The Evaluation of Thrombogenicity in Patients Undergoing WATCHMAN Left Atrial Appendage Closure Trial
Conditions: Left Atrial Appendage Closure, WATCHMAN Device Implantation
Sponsor: Inova Health Care Services

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The Evaluation of Thrombogenecity in Patients Undergoing WATCHMAN Left Atrial 
Appendage Closure (TARGET-WATCHMAN) Trial 
 
 
 
 
Principal Investigators: Paul A. Gurbel, M.D.  
 
 
 
 
Device Name: The WATCHMANTM Device 
 
 
 
Sponsor: Boston Scientific, Inc. 
 
 
 
Site of Investigation: Inova Heart and Vascular Institute at Inova Fairfax Hospital,  
Falls Church, VA 
 
 
Date of Protocol:  5 January 2018 
 
Contact Information:  
Paul A. Gurbel, M.D. 
Inova Center for Thrombosis Research and Drug Development 
Inova Heart and Vascular Institute 
3300 Gallows Road 
Falls Church, VA 22042 
Phone: 410-367-2590 
Fax: 410-367-2596 
Email: paul.gurbel@inova.org 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
Title: The evaluation of thrombogenecity in patients undergoing WATCHMAN left atrial 
appendage closure trial 
 
Short Title:  TARGET-WATCHMAN  
 
Rationale: The results of this study will aid clinicians in better risk stratification of patients 
undergoing WATCHMAN left atrial appendage closure to prevent future thromboembolic and 
bleeding events. Additionally, the information will help guide the management of 
anticoagulation post-WATCHMAN implant, in particular the duration of anticoagulation and 
anti-platelet therapy. 
 
Objectives 
Primary: To identify biomarkers, parameters of thrombosis and platelet function to assist in 
identification of a thrombogenic phenotype in patients undergoing implantation of the 
WATCHMAN left atrial appendage closure device. 
 
Secondary:  
1. Determine differences in thrombogenicity among patients undergoing WATCHMAN left 
atrial appendage closure pre- and up to 1 year post- implant. 
2. Identify blood biomarkers for predicting thrombo-embolic events and/or presence of LA 
thrombus detected on TEE performed 45 days, and at 1-year post-WATCHMAN implant. 
3. Identify blood biomarkers for predicting major or clinically relevant non-major bleeding 
(CRNM) up to 1-year post-WATCHMAN implant. 
5. Determine frequency of high on-treatment platelet reactivity and correlate to outcomes.  
6. Determine frequency of low, medium, and high risk thrombogenic phenotype within the study 
population.  
7. Identify changes in Galectin-3 and sST2 post-WATCHMAN implant and correlate to other 
biomarkers studied. 
 
Study Type: Observational study design.  
 
Study Design: Prospective, single center, observational study. 
 
Study Methodology: This investigation will be conducted in subjects >18 years of age 
scheduled for WATCHMAN device implantation procedure. The study explores novel 
biomarkers to assess thrombogenicity in patients undergoing WATCHMAN left atrial appendage 
closure. Patients will undergo serial assessment of thrombogenicity and fibrosis over a twelve-
month follow-up. 
 
Patients:  A total of 30 patients receiving WATCHMAN device implantation. It is expected that 
an additional 10 patients may be required to be enrolled to account for screen failures. 
 

3 
 
Statistical Methodology: Pearsons’ correlation coefficient, univariate and multivariate logistic 
regression models, ROC curve analysis. Statistical calculations will be carried out using SAS® 
for Windows, version 9.3 or later (Cary, NC). 
 
1 
INTRODUCTION 
1.1 
Specific Aims 
 To quantify and characterize specific biomarkers of thrombogenicity in patients 
undergoing WATCHMAN implant, both pre- and post-procedure. 
 To identify variations in thrombogenic phenotypes which play a role in the varied 
incidence of thromboembolic complications amongst patients undergoing percutaneous 
left atrial appendage closure with the WATCHMAN implant 
 Obtain pilot data for future translational trials aimed at personalizing antithrombotic  
therapy  (duration of anticoagulation and anti-platelet therapy) by thrombogenic 
phenotype in WATCHMAN patients.  
 
1.2 
Hypothesis 
We hypothesize that serial evaluation of (a) platelet activation and aggregation, (b) intrinsic 
thrombogenicity measured by thrombelastography, and (c) selected biomarkers will provide 
the “blueprint” of individual hemostasis to precisely characterize patients who have 
thrombotic or bleeding tendencies.  The latter will facilitate future efforts to personalize 
antithrombotic therapy regimens during and following WATCHMAN implant.  
 
1.3 
Background and Significance 
Atrial fibrillation (AF) is associated with an increased risk of stroke and thromboembolism.1 
Anticoagulation, with either warfarin or the novel anticoagulants (NOACs) is recommended 
for patients at increased risk of stroke, based on the CHA2DS2-VASc scoring system. 
However, treatment with these agents is not without its limitations and may be associated 
with serious side effects, of which major gastrointestinal bleeding and hemorrhagic stroke are 
the most devastating. Non-pharmacologic strategies for stroke prevention in patients with 
atrial fibrillation exist.  Percutaneous left atrial appendage closure with the WATCHMAN 
device is an FDA approved modality, and exists as an option for stroke reduction in patients 
with atrial fibrillation, deemed to be at high risk for long term anticoagulation.   
 
Current guidelines for WATCHMAN implant require that a patient must be treated with at 
least 45 days of warfarin post WATCHMAN implant and then six months of a combination 
of aspirin and clopidogrel. This duration of therapy is based on the data from two large 
clinical trials (Protect AF and Prevail) involving WATCHMAN implant and several CAP 
registries.2-5  
 
No data exists on whether there are differences in markers of thrombogenicity among 
patients undergoing WATCHMAN implant, and whether those differences could be used to 
guide the management of anticoagulation and anti-platelet therapy pre- and post-
WATCHMAN implant. The purpose of this study will be to quantify and characterize 
specific biomarkers of thrombogenicity in patients undergoing WATCHMAN implant, both 
pre- and post-procedure. In addition, we seek to find variations in thrombogenic phenotypes 

4 
 
which play a role in the varied incidence of thromboembolic complications amongst patients 
undergoing percutaneous left atrial appendage closure with the WATCHMAN implant. 
Furthermore, the individual thrombogenic phenotype may be used to guide anticoagulation in 
these patients, more specifically the duration of anticoagulation and anti-platelet therapy. 
This will be established by utilizing biomarkers assessed by thrombelastography (TEG), 
platelet aggregation, CAT assay, fibrinogen levels, urinary thromboxane, D-dimer, CRP and 
PAI-1. We hypothesize that by utilizing these assays, we can accurately identify a 
thrombogenic phenotype in patients undergoing WATCHMAN implant for left atrial 
appendage closure and help predict and manage the risk of subsequent thrombotic 
complications. The proteins soluble ST2 (sST2) and galectin-3 are currently gaining 
mounting interest as candidate biomarkers in cardiac disease which have been utilized to 
measure acute inflammation to chronic inflammation and tissue fibrinogenisis. In this pilot 
study, we will assess changes in Galectin-3 and sST2 post-WATCHMAN implant and 
correlate to other biomarkers studied. 
 
2 
POST-IMPLANTATION CARE 
The device implantation procedure is performed in a standard fashion per device implant 
protocol in the cardiac catheterization laboratory. Device selection is based on accurate left atrial 
appendage measurements obtained in multiple angles. The device is permeable to blood thus 
patients require post-procedure warfarin therapy for 45 days on a dose assuring a therapeutic 
INR level and ASA 81mg. A transesophageal echocardiography (TEE) is performed for device 
assessment 45 days post-procedure after which a decision is made to discontinue warfarin. If the 
TEE shows no leak > 5mm around the device and no left atrial (LA) thrombus, warfarin is 
discontinued and the patient is treated with clopidogrel 75 mg and aspirin 325mg for up to 6 
months, after which the clopidogrel is discontinued and aspirin 162-325mg thereafter. If the 
follow-up TEE at 45 days shows a leak > 5mm around the device or a LA thrombus is noted, the 
patient will need to remain on warfarin for another 6 months (or upon resolution of thrombus), 
and another TEE performed thereafter.  
 
If the TEE performed at 45 days shows that the opening of the LAA is not adequately closed, 
another TEE may be scheduled at around 6 months to re-evaluate whether adequate closer of the 
LAA has occurred. At about 12 months after the WATCHMAN implant, another TEE is 
performed to check on the device and make sure that the LAA is still closed. 
 
3 
STUDY DESIGN AND SUBJECT SELECTION 
3.1 
Study Type 
This is an observational study that will be conducted in subjects scheduled for the 
WATCHMAN device implantation. The laboratory assessments (see section 1.1) will be 
performed at the baseline (pre-procedure), post-implantation, 45 days, 6 months, and 12 
months post-procedure (see table 1).  
 
3.2 
Duration of Study 
Subject participation will be for 12 months after obtaining consent. 
 
3.3 
Number of Subjects 
Thirty patients scheduled for WATCHMAN device implantation. 

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3.4 
Study Population 
3.4.1 
Population Characteristics 
3.4.1.1 Gender and racial and ethnic origin of subjects 
The study’s intended population is inclusive of both genders (males and females), and all 
racial and ethnic groups and subgroups.   
 
3.4.1.2 Age of subjects 
Subject enrollment will be comprised of subjects >18 years of age. 
 
3.4.2 
Vulnerable Population 
Children, pregnant women, institutionalized persons, and persons with decisional 
incapacity will be not be enrolled in this study.  
 
3.5 
Recruitment 
Recruitment will occur at the Inova Heart and Vascular Institute. The expected length of the 
recruitment period is 16 months. The average number of WATCHMAN left atrial appendage 
closure procedures performed at INOVA is approximated to be 60 per year. If the study 
conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) does not 
suggest a proper completion of the trial within the reasonable time frame as agreed upon, the 
recruitment period may be extended to reach the desired sample size. 
 
3.6 
Inclusion Criteria 
o 
Subject indicated and scheduled for WATCHMAN device implantation at IHVI. 
o 
Subject may be of either sex and of any race, and must be >18 years of age. 
o 
Subject must be willing and able to give appropriate informed consent. 
o The subject is able to read and has signed and dated the informed consent document 
including authorization permitting release of personal health information approved by the 
investigator's Institutional Review Board (IRB). 
 
3.7 
Exclusion Criteria 
Subjects will be excluded from entry if ANY of the criteria listed below are met: 
o Subjects with contraindications for WATCHMAN device implantation 
- Intracardiac thrombus is visualized by echocardiographic imaging 
- An atrial septal defect repair or closure device or a patent foramen ovale repair or 
closure device is present 
- The LAA anatomy will not accommodate a device 
- Any of the customary contraindications for other percutaneous catheterization 
procedures (e.g., patient size too small to accommodate TEE probe or required 
catheters) or conditions (e.g., active infection, bleeding disorder) are present. 
- There are contraindications to the use of warfarin, aspirin, or clopidogrel 
- The patient has a known hypersensitivity to any portion of the device material or 
the individual components such that the use of the WATCHMAN Device is 
contraindicated 
o Ligated or oversewn left atrium 
o Concurrent participation in any investigational study 

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o Subject likely to not be available to complete all protocol-required study visits or 
procedures, to the best of the subject's and investigator's knowledge 
o History or evidence of any other clinically significant disorder, condition, or disease other 
than those outlined above that, in the opinion of the investigator, may compromise the 
ability of the subject to give written informed consent, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion. 
 
4 
STUDY METHODS 
4.1 
Laboratory Measurements 
Phlebotomy sites will be carefully chosen to minimize risk and platelet activation. In 
addition, blood from the left atrium via transeptal sheath will be collected during the 
procedure to compare clotting at the site of implant and the periphery. After discarding the 
first 2-3mL of free flowing blood, the blood collection tubes will be filled to capacity and 
gently inverted 3 to 5 times to ensure complete mixing of the anticoagulant. At each visit 
blood (total=approximately 17 ml each visit) will be collected in two 3.2% trisodium citrate 
tubes (light transmittance aggregometry and thrombelastography), one CTAD tube 
containing buffered citrate solution, theophylline, adenosine and dipyridamole (activation 
markers) and one serum separator tube ( lipid and biomarker measurements).  
 
 Platelet Aggregation by Light Transmittance Aggregometry (LTA) (Chronolog)  
      Platelet aggregation will be assessed in platelet-rich plasma using a Chronolog  
Lumi-Aggregometer (model 490-4D) with the AggroLink software package after  
stimulation with 5 and 20 µM ADP, 2mM AA, and 4ug/ml collagen.6 
 
 TEG6S with citrated multi-channel cartridge  
The TEG6s instrument is a microfluidic fully automated cartridge-based device. The 
standard hemostasis assay cartridge (Citrated Multi-Channel, CMC) uses a citrated blood 
sample that is mixed with dried reagents within each of the 4 channels, each with calcium 
chloride (to reverse the sodium citrate) and: (1) kaolin, (2) kaolin+ tissue factor activated 
(RapidTEG), (3) kaolin + heparinase, and (4) kaolin + abciximab (functional 
fibrinogen).7 
 
 Thrombogram (CAT assay): Uses a slow fluorogenic thrombin substrate and continuous 
comparison to a simultaneously run calibrator, thrombin generation can be monitored 
automatically, on line, in clotting PPP or PRP at a throughput of up to 100 samples per 
hour. The resulting "Thrombogram" in PPP measure patients with hypo- or 
hypercoagulable phenotypes.8 
 Urinary 11-dehydrothromboxane B2 (UTBx): Measures endogenous platelet activation.9 
 
 Soluble biomarkers (fibrinogen, d-dimer, hsCRP, and PAI) to indicate thrombogenicity, 
oxidative stress, endothelial dysfunction, and inflammation. 
 
 Markers of fibrosis: sST2 and Galectin-3 markers measure maladaptive response to tissue 
fibrosis.10 

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4.2 
Primary and Secondary Objectives 
4.2.1 
Primary Objective 
To identify biomarkers, parameters of thrombosis and platelet function to assist in               
identification of a thrombogenic phenotype in patients undergoing implantation of the 
WATCHMAN left atrial appendage closure device. 
 
4.2.2 
Secondary Objectives 
 Identify blood biomarkers for predicting thrombo-embolic events  and/or presence 
of LA thrombus detected on TEE performed 45 days, and at 1-year post-
WATCHMAN implant. 
 Determine differences in thrombogenicity among patients undergoing 
WATCHMAN left atrial appendage closure pre- and up to 1 year post- implant. 
 Identify blood biomarkers for predicting thrombo-embolic events  and/or presence 
of LA thrombus detected on TEE performed 45 days, and at 1-year post-
WATCHMAN implant. 
  Identify blood biomarkers for predicting major or clinically relevant non-major 
bleeding (CRNM) up to 1-year post-WATCHMAN implant. 
 Determine frequency of high on-treatment platelet reactivity and correlate to 
outcomes.  
 Determine frequency of low, medium, and high risk thrombogenic phenotype 
within the study population.  
 Identify changes in Galectin-3 and sST2 post-WATCHMAN implant and correlate 
to other biomarkers studied. 
 
4.2.3 
Clinical Endpoints 
 Thrombo-embolic events (Death, Stroke, and MI) and/or presence of LA thrombus 
detected on TEE. 
 Bleeding using Academic Research Consortium (BARC) definition. 
 
4.3 
Informed Consent 
The research staff will meet with the participant to discuss the study, explain the goals, 
risks/benefits, answer questions, while allowing adequate time and privacy for decision 
making, and then obtaining a signed consent document. Patients incapable of providing 
consent due to a medical situation will not be approached for study participation. No study 
related procedures may commence without a signed consent form. 
 
5 
STATISTICAL CONSIDERATIONS/DATA ANALYSIS  
 
  
5.1 Statistical Calculations 
No data exists on whether there are differences in markers of thrombogenicity among 
patients undergoing WATCHMAN implant, and if those differences could be used to guide 
the management of anticoagulation and anti-platelet therapy pre- and post-WATCHMAN 
implant. Similar pharmacodynamic studies conducted in device trials (Coronary Stent, 
TAVR) have typically enrolled 30- 75 patients to determine serial changes in 
thrombogenicity and in biomarkers after implant. No similar size analysis has been 

8 
 
performed with WATCHMAN patients.  As such a reasonable calculation of a sample size 
based on the accepted error rate is currently not feasible.   
5.2 Statistical Analysis 
Categorical variables will be expressed as n (%). Continuous variables with normal 
distributions will be reported as mean [standard deviation (SD)], while variables not having a 
normal distribution were reported as median (interquartile). Wilcoxon signed rank tests or 
paired t-tests will be performed to test differences in lab values before and after implant.  
Correlation analysis will be performed by Pearson’s correlation coefficient.  Univariate and 
multivariate logistic regression models will be used to determine predictors of clinical 
endpoints.  The predictive cut-point values of platelet function tests or rate of fibrinolysis 
will be assessed by ROC curve analysis. Statistical calculations will be carried out using 
SAS® for Windows, version 9.3 or later (Cary, NC).  
 
5.3 Future Experiments:  
Our initial pilot study will allow for adjustments to our experimental methodology and will 
provide insights into the potential value of this analysis for determining an individual 
WATCHMAN recipient’s degree of antithrombotic therapy.   If our pilot data is interesting 
we then plan to expand our analysis to a consortium of WATCHMAN research centers. A 
larger cohort will allow validation of our initial findings.  Future experiments will then focus 
on titration of anticoagulation and antiplatelet therapy to reduce the risk of bleeding and 
thrombotic complications. In addition, the individual thrombogenic phenotype may be used 
to guide anticoagulation in these patients, more specifically the duration of anticoagulation 
and anti-platelet therapy. To facilitate these and future studies, we plan to submit our pilot 
data generated from this grant as part of future grant applications.   
 
6 
VISIT SCHEDULE AND ASSESSMENTS 
Informed consent will be obtained from subjects meeting the inclusion criteria and none of the 
exclusion criteria before the initiation of any study-specific procedures. The study comprises of 4 
periods: (1) Procedural (pre and post WATCHMAN implantation, (2) 45 days post-procedure, 
(3) 6 months post-procedure, and (4) 12 months post-procedure. Required assessments for each 
study visit are listed in Table 1. Subjects should be seen for visits on the designated day or 
according to the allowed window period (see Table 1).  
 
Each clinic visit includes laboratory measurements, safety assessment, and health and 
concomitant medication review. A complete physical exam is required for visit 1 (baseline). 
 
 Laboratory measurements  
Laboratory measurements (see section 4.1) will be obtained at baseline (prior to device 
implantation procedure), immediately post-procedure, 45 days, 6 months, and 12 months 
post-procedure. Laboratory measurements needed at baseline and immediately post-
procedure will be done while the subject is on the pre-op area, angiography suite, and/or 
recovery area. The study will require clinic visits during the required laboratory 
measurements for 45 days, 6 months, and 12 month post-procedure.  
 
 

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 Health and concomitant medication review 
During the follow-up clinic visits, changes in participant’s medical condition (any new 
diagnosis, etc.) and concomitant medications should be updated. Note that only 
anticoagulation and anti-platelet therapies will be collected. Adverse events will be reported, 
side effects and symptoms assessed. 
 
 Physical Exam 
A physical exam will be conducted by the investigator during the screening period after 
obtaining consent to evaluate the general status of the subject and to further elucidate patient 
symptoms, risk factors, or concerns that may increase the subject’s risk for adverse events.  
 
 Safety assessments 
Safety assessments will consist of monitoring and recording of serious adverse events (see 
section 10). The occurrence of adverse events should be sought by non-directive questioning 
of the subject at each visit during the study. AEs may also be detected when these are 
volunteered by the subject during or between visits or through physical examination, 
laboratory test, or other assessments. For the purpose of this study, only (a) thromboembolic 
and (b) bleeding events, and (c) serious adverse events (SAEs) directly related to study 
procedures, or (d) SAEs not previously reported to a left atrial appendage closure device or 
implantation (see device package insert) with potential relatedness to the WATCHMAN 
device will be collected and reported (see section 10).  
 
Additional assessments required to ensure safety of subjects should be administered as 
deemed necessary by the investigator on a case by case basis.  
 
Table 1 
Schedule of Events 
 
V1 
 
V25 
V35 
V45 
 
Pre-
procedure 
Immediately 
post-
procedure 
45 days 
post-
procedure 
(+ 10 days) 
6 months 
post-
procedure 
(+1 month) 
12 months post-
procedure   
(+ 1-month) 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Review Prior/Concomitant 
Medications1 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
Height, weight, Blood 
pressure, heart rate 
measurements 
X 
 
 
 
 
TEE2 
X 
 
X 
 
X 
Laboratory Measurements: 
TEG6S and platelet 
aggregation  
X 
X 
X 
X 
X 

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V1 
 
V25 
V35 
V45 
 
Pre-
procedure 
Immediately 
post-
procedure 
45 days 
post-
procedure 
(+ 10 days) 
6 months 
post-
procedure 
(+1 month) 
12 months post-
procedure   
(+ 1-month) 
Laboratory Measurements: 
Thrombogram (CAT assay), 
urinary 
thromboxane,biomarkers, 
markers of fibrosis 
X 
X6 
X 
X 
X3 
Adverse events4 
X 
X 
X 
X 
X 
 
1 Anticoagulation and anti-platelet therapies only 
2 Standard of care procedure 
3 Thrombogram, urinary thromboxane, biomarkers, and markers of fibrosis obtained only if subject have 
reports of thromboembolic events post-implantation 
4Only thromboembolic and bleeding events, SAEs not previously reported to WATCHMAN device or 
implantation procedure (see device package insert) with potential relatedness to the WATCHMAN 
device/implantation procedure and SAEs directly related to study procedures will be collected 
5The 45 days, 6 months, and 12 month visits post-procedure coincide with recommended standard of care 
follow-up visits post-WATCHMAN implantation procedure.  
6Urinary thromboxane will not be performed at post-procedure time point 
 
6.1 
Timing of Assessments 
6.1.1 
Visit 1: Procedural Day 
6.1.1.1 Pre-procedure 
The site principal investigator is responsible for reviewing and confirming that the 
subject signed and dated the ICF prior to any study-related procedures. Additionally, 
the site PI is responsible for reviewing and confirming that each subject met all 
inclusion and none of the exclusion criteria prior to WATCHMAN device placement. 
 
       The following tests and procedures are performed prior to device implantation: 
 Subject demographic and baseline characteristics. 
- Demographic data to be collected on all subjects include: date of birth, 
age, sex, race, and ethnicity.  
 Past medical history and co-morbidities  
 Height and weight blood pressure and heart rate prior to procedure 
 Concomitant medication review. Only anticoagulants and anti-platelet 
medications will be recorded in source documents (CRFs). 
 Perform complete physical examination. 
 Laboratory measurements for TEG 6S, platelet aggregation, thrombogram, 
urinary thromboxane, biomarkers, and markers of fibrosis will be obtained 
prior to implantation procedure. 
 
6.1.1.2 Immediately post-procedure 
The procedure will be completed according to operating physician’s standard practice 
in an angiography suite. The following tests and procedures are performed 
immediately after device implantation: 

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 Laboratory measurements for TEG 6S, platelet aggregation, thrombogram, , 
biomarkers, and markers of fibrosis will be obtained immediately post-
procedure. 
 Concomitant medication: all anticoagulant and antiplatelet medications will be 
collected. 
 Safety assessment (see section 10) 
 
6.1.2 
Treatment Failures 
Failure to implant the WATCHMAN device will be recorded on the paper CRF as a 
treatment failure. In the event of a failure to implant the device, each site will follow their 
standard of care procedures and/or commercially available products to ensure safety of the 
subject. The reason for unsuccessful implantation (e.g. product malfunction) will be 
documented. Subjects will be exited from the study after failure and no other study-related 
procedures are required. 
 
6.1.3 
Follow-Up Assessments 
Subjects are followed until 12 months after device implantation. Subjects will have follow-
up visits at 45 days, 6 months, and 12 months post-procedure. These visits may coincide 
with standard of care follow-up visits post WATCHMAN device implantation procedure. 
 
The following assessments will be performed at each in-person follow-up visit  
 Laboratory measurements (see table 1 for laboratory measurements required 
for each follow-up visit) will be obtained. 
 Adverse event monitoring (see section 10). 
 Health and medication review. Anticoagulant and antiplatelet therapies will be 
collected.  
 
6.2 Lost to Follow-Up and Subject Withdrawal 
All subjects should be encouraged to return for protocol-required clinic visits for evaluation 
during the study follow-up period. If a subject is unable to return for a clinic visit, all attempts 
should be documented in the source documents. If the subject does not respond to 3 telephone 
calls, then the Investigator must send the subject a certified letter. Only after failing to contact 
the subject using the methods above will the subject be considered a lost to follow-up.  
 
If the subject withdraws from the study, the reason for withdrawal must be documented. 
Possible reasons for early withdrawal may include but are not limited to the following: 
 
Subject decides to withdraw from the study. Documentation of subject’s decision 
to withdraw is documented in the CRFs. 
 
The Investigator may choose to withdraw a subject from the study if there are 
safety concerns. 
 
Death 
 
7 
DATA MANAGEMENT 
7.1 Data Storage and Management 
Designated study site staff will record data required by the protocol into the CRFs and enter it 
into the electronic database. Authorized research staff will review the CRFs for completeness 

12 
 
and accuracy and make any necessary corrections to the data entered into the electronic 
database. Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Each subject screened and enrolled will be assigned a subject identification number (ID) and a 
list of subjects with their corresponding subject ID will be maintained separately from 
collected data. Physical CRFs will be stored in the research site in a locked office and 
electronic subject data will be locked in a password protected file on a secure internet server, 
accessed only by authorized research staff.   
 
7.2 Records Retention  
The Investigator will maintain the records of final CRFs (CDROM copies), worksheets, paper 
source documents, and all other study-specific documentation in accordance with ICH 
Guidelines. Essential documents should be retained until at least two (2) years after the 
investigation is formally discontinued. 
 
7.3 Confidentiality 
Subject information will be kept confidential as according to HIPAA requirements. Subject 
data will be stored and managed as outlined in section 7.1. All data records will be stored on 
site until 2 years after the investigation is formally discontinued. Paper records will be 
shredded and recycled. Records stored on a computer hard drive will be erased using a 
commercial software application designed to remove all data from the storage device.   
 
7.4 Oversight 
The principal investigator holds ultimate responsibility for the oversight and execution of the 
data and safety monitoring plan. This research site will be fully committed in the ongoing 
review and refinement of the trial’s processes to assure subject safety, data validity and 
integrity, and regulatory compliance. 
 
8 
HUMAN SUBJECTS PROTECTION (RISKS, BENEFITS, AND ALTERNATIVES) 
8.1 Risks 
8.1.2 Potential Loss of Privacy 
Protected health information (PHI) will be collected during the study. The risk for breach of 
confidentiality and privacy will be minimized by shielding the subjects unlinking his or her 
identity from his or her personal health information. 
8.1.3 Potential Adverse Events 
For the purpose of this study (see section 10), only thromboembolic and bleeding events, 
SAEs related to study procedures (e.g. nerve damage directly related to blood draw), and 
SAEs not previously reported by device manufacturer with potential relatedness to the device 
or implantation procedure (see package insert) will be collected and reported. SAEs should 
be treated appropriately and managed as according to standard of care.  
 
8.1.4 Economic risk 
Subjects in the study may lose time at work or home and spend more time in the research site 
more than usual. Visit schedules will be made flexible for subjects (as allowed by protocol). 
 
 

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8.2 Benefits and Alternatives 
There are no direct benefits to the patient. Participation in the study is entirely voluntary. The 
alternative is not to participate in the trial. 
 
9 
SUBJECT COMPENSATION 
9.1  Costs 
This is an investigator-initiated study sponsored by Boston Scientific, Inc. The subject or their 
insurance company will not be billed for study-specific procedures (e.g. laboratory 
measurements for TEG 6S, etc.). All study-specific tests and procedures will be paid for by the 
research site.  
 
9.2  Payment 
Subjects may receive up to $75 for their participation in this study. Subjects will be reimbursed 
$25 for each follow-up visit at the study site to cover their expenses associated with those 
visits. 
 
10 ADVERSE EVENT REPORTING 
10.1 AE Reporting 
  For the purpose of this study, only the following adverse events will be collected and reported: 
 
-Thromboembolic events 
-Bleeding events using BARC definitions (see section 10.5) 
-SAEs related to study procedures (i.e. SAEs directly related to phlebotomy procedure) 
-SAEs not previously reported by device manufacturer with potential relatedness to the 
device or implant procedure. For serious adverse events not previously documented in 
study device’s Package Insert (new occurrence) and are thought to be related to the study 
device or implant procedure, the investigator may urgently require further information 
from the investigator for Health Authority reporting. Boston Scientific Corporation or 
designee may need to issue an IDE Safety Report (Investigator Notification) to inform all 
investigators involved in any study with the same device that this SAE has been reported. 
 
10.2 Adverse Events Treatment 
All AEs should be treated appropriately and managed as according to standard of care. The 
action taken to treat the AE should be recorded on the AE CRF (see section 10.3). Assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity, 
relationship to the study procedures (if applicable), the interventions required to treat it, and the 
outcome. 
 
10.3 Adverse Event Reporting   
The principal investigator has the primary responsibility for SAE identification, documentation, 
grading, and assignment of attribution to the study intervention. Note that only SAEs related to 
study procedures (e.g. arterial puncture, etc.), clinical endpoints (see section 4.2.3), and SAEs 
not previously reported by manufacturer with potential relatedness to device or implantation 
procedure will be collected and reported. SAEs must be recorded in the AE CRF with the 
following information:  
 -AE term 
 -The intensity grade (CTCAE v4.03 grading) 

14 
 
 -The relationship to study procedure 
 -Attribution 
 -Duration 
 -Occurrence (known risks for study procedure-expected, unexpected) 
 -Other contributing causes 
 -Actions in response to event 
 -Outcome 
 -Criteria for SAE  
 
10.4 AE Grading Scale 
The descriptions and grading scales found in NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 will be used for AE reporting. Each AE term is associated with a 
5-point severity scale.  
 
10.5 Bleeding Definitions 
Bleeding events will be documented using the Bleeding Academic Research Consortium 
(BARC) standard definitions described below (excluding Type 4) .11 
 
Bleeding Academic Research Consortium Definition for Bleeding 
Type 0: No bleeding 
Type 1: 
Bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a health-care professional; may 
include episodes leading to self-discontinuation of medical therapy by the patient without 
consulting a health-care professional. 
Type 2: 
Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit the 
criteria for type 3, 4, or 5 but does meet at least one of the following criteria:  
• 
requiring nonsurgical, medical intervention by a health-care professional,  
• 
leading to hospitalization or increased level of care, or 
• 
prompting evaluation 
Type 3: 
Type 3a: 
• 
Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided hemoglobin drop is 
related to bleed) 
• 
Any transfusion with overt bleeding 
Type 3b: 
• 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to  
      bleed),  
• 
Cardiac tamponade,  
• 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid),  
• 
Bleeding requiring intravenous vasoactive agents 
Type 3c: 
• 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation,  

15 
 
      does include intraspinal),  
• 
Subcategories confirmed by autopsy or imaging or lumbar puncture, 
• 
Intraocular bleed compromising vision. 
Type 4: (not required for this trial) 
• 
CABG-related bleeding,  
• 
Perioperative intracranial bleeding within 48 h,  
• 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
• 
Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-h period,  
• 
Chest tube output more than or equal to 2L within a 24-h period 
Type 5: Fatal bleeding 
Type 5a: 
• 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
Type 5b: 
• 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation  
 
10.6 Protocol Deviations and Violations 
The principal investigator will not deviate from the protocol without obtaining approval from 
the IRB or Ethics Committee and the sponsor. Protocol deviations that occur will be reported 
to the Inova IRB at the time of continuing review. Protocol violations that affect the subject’s 
rights and safety, and/or affects study integrity will be reported to the Inova IRB within 10 
working days of event knowledge.  
 
11 FUNDING 
This is an investigator-initiated study sponsored by Boston Scientific, Inc. There is no 
investigational product involved. Treatment received by the subject will be as according to main 
provider’s discretion as according to standard of care. 
 
12 CONFLICTS OF INTEREST   
The investigators declare no conflicts of interest linked to this study.  
 
13 FACILITIES AND EQUIPMENT  
The research site is equipped with its own laboratory equipment, which includes state of the art 
technologies for platelet assays, centrifuges, refrigerators, and freezers for study specimen 
processing and storage. For outpatient visits, subjects will be seen in the site’s outpatient clinic 
room equipped with supplies and equipment for necessary for subject assessment. 
 
14 OUTSIDE CONSULTANTS/COLLABORATORS  
There are no outside consultants/collaborators participating. 
 
15 CONTRACTURAL AGREEMENTS   
   
There are no outside consultants/collaborators participating. 
 
 
 
 
 

16 
 
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