,021208C,02
1208F,021208W,0212093,0212
098,0212099,021209C,021209F,
021209W,02120A3,02120A8,02
120A9,02120AC,02120AF,0212
0AW,02120J3,02120J8,02120J9
,02120JC,
02120JF,02120JW,02120K3,02
120K8,02120K9,02120KC,0212
0KF,02120KW,02120Z3,02120
Z8,02120Z9,02120ZC,02120ZF,
0212344,02123D4,0212444,021
2483,0212488,0212489,021248
C,021248F,021248W,0212493,0
212498,0212499,021249C,0212
49F,021249W,02124A3,02124A
8,02124A9,02124AC,02124AF,
02124AW,02124D4,02124J3,02
124J8,02124J9,02124JC,02124J
F,02124JW,02124K3,02124K8,
02124K9,02124KC,02124KF,02
124KW,02124Z3,02124Z8,0212
4Z9,02124ZC,02124ZF,021308
3,0213088,0213089,021308C,02
1308F,021308W,0213093,0213

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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
098,0213099,021309C,021309F,
021309W,02130A3,02130A8,02
130A9,02130AC,02130AF,0213
0AW,
02130J3,02130J8,02130J9,0213
0JC,02130JF,02130JW,02130K
3,02130K8,02130K9,02130KC,
02130KF,02130KW,02130Z3,0
2130Z8,02130Z9,02130ZC,021
30ZF,0213344,02133D4,021344
4, 
0213483,0213488,0213489,021
348C,021348F,021348W,02134
93,0213498,0213499,021349C,0
21349F,021349W,02134A3,021
34A8,02134A9,02134AC,02134
AF,02134AW,02134D4,02134J
3,02134J8,02134J9,02134JC,02
134JF,02134JW,02134K3,0213
4K8,02134K9,02134KC,02134
KF,02134KW,02134Z3,02134Z
8,02134Z9,02134ZC,02134ZF,0
21608P,021608Q,021608R,0216
09P,
021609Q,021609R,02160AP,02
160AQ,02160AR,02160JP,0216
0JQ,02160JR,02160KP,02160K
Q,02160KR,02160Z7,02160ZP,
02160ZQ,02160ZR,021648P,02
1648Q,021648R,021649P,02164
9Q,021649R,02164AP,02164A
Q,02164AR,02164JP,02164JQ,0
2164JR,02164KP,02164KQ,021
64KR,02164Z7,02164ZP,02164
ZQ,02164ZR,021708P,021708Q
,021708R,021708S,021708T,02
1708U,021709P,021709Q,0217
09R,021709S,021709T,021709
U,02170AP,02170AQ,02170AR

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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
,02170AS,02170AT,02170AU,0
2170JP,02170JQ,02170JR,0217
0JS,02170JT,02170JU,02170KP
,02170KQ,02170KR,02170KS,0
2170KT,02170KU,02170ZP,021
70ZQ,02170ZR,02170ZS,02170
ZT,02170ZU,
021748P,021748Q,021748R,021
748S,021748T,021748U,021749
P,021749Q,021749R,021749S,0
21749T,021749U,02174AP,021
74AQ,02174AR,02174AS,0217
4AT,02174AU,02174JP,02174J
Q,02174JR,02174JS,02174JT,02
174JU,02174KP,02174KQ,0217
4KR,02174KS,02174KT,02174
KU,02174ZP,02174ZQ,02174Z
R,02174ZS,02174ZT,02174ZU,
021K08P,021K08Q,021K08R,0
21K09P,021K09Q,021K09R,02
1K0AP,021K0AQ,021K0AR,02
1K0JP,021K0JQ,021K0JR,021
K0KP,021K0KQ,021K0KR,021
K0Z5,021K0Z8,021K0Z9,021K
0ZC,021K0ZF,021K0ZP,021K0
ZQ,021K0ZR,021K0ZW,
021K48P,021K48Q,021K48R,0
21K49P,021K49Q,021K49R,02
1K4AP,021K4AQ,021K4AR,02
1K4JP,021K4JQ,021K4JR,021
K4KP,021K4KQ,021K4KR,021
K4Z5,021K4Z8,021K4Z9,021K
4ZC,021K4ZF,021K4ZP,021K4
ZQ,021K4ZR,021K4ZW,021L0
8P,021L08Q,021L08R,021L09P
,021L09Q,021L09R,021L0AP,0
21L0AQ,021L0AR,021L0JP,02
1L0JQ,021L0JR,021L0KP,021L
0KQ,021L0KR,021L0Z5,021L0
Z8,021L0Z9,021L0ZC,021L0Z
F,021L0ZP,021L0ZQ,021L0ZR,
021L0ZW,021L48P,021L48Q,0
21L48R,021L49P,021L49Q,021

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001-MCS-90-124_RD-01 (4.0)
L49R,021L4AP,021L4AQ,021L
4AR,021L4JP,021L4JQ,021L4J
R,
021L4KP,021L4KQ,021L4KR,0
21L4Z5,021L4Z8,021L4Z9,021
L4ZC,021L4ZF,021L4ZP,021L
4ZQ,021L4ZR,021L4ZW,021V
08S,021V08T,021V08U,021V0
9S,021V09T,021V09U,021V0A
S,021V0AT,021V0AU,021V0JS
,021V0JT,021V0JU,021V0KS,0
21V0KT,021V0KU,021V0ZS,0
21V0ZT,021V0ZU,021V48S,02
1V48T,021V48U,021V49S,021
V49T,021V49U,021V4AS,021
V4AT,021V4AU,021V4JS,021
V4JT,021V4JU,021V4KS,021V
4KT,021V4KU,021V4ZS,021V
4ZT,021V4ZU,024F07J,024F08
J,024F0JJ,024F0KJ,024G072,02
4G082,024G0J2,024G0K2,024J
072,024J082,024J0J2,024J0K2,
02540ZZ,02543ZZ,02544ZZ,02
550ZZ,02553ZZ,02554ZZ,
02560ZZ,02563ZZ,02564ZZ,02
570ZK,02570ZZ,02573ZK,0257
3ZZ,02574ZK,02574ZZ,02580Z
Z,02583ZZ,02584ZZ,02590ZZ,
02593ZZ,02594ZZ,025D0ZZ,02
5D3ZZ,025D4ZZ,025F0ZZ,025
F3ZZ,025F4ZZ,025G0ZZ,025G
3ZZ,025G4ZZ,025H0ZZ,025H3
ZZ,025H4ZZ,025J0ZZ,025J3ZZ
,025J4ZZ,025K0ZZ,025K3ZZ,0
25K4ZZ,025L0ZZ,025L3ZZ,02
5L4ZZ,025M0ZZ,025M3ZZ,02
5M4ZZ,025N0ZZ,025N3ZZ,02
5N4ZZ,0270046,027004Z,0270
056,027005Z,0270066,027006Z,
0270076,027007Z,02700D6,027

Boehringer Ingelheim
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BI Study Number 1160.274
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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
00DZ,02700E6,02700EZ,02700
F6,02700FZ,02700G6,
02700GZ,02700T6,02700TZ,02
700Z6,02700ZZ,0270346,02703
4Z,0270356,027035Z,0270366,0
27036Z,0270376,027037Z,0270
3D6,02703DZ,02703E6,02703E
Z,02703F6,02703FZ,02703G6,0
2703GZ,02703T6,02703TZ,027
0446,027044Z,0270456,027045
Z,0270466,027046Z,0270476,02
7047Z,02704D6,02704DZ,0270
4E6,02704EZ,02704F6,02704F
Z,02704G6,02704GZ,02704T6,
02704TZ,0271046,027104Z,027
1056,027105Z,0271066,027106
Z,0271076,027107Z,02710D6,0
2710DZ,02710E6,02710EZ,027
10F6,02710FZ,02710G6,02710
GZ,02710T6,02710TZ,02710Z6
,02710ZZ,0271346,027134Z,
0271356,027135Z,0271366,027
136Z,0271376,027137Z,02713D
6,02713DZ,02713E6,02713EZ,0
2713F6,02713FZ,02713G6,0271
3GZ,02713T6,02713TZ,027144
6,027144Z,0271456,027145Z,02
71466,027146Z,0271476,02714
7Z,02714D6,02714DZ,02714E6
,02714EZ,02714F6,02714FZ,02
714G6,02714GZ,02714T6,0271
4TZ,0272046,027204Z,0272056
,027205Z,0272066,027206Z,027
2076,027207Z,02720D6,02720
DZ,02720E6,02720EZ,02720F6,
02720FZ,02720G6,02720GZ,02
720T6,02720TZ,02720Z6,02720
ZZ,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
0272346,027234Z,0272356,027
235Z,0272366,027236Z,027237
6,027237Z,02723D6,02723DZ,0
2723E6,02723EZ,02723F6,0272
3FZ,02723G6,02723GZ,02723T
6,02723TZ,0272446,027244Z,0
272456,027245Z,0272466,0272
46Z,0272476,027247Z,02724D6
,02724DZ,02724E6,02724EZ,02
724F6,02724FZ,02724G6,02724
GZ,02724T6,02724TZ,0273046,
027304Z,0273056,027305Z,027
3066,027306Z,0273076,027307
Z,02730D6,02730DZ,02730E6,
02730EZ,02730F6,02730FZ,027
30G6,02730GZ,02730T6,02730
TZ,02730Z6,02730ZZ,0273346,
027334Z,0273356,027335Z,027
3366,027336Z,0273376,027337
Z,02733D6,02733DZ,02733E6,
02733EZ,02733F6,02733FZ,
02733G6,02733GZ,02733T6,02
733TZ,0273446,027344Z,02734
56,027345Z,0273466,027346Z,0
273476,027347Z,02734D6,0273
4DZ,02734E6,02734EZ,02734F
6,02734FZ,02734G6,02734GZ,0
2734T6,02734TZ,027F04Z,027
F0DZ,027F0ZZ,027F34Z,027F3
DZ,027F3ZZ,027F44Z,027F4D
Z,027F4ZZ,027G04Z,027G0DZ
,027G0ZZ,027G34Z,027G3DZ,
027G3ZZ,027G44Z,027G4DZ,0
27G4ZZ,027H04Z,027H0DZ,02
7H0ZZ,027H34Z,027H3DZ,027
H3ZZ,027H44Z,027H4DZ,027
H4ZZ,027J04Z,027J0DZ,027J0
ZZ,027J34Z,027J3DZ,027J3ZZ,
027J44Z,027J4DZ,027J4ZZ,027
K04Z,027K0DZ,027K0ZZ,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
027K34Z,027K3DZ,027K3ZZ,0
27K44Z,027K4DZ,027K4ZZ,02
7P04Z,027P34Z,027P44Z,027Q
04Z,027Q34Z,027Q44Z,027R04
T,027R04Z,027R0DT,027R0ZT
,027R34T,027R34Z,027R3DT,0
27R3ZT,027R44T,027R44Z,027
R4DT,027R4ZT,027S04Z,027S
34Z,027S44Z,027T04Z,027T34
Z,027T44Z,027V04Z,027V34Z,
027V44Z,027W04Z,027W34Z,0
27W44Z,027X04Z,027X34Z,02
7X44Z,02880ZZ,02883ZZ,0288
4ZZ,02890ZZ,02893ZZ,02894Z
Z,028D0ZZ,028D3ZZ,028D4ZZ
,02B40ZX,02B40ZZ,02B43ZX,
02B43ZZ,02B44ZX,02B44ZZ,0
2B50ZX,02B50ZZ,02B53ZX,02
B53ZZ,02B54ZX,02B54ZZ,
02B60ZX,02B60ZZ,02B63ZX,0
2B63ZZ,02B64ZX,02B64ZZ,02
B70ZK,02B70ZX,02B70ZZ,02
B73ZK,02B73ZX,02B73ZZ,02
B74ZK,02B74ZX,02B74ZZ,02
B80ZX,02B80ZZ,02B83ZX,02
B83ZZ,02B84ZX,02B84ZZ,02B
90ZX,02B90ZZ,02B93ZX,02B9
3ZZ,02B94ZX,02B94ZZ,02BD
0ZX,02BD0ZZ,02BD3ZX,02B
D3ZZ,02BD4ZX,02BD4ZZ,02B
F0ZX,02BF0ZZ,02BF3ZX,02B
F3ZZ,02BF4ZX,02BF4ZZ,02B
G0ZX,02BG0ZZ,02BG3ZX,02
BG3ZZ,02BG4ZX,02BG4ZZ,02
BH0ZX,02BH0ZZ,02BH3ZX,0
2BH3ZZ,02BH4ZX,02BH4ZZ,0
2BJ0ZX,02BJ0ZZ,02BJ3ZX,02
BJ3ZZ,02BJ4ZX,02BJ4ZZ,02B
K0ZX,02BK0ZZ,02BK3ZX,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
02BK3ZZ,02BK4ZX,02BK4ZZ,
02BL0ZX,02BL0ZZ,02BL3ZX,
02BL3ZZ,02BL4ZX,02BL4ZZ,
02BM0ZX,02BM0ZZ,02BM3Z
X,02BM3ZZ,02BM4ZX,02BM4
ZZ,02BN0ZX,02BN0ZZ,02BN3
ZX,02BN3ZZ,02BN4ZX,02BN
4ZZ,02C00Z6,02C00ZZ,02C03
Z6,02C03ZZ,02C04Z6,02C04Z
Z,02C10Z6,02C10ZZ,02C13Z6,
02C13ZZ,02C14Z6,02C14ZZ,0
2C20Z6,02C20ZZ,02C23Z6,02
C23ZZ,02C24Z6,02C24ZZ,02C
30Z6,02C30ZZ,02C33Z6,02C33
ZZ,02C34Z6,02C34ZZ,02C40Z
Z,02C43ZZ,02C44ZZ,02C50ZZ
,02C53ZZ,02C54ZZ,02C60ZZ,0
2C63ZZ,02C64ZZ,02C70ZZ,02
C73ZZ,02C74ZZ,02C80ZZ,02C
83ZZ,
02C84ZZ,02C90ZZ,02C93ZZ,0
2C94ZZ,02CD0ZZ,02CD3ZZ,0
2CD4ZZ,02CF0ZZ,02CF3ZZ,0
2CF4ZZ,02CG0ZZ,02CG3ZZ,0
2CG4ZZ,02CH0ZZ,02CH3ZZ,0
2CH4ZZ,02CJ0ZZ,02CJ3ZZ,02
CJ4ZZ,02CK0ZZ,02CK3ZZ,02
CK4ZZ,02CL0ZZ,02CL3ZZ,02
CL4ZZ,02CM0ZZ,02CM3ZZ,0
2CM4ZZ,02CN0ZZ,02CN3ZZ,
02CN4ZZ,02FN0ZZ,02FN3ZZ,
02FN4ZZ,02H402Z,02H403Z,0
2H40DZ,02H40JZ,02H40KZ,02
H40MZ,02H432Z,02H433Z,02
H43DZ,02H43JZ,02H43KZ,02
H43MZ,02H442Z,02H443Z,02
H44DZ,02H44JZ,02H44KZ,02
H44MZ,02H602Z,02H603Z,02
H60DZ,02H60JZ,02H60KZ,02
H60MZ,02H632Z,02H63DZ,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
02H63JZ,02H63KZ,02H63MZ,
02H642Z,02H643Z,02H64DZ,0
2H64JZ,02H64KZ,02H64MZ,0
2H702Z,02H703Z,02H70DZ,02
H70JZ,02H70KZ,02H70MZ,02
H732Z,02H733Z,02H73DZ,02H
73JZ,02H73KZ,02H73MZ,02H
742Z,02H743Z,02H74DZ,02H7
4JZ,02H74KZ,02H74MZ,02HA
0QZ,02HA0RS,02HA0RZ,02H
A3QZ,02HA3RS,02HA3RZ,02
HA4QZ,02HA4RS,02HA4RZ,0
2HK00Z,02HK02Z,02HK03Z,0
2HK0DZ,02HK0JZ,02HK0KZ,
02HK0MZ,02HK30Z,02HK32Z
,02HK3DZ,02HK3JZ,02HK3K
Z,02HK3MZ,02HK40Z,02HK4
2Z,02HK43Z,02HK4DZ,02HK4
JZ,02HK4KZ,02HK4MZ,02HL
02Z,02HL03Z,02HL0DZ,02HL
0JZ,
02HL0KZ,02HL0MZ,02HL32Z,
02HL33Z,02HL3DZ,02HL3JZ,0
2HL3KZ,02HL3MZ,02HL42Z,0
2HL43Z,02HL4DZ,02HL4JZ,02
HL4KZ,02HL4MZ,02HN00Z,0
2HN02Z,02HN0JZ,02HN0KZ,0
2HN0MZ,02HN30Z,02HN32Z,
02HN3JZ,02HN3KZ,02HN3MZ
,02HN40Z,02HN42Z,02HN4JZ,
02HN4KZ,02HN4MZ,02HW00
Z,02HW30Z,02HW40Z,02HX0
0Z,02HX30Z,02HX40Z,02JA3Z
Z,02JY3ZZ,02K80ZZ,02K83ZZ
,02K84ZZ,02L70CK,02L70DK,
02L70ZK,02L73CK,02L73DK,
02L73ZK,02L74CK,02L74DK,
02L74ZK,02LH0CZ,02LH0DZ,
02LH0ZZ,02LH3CZ,02LH3DZ,
02LH3ZZ,02LH4CZ,02LH4DZ,
02LH4ZZ,02LR0ZT,02LS0ZZ,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
02LT0ZZ,02N40ZZ,02N43ZZ,0
2N44ZZ,02N50ZZ,02N53ZZ,02
N54ZZ,02N60ZZ,02N63ZZ,02
N64ZZ,02N70ZZ,02N73ZZ,02
N74ZZ,02N80ZZ,02N83ZZ,02
N84ZZ,02N90ZZ,02N93ZZ,02
N94ZZ,02ND0ZZ,02ND3ZZ,02
ND4ZZ,02NF0ZZ,02NF3ZZ,02
NF4ZZ,02NG0ZZ,02NG3ZZ,02
NG4ZZ,02NH0ZZ,02NH3ZZ,0
2NH4ZZ,02NJ0ZZ,02NJ3ZZ,02
NJ4ZZ,02NK0ZZ,02NK3ZZ,02
NK4ZZ,02NL0ZZ,02NL3ZZ,02
NL4ZZ,02NM0ZZ,02NM3ZZ,0
2NM4ZZ,02NN0ZZ,02NN3ZZ,
02NN4ZZ,02PA02Z,02PA03Z,0
2PA07Z,02PA08Z,02PA0CZ,02
PA0DZ,02PA0JZ,02PA0KZ,02
PA0MZ,02PA0QZ,02PA0RZ,02
PA32Z,02PA33Z,02PA37Z,
02PA38Z,02PA3CZ,02PA3DZ,
02PA3JZ,02PA3KZ,02PA3MZ,
02PA3QZ,02PA3RZ,02PA42Z,
02PA43Z,02PA47Z,02PA48Z,0
2PA4CZ,02PA4DZ,02PA4JZ,02
PA4KZ,02PA4MZ,02PA4QZ,0
2PA4RZ,02PAXMZ,02Q00ZZ,
02Q03ZZ,02Q04ZZ,02Q10ZZ,0
2Q13ZZ,02Q14ZZ,02Q20ZZ,02
Q23ZZ,02Q24ZZ,02Q30ZZ,02
Q33ZZ,02Q34ZZ,02Q40ZZ,02
Q43ZZ,02Q44ZZ,02Q50ZZ,02
Q53ZZ,02Q54ZZ,02Q60ZZ,02
Q63ZZ,02Q64ZZ,02Q70ZZ,02
Q73ZZ,02Q74ZZ,02Q80ZZ,02
Q83ZZ,02Q84ZZ,02Q90ZZ,02
Q93ZZ,02Q94ZZ,02QA0ZZ,02
QA3ZZ,02QA4ZZ,02QB0ZZ,02
QB3ZZ,02QB4ZZ,02QC0ZZ,02
QC3ZZ,02QC4ZZ,02QD0ZZ,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
02QD3ZZ,02QD4ZZ,02QF0ZJ,
02QF0ZZ,02QF3ZJ,02QF3ZZ,0
2QF4ZJ,02QF4ZZ,02QG0ZE,02
QG0ZZ,02QG3ZE,02QG3ZZ,0
2QG4ZE,02QG4ZZ,02QH0ZZ,
02QH3ZZ,02QH4ZZ,02QJ0ZG,
02QJ0ZZ,02QJ3ZG,02QJ3ZZ,0
2QJ4ZG,02QJ4ZZ,02QK0ZZ,02
QK3ZZ,02QK4ZZ,02QL0ZZ,02
QL3ZZ,02QL4ZZ,02QM0ZZ,02
QM3ZZ,02QM4ZZ,02QN0ZZ,0
2QN3ZZ,02QN4ZZ,02R507Z,0
2R508Z,02R50JZ,02R50KZ,02
R547Z,02R548Z,02R54JZ,02R5
4KZ,02R607Z,02R608Z,02R60J
Z,02R60KZ,02R647Z,02R648Z,
02R64JZ,02R64KZ,02R707Z,02
R708Z,02R70JZ,02R70KZ,02R
747Z,02R748Z,02R74JZ,02R74
KZ,02R907Z,
02R908Z,02R90JZ,02R90KZ,02
R947Z,02R948Z,02R94JZ,02R9
4KZ,02RD07Z,02RD08Z,02RD
0JZ,02RD0KZ,02RD47Z,02RD
48Z,02RD4JZ,02RD4KZ,02RF0
7Z,02RF08Z,02RF0JZ,02RF0K
Z,02RF37H,02RF37Z,02RF38H
,02RF38Z,02RF3JH,02RF3JZ,0
2RF3KH,02RF3KZ,02RF47Z,0
2RF48Z,02RF4JZ,02RF4KZ,02
RG07Z,02RG08Z,02RG0JZ,02
RG0KZ,02RG37H,02RG37Z,02
RG38H,02RG38Z,02RG3JH,02
RG3JZ,02RG3KH,02RG3KZ,02
RG47Z,02RG48Z,02RG4JZ,02
RG4KZ,02RH07Z,02RH08Z,02
RH0JZ,02RH0KZ,02RH37H,02
RH37Z,02RH38H,02RH38Z,02
RH3JH,02RH3JZ,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
02RH3KH,02RH3KZ,02RH47Z
,02RH48Z,02RH4JZ,02RH4KZ,
02RJ07Z,02RJ08Z,02RJ0JZ,02
RJ0KZ,02RJ47Z,02RJ48Z,02RJ
4JZ,02RJ4KZ,02RK07Z,02RK0
8Z,02RK0JZ,02RK0KZ,02RK4
7Z,02RK48Z,02RK4JZ,02RK4
KZ,02RL07Z,02RL08Z,02RL0J
Z,02RL0KZ,02RL47Z,02RL48
Z,02RL4JZ,02RL4KZ,02RM07
Z,02RM08Z,02RM0JZ,02RM0
KZ,02RM47Z,02RM48Z,02RM
4JZ,02RM4KZ,02RN07Z,02RN
08Z,02RN0JZ,02RN0KZ,02RN
47Z,02RN48Z,02RN4JZ,02RN4
KZ,02RP0JZ,02RQ07Z,02RQ0J
Z,02RR07Z,02RR0JZ,02S00ZZ,
02S10ZZ,02SP0ZZ,02SW0ZZ,0
2SX0ZZ,02T50ZZ,02T53ZZ,02
T54ZZ,02T80ZZ,02T83ZZ,02T
84ZZ,02T90ZZ,02T93ZZ,02T9
4ZZ,02TD0ZZ,02TD3ZZ,02TD
4ZZ,
02TH0ZZ,02TH3ZZ,02TH4ZZ,
02TM0ZZ,02TM3ZZ,02TM4ZZ
,02TN0ZZ,02TN3ZZ,02TN4ZZ,
02U507Z,02U508Z,02U50JZ,02
U50KZ,02U537Z,02U538Z,02U
53JZ,02U53KZ,02U547Z,02U5
48Z,02U54JZ,02U54KZ,02U60
7Z,02U608Z,02U60JZ,02U60K
Z,02U637Z,02U638Z,02U63JZ,
02U63KZ,02U647Z,02U648Z,0
2U64JZ,02U64KZ,02U707Z,02
U708Z,02U70JZ,02U70KZ,02U
737Z,02U738Z,02U73JZ,02U73
KZ,02U747Z,02U748Z,02U74J
Z,02U74KZ,02U907Z,02U908Z
,02U90JZ,02U90KZ,02U937Z,0
2U938Z,02U93JZ,02U93KZ,02
U947Z,02U948Z,02U94JZ,02U
94KZ,02UA07Z,02UA08Z,02U
A0JZ,02UA0KZ,02UA37Z,02U
A38Z,02UA3JZ,02UA3KZ,02U
A47Z,02UA48Z,02UA4JZ,02U
A4KZ,02UD07Z,02UD08Z,02U
D0JZ,02UD0KZ,02UD37Z,02U

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
D38Z,02UD3JZ,
02UD3KZ,02UD47Z,02UD48Z,
02UD4JZ,02UD4KZ,02UF07J,0
2UF07Z,02UF08J,02UF08Z,02
UF0JJ,02UF0JZ,02UF0KJ,02U
F0KZ,02UF37J,02UF37Z,02UF
38J,02UF38Z,02UF3JJ,02UF3J
Z,02UF3KJ,02UF3KZ,02UF47J
,02UF47Z,02UF48J,02UF48Z,0
2UF4JJ,02UF4JZ,02UF4KJ,02U
F4KZ,02UG07E,02UG07Z,02U
G08E,02UG08Z,02UG0JE,02U
G0JZ,02UG0KE,02UG0KZ,02
UG37E,02UG37Z,02UG38E,02
UG38Z,02UG3JE,02UG3JZ,02
UG3KE,02UG3KZ,02UG47E,0
2UG47Z,02UG48E,02UG48Z,0
2UG4JE,02UG4JZ,02UG4KE,0
2UG4KZ,02UH07Z,02UH08Z,0
2UH0JZ,02UH0KZ,02UH37Z,0
2UH38Z,02UH3JZ,02UH3KZ,0
2UH47Z,02UH48Z,02UH4JZ,0
2UH4KZ,02UJ07G,02UJ07Z,02
UJ08G,02UJ08Z,02UJ0JG,02UJ
0JZ,02UJ0KG,02UJ0KZ,02UJ3
7G,02UJ37Z,02UJ38G,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
02UJ38Z,02UJ3JG,02UJ3JZ,02
UJ3KG,02UJ3KZ,02UJ47G,02
UJ47Z,02UJ48G,02UJ48Z,02UJ
4JG,02UJ4JZ,02UJ4KG,02UJ4
KZ,02UK07Z,02UK08Z,02UK0
JZ,02UK0KZ,02UK37Z,02UK3
8Z,02UK3JZ,02UK3KZ,02UK4
7Z,02UK48Z,02UK4JZ,02UK4
KZ,02UL07Z,02UL08Z,02UL0J
Z,02UL0KZ,02UL37Z,02UL38
Z,02UL3JZ,02UL3KZ,02UL47
Z,02UL48Z,02UL4JZ,02UL4K
Z,02UM07Z,02UM08Z,02UM0
JZ,02UM0KZ,02UM37Z,02UM
38Z,02UM3JZ,02UM3KZ,02U
M47Z,02UM48Z,02UM4JZ,02
UM4KZ,02UN07Z,02UN08Z,0
2UN0JZ,02UN0KZ,02UN37Z,0
2UN38Z,02UN3JZ,02UN3KZ,0
2UN47Z,02UN48Z,02UN4JZ,0
2UN4KZ,02VA0CZ,02VA0ZZ,
02VA3CZ,02VA3ZZ,02VA4CZ
,02VA4ZZ,02VR0ZT,02W50JZ,
02W54JZ,02WA02Z,02WA03Z
,02WA07Z,02WA08Z,02WA0C
Z,02WA0DZ,02WA0JZ,02WA0
KZ,02WA0MZ,02WA0QZ,02W
A0RZ,02WA32Z,02WA33Z,02
WA37Z,02WA38Z,02WA3CZ,
02WA3DZ,02WA3JZ,02WA3K
Z,02WA3MZ,02WA3QZ,02WA
3RZ,02WA42Z,02WA43Z,02W
A47Z,02WA48Z,02WA4CZ,02
WA4DZ,02WA4JZ,02WA4KZ,
02WA4MZ,02WA4QZ,02WA4
RZ,02WF07Z,02WF08Z,02WF
0JZ,02WF0KZ,02WF47Z,02WF
48Z,02WF4JZ,02WF4KZ,02W
G07Z,02WG08Z,02WG0JZ,02
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02WG4JZ,02WG4KZ,02WH07
Z,02WH08Z,02WH0JZ,02WH0
KZ,02WH47Z,02WH48Z,02W
H4JZ,02WH4KZ,02WJ07Z,02
WJ08Z,02WJ0JZ,02WJ0KZ,02
WJ47Z,02WJ48Z,02WJ4JZ,02
WJ4KZ,02WM0JZ,02WM4JZ,0

Boehringer Ingelheim
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BI Study Number 1160.274
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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
2YA0Z0,02YA0Z1,02YA0Z2,0
370046,037004Z,0370056,0370
05Z,0370066,037006Z,0370076,
037007Z,
0370346,037034Z,0370356,037
035Z,0370366,037036Z,037037
6,037037Z,0370446,037044Z,03
70456,037045Z,0370466,03704
6Z,0370476,037047Z,0371046,0
37104Z,0371056,037105Z,0371
066,037106Z,0371076,037107Z,
0371346,037134Z,0371356,037
135Z,0371366,037136Z,037137
6,037137Z,0371446,037144Z,03
71456,037145Z,0371466,03714
6Z,0371476,037147Z,0372046,0
37204Z,0372056,037205Z,0372
066,037206Z,0372076,037207Z,
0372346,037234Z,0372356,037
235Z,0372366,037236Z,037237
6,037237Z,0372446,037244Z,03
72456,037245Z,0372466,03724
6Z,0372476,037247Z,0373046,0
37304Z,
0373056,037305Z,0373066,037
306Z,0373076,037307Z,037334
6,037334Z,0373356,037335Z,03
73366,037336Z,0373376,03733
7Z,0373446,037344Z,0373456,0
37345Z,0373466,037346Z,0373
476,037347Z,0374046,037404Z,
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6,037434Z,0374356,037435Z,03
74366,037436Z,0374376,03743
7Z,0374446,037444Z,0374456,0
37445Z,0374466,037446Z,0374
476,037447Z,0375046,037504Z,
0375056,037505Z,0375066,037
506Z,0375076,037507Z,037534

Boehringer Ingelheim
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BI Study Number 1160.274
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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
6,037534Z,0375356,037535Z,03
75366,037536Z,0375376,03753
7Z,0375446,037544Z,0375456,0
37545Z,0375466,
037546Z,0375476,037547Z,037
6046,037604Z,0376056,037605
Z,0376066,037606Z,0376076,03
7607Z,0376346,037634Z,03763
56,037635Z,0376366,037636Z,0
376376,037637Z,0376446,0376
44Z,0376456,037645Z,0376466,
037646Z,0376476,037647Z,037
7046,037704Z,0377056,037705
Z,0377066,037706Z,0377076,03
7707Z,0377346,037734Z,03773
56,037735Z,0377366,037736Z,0
377376,037737Z,0377446,0377
44Z,0377456,037745Z,0377466,
037746Z,0377476,037747Z,037
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Z,0378066,037806Z,0378076,03
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56,037835Z,0378366,037836Z,0
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44Z,0378456,037845Z,0378466,
037846Z,0378476,037847Z,037
9046,037904Z,0379056,
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46,037944Z,0379456,037945Z,0
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47Z,037A046,037A04Z,037A05
6,037A05Z,037A066,037A06Z,
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7A34Z,037A356,037A35Z,037
A366,037A36Z,037A376,037A
37Z,037A446,037A44Z,037A45
6,037A45Z,037A466,037A46Z,
037A476,037A47Z,037B046,03

Boehringer Ingelheim
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BI Study Number 1160.274
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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
7B04Z,037B056,037B05Z,037B
066,037B06Z,037B076,037B07
Z,037B346,037B34Z,037B356,0
37B35Z,037B366,037B36Z,037
B376,037B37Z,037B446,037B4
4Z,037B456,037B45Z,037B466,
037B46Z,
037B476,037B47Z,037C046,03
7C04Z,037C056,037C05Z,037C
066,037C06Z,037C076,037C07
Z,037C346,037C34Z,037C356,0
37C35Z,037C366,037C36Z,037
C376,037C37Z,037C446,037C4
4Z,037C456,037C45Z,037C466,
037C46Z,037C476,037C47Z,03
7D046,037D04Z,037D056,037
D05Z,037D066,037D06Z,037D
076,037D07Z,037D346,037D34
Z,037D356,037D35Z,037D366,
037D36Z,037D376,037D37Z,03
7D446,037D44Z,037D456,037
D45Z,037D466,037D46Z,037D
476,037D47Z,037F046,037F04
Z,037F056,037F05Z,037F066,0
37F06Z,037F076,037F07Z,037F
346,037F34Z,037F356,037F35Z
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7F37Z,
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6,037F47Z,037G046,037G04Z,0
37G056,037G05Z,037G066,037
G06Z,037G076,037G07Z,037H
046,037H04Z,037H056,037H05
Z,037H066,037H06Z,037H076,
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7H356,037H35Z,037H366,037
H36Z,037H376,037H37Z,037H
446,037H44Z,037H456,037H45
Z,037H466,037H46Z,037H476,
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J056,037J05Z,037J066,037J06Z
,037J076,037J07Z,037J346,037J
34Z,037J356,037J35Z,037J366,

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
037J36Z,037J376,037J37Z,037J
446,037J44Z,037J456,037J45Z,
037J466,037J46Z,037J476,037J
47Z,037K046,037K04Z,037K05
6,037K05Z,
037K066,037K06Z,037K076,03
7K07Z,037K346,037K34Z,037
K356,037K35Z,037K366,037K
36Z,037K376,037K37Z,037K44
6,037K44Z,037K456,037K45Z,
037K466,037K46Z,037K476,03
7K47Z,037L046,037L04Z,037L
056,037L05Z,037L066,037L06
Z,037L076,037L07Z,037L346,0
37L34Z,037L356,037L35Z,037
L366,037L36Z,037L376,037L3
7Z,037L446,037L44Z,037L456,
037L45Z,037L466,037L46Z,03
7L476,037L47Z,037M046,037
M04Z,037M056,037M05Z,037
M066,037M06Z,037M076,037
M07Z,037M346,037M34Z,037
M356,037M35Z,037M366,037
M36Z,037M376,037M37Z,037
M446,037M44Z,037M456,037
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37N046,037N04Z,037N056,037
N05Z,037N066,037N06Z,037N
076,037N07Z,037N346,037N34
Z,037N356,037N35Z,037N366,
037N36Z,037N376,037N37Z,03
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476,037N47Z,037P046,037P04
Z,037P056,037P05Z,037P066,0
37P06Z,037P076,037P07Z,037P
346,037P34Z,037P356,037P35Z
,037P366,037P36Z,037P376,03
7P37Z,037P446,037P44Z,037P4
56,037P45Z,037P466,037P46Z,
037P476,037P47Z,037Q046,037

Boehringer Ingelheim
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BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
Q04Z,037Q056,037Q05Z,037Q
066,037Q06Z,037Q076,037Q07
Z,037Q346,037Q34Z,037Q356,
037Q35Z,037Q366,037Q36Z,03
7Q376,
037Q37Z,037Q446,037Q44Z,03
7Q456,037Q45Z,037Q466,037
Q46Z,037Q476,037Q47Z,037R
046,037R04Z,037R056,037R05
Z,037R066,037R06Z,037R076,0
37R07Z,037R346,037R34Z,037
R356,037R35Z,037R366,037R3
6Z,037R376,037R37Z,037R446,
037R44Z,037R456,037R45Z,03
7R466,037R46Z,037R476,037R
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037V076,037V07Z,037V346,03
7V34Z,037V356,037V35Z,037
V366,037V36Z,037V376,037V

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
37Z,037V446,
037V44Z,037V456,037V45Z,03
7V466,037V46Z,037V476,037
V47Z,037Y046,037Y04Z,037Y
056,037Y05Z,037Y066,037Y06
Z,037Y076,037Y07Z,037Y346,
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456,037Y45Z,037Y466,037Y46
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066,047006Z,0470076,047007Z,
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035Z,0470366,047036Z,047037
6,047037Z,0470446,047044Z,04
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6Z,0470476,047047Z,0471046,0
47104Z,0471056,047105Z,0471
066,047106Z,0471076,047107Z,
0471346,047134Z,0471356,
047135Z,0471366,047136Z,047
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Z,0471456,047145Z,0471466,04
7146Z,0471476,047147Z,04720
46,047204Z,0472056,047205Z,0
472066,047206Z,0472076,0472
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473066,047306Z,0473076,0473
07Z,0473346,047334Z,0473356,
047335Z,0473366,047336Z,047
3376,047337Z,0473446,047344
Z,0473456,047345Z,0473466,04

Boehringer Ingelheim
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BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
7346Z,0473476,047347Z,04740
46,047404Z,0474056,047405Z,0
474066,047406Z,0474076,
047407Z,0474346,047434Z,047
4356,047435Z,0474366,047436
Z,0474376,047437Z,0474446,04
7444Z,0474456,047445Z,04744
66,047446Z,0474476,047447Z,0
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047507Z,0475346,047534Z,047
5356,047535Z,0475366,047536
Z,0475376,047537Z,0475446,04
7544Z,0475456,047545Z,04754
66,047546Z,0475476,047547Z,0
476046,047604Z,0476056,0476
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Z,0476376,047637Z,0476446,04
7644Z,0476456,047645Z,04764
66,047646Z,0476476,047647Z,0
477046,047704Z,0477056,0477
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56,047905Z,0479066,047906Z,0
479076,047907Z,0479346,0479
34Z,0479356,047935Z,0479366,

Boehringer Ingelheim
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BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
047936Z,0479376,047937Z,047
9446,047944Z,0479456,047945
Z,0479466,047946Z,0479476,04
7947Z,047A046,047A04Z,047A
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047A456,047A45Z,047A466,04
7A46Z,047A476,047A47Z,047
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5Z,047B066,047B06Z,047B076,
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6,047B44Z,047B456,047B45Z,0
47B466,047B46Z,047B476,047
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366,047C36Z,047C376,047C37
Z,047C446,047C44Z,047C456,0
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47F066,047F06Z,047F076,047F
07Z,047F346,047F34Z,047F356
,047F35Z,047F366,047F36Z,04

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
7F376,047F37Z,047F446,047F4
4Z,047F456,047F45Z,047F466,
047F46Z,047F476,047F47Z,047
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05Z,047H066,047H06Z,047H07
6,047H07Z,047H346,047H34Z,
047H356,047H35Z,047H366,04
7H36Z,047H376,047H37Z,047
H446,
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6,047J44Z,047J456,047J45Z,04
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7K06Z,047K076,047K07Z,047
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M446,047M44Z,047M456,047
M45Z,047M466,047M46Z,047
M476,047M47Z,047N041,047N

Boehringer Ingelheim
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BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
046,047N04Z,047N056,047N05
Z,047N066,047N06Z,047N076,
047N07Z,047N341,047N346,04
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37Z,047N441,047N446,047N44
Z,047N456,
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34Z,047T356,047T35Z,047T36
6,047T36Z,047T376,047T37Z,0
47T446,047T44Z,047T456,047

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001-MCS-90-124_RD-01 (4.0)
T45Z,047T466,047T46Z,047T4
76,047T47Z,047U046,047U04Z
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6,047W44Z,047W456,047W45
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W9D0ZX,0W9D0ZZ,0W9D30Z

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
c14336616-01
Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-124_RD-01 (4.0)
,0W9D3ZX,0W9D3ZZ,0W9D4
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41Z,0WWD43Z,0WWD4YZ,3E
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70GC,3E070KZ,3E070PZ,3E07
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F032,X2RF332,X2RF432

Boehringer Ingelheim
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Protocol for non-interventional studies based on existing data
BI Study Number 1160.274
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001-MCS-90-124_RD-01 (4.0)
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
N/A

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
ANNEX 3. ADDITIONAL INFORMATION
N/A

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14336616
1.0
1160-0274-final-protocol
The Comparative Safety and Effectiveness of dabigatran, versus rivaroxaban, and
apixaban Utilized in the Department of Defense (DoD) Non-Valvular Atrial
Fibrillation Patient Population-A Retrospective Database Analysis
Approval-Clinical 
17 Dec 2016 21:07 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14336616
1.0