Clinical trial NCT03539055
Conditions: Atrial Fibrillation Device Related Thrombus Left Atrial Appendage Thrombosis Watchman LAA Closure Device
Keywords: DRT Device related thrombus Dabigatran etexilate Aspirin Watchman
Sponsor: Vanderbilt University Medical Center
Start date: 2018-09-01; Completion date: 2024-02-29
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single arm, prospective unblinded study on post Watchman LAA closure device implant anti-coagulation management at a primary center (Vanderbilt Medical Center) and up to 5 additional high volume LAA implant centers. This trial will be designed to evaluate the use of dabigatran for 90 days post implantation of an LAA closure device (Watchman LAA Closure Device, Boston Scientific Inc.) to prevent device related thrombus.

Detailed description:
Single arm, prospective unblinded study on post Watchman LAA closure device implant anti-coagulation management at a primary center (Vanderbilt Medical Center) and up to 5 additional high volume LAA implant centers. This trial will be designed to evaluate the use of dabigatran for 90 days post implantation of an LAA closure device (Watchman LAA Closure Device, Boston Scientific Inc.).

The drug will be initiated on the morning following device implantation, taken BID per package insert dosing and until follow-up 90-day post implant TEE. Aspirin monotherapy will be utilized in conjunction at 81 mg for up to 12 months, after which the patients will be exited from the study and further treatment decisions will be made by the following physician (see Schedule of Study Procedures at end of protocol). The objective of this trial is to evaluate safety and efficacy of a 90-day period of dabigatran etexilate following LAA closure to prevent device associated thrombus, while minimizing adverse bleeding by eliminating the need for clopidogrel.

This is a single arm pilot study with the option (pending collaboration with additional funding source) to expand to a full single arm non-inferiority trial design with 80% power to detect a 1.4% difference with the non-inferiority margin 1% in absolute rate of DAT (control rate 3.9%).

Prospective, non-randomized single arm study. Comparison will be made to historical controls based on published one year DAT rates from PROTECT-AF, PREVAIL clinical trials, and EWOLUTION, and ACP/Amulet registries.

Echocardiography (TEE) will be performed at 90 days (3 months, +/- 2-week window), and again at 1-year post implant (+/- 4 weeks). Selected images will be interpreted by echo lab at coordinating center in an anonymous fashion (patient data de-identified). Ideal imaging will incorporate 0, 45, 90 and 135 degree angled views on the device at follow up.

Drug will be dispensed as part of the clinical trial supplied from the sponsor and each patient will receive a complete 90 days' supply up front. They will have a drug visit on the day of TEE with the research coordinator to hand back any remaining dabigatran, with clear instruction to stop the drug and only take ASA following confirmation of closure on TEE (no peri-device leak on Doppler of \>5mm). A decision to continue anti-coagulation post closure 90day TEE will be made by the physician discretion based on TEE findings. If thrombus is found at the 90 days TEE, anti-coagulation may be extended another 6 weeks with repeat TEE imaging to confirm clot resolution at the discretion of the investigator. In the unlikely event of embolization or Doppler leak \>5mm, decision on extending anti-coagulation, or re-implanting a device will be made by the following physician.

Additional baseline data collection: Patient demographics, medical history, age, sex, and prior use of anti-coagulants or anti-platelet medications will be collected. CHADS 2 Vasc, and HAS-BLED score calculated. Main indication for LAA closure must be documented. Baseline CBC and BMP required on day of implant or up to 1 week pre-procedure (typical standard of care labs at time of implant). This will include a recent calculation of Creatinine Clearance (using Cockroft Gault and using patients actual body weight) and dosing of study drug will be made in accordance (see below). Repeat PCV or hematocrit on the morning after Watchman LAAC implantation will be per hospital standard. PCV or hematocrit value pre-implant and at the post 90-day visit will be analyzed.

Calculation for dabigatran dosing:

CCr={ (l40-age) x weight in kg)/(72 x SCr) } x 0.85 (if female)

Implant procedure variables to collect include access site, sheath used for deployment (WAS), device size at implant and number of implant attempts. LA pressure mean if available. Presence of angiography contrast or Doppler Echo leak, thrombus, or pericardial effusion post implant will be recorded. At 90 days, TEE report findings and image review (standard of care) with drug dosing visit with research coordinator and return of any remaining study drug.

1 year TEE (standard of care) with a research exit visit with MD, physician extender, or research coordinator, with documentation of ASA tolerance, dosing, and any late bleeding episodes or hospitalizations (typically should be reported as AE/SAE when first knowledge of event is determined). TEE images will be sent to the primary study site (Vanderbilt University Medical Center) and core TEE lab will review to confirm presence or absence of DAT. In cases of CTA utilized for follow up, similarly images will be reviewed by chest radiology team at Vanderbilt.

Medication administration with 90 days of dabigatran to be dispensed by pharmacy ideally one time (180 capsules).

Arms: arm 1: Dabigatran 75 or 150mg BID x 90 days plus ASA 81mg daily.

Single arm, prospective unblinded study on post Watchman LAA closure device implant anti-coagulation management at a primary center (Vanderbilt Medical Center) and up to 5 additional high volume LAA implant centers. This trial will be designed to evaluate the use of dabigatran for 90 days post implantation of an LAA closure device (Watchman LAA Closure Device, Boston Scientific Inc.)
Interventions: intervention 1: Dabigatran Etexilate Oral Capsule
Intervention descriptions: intervention 1: Oral use of Dabigatran etexilate for 90 days BID per product labeling for dosage to reduce incidence of device related thrombus after implantation of a Watchman LAA device.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Efficacy of short term dabigatran etexilate followed by 
aspirin monotherapy after LAA (left atrial appendage) 
device closure (the DEA-LAA study). 
Protocol version 1 dated May 15, 2018 
 
Principle Investigator:  
Christopher Randall Ellis, MD, FACC, FHRS 
Associate Professor of Medicine, Director LAA Closure Program 
Vanderbilt Heart and Vascular Institute 
Medicine- Cardiac Electrophysiology 
1215 21st Ave South 
Medical Center East Suite 5209 
Nashville, TN 37232-8802 
615-480-0829 
615-936-5064 
 
Additional study sites to be coordinated through VHVI/VUMC: Wake Forest Medical Center 
(PI, S. Patrick Whalen, MD), Duke University Medical Center (PI, John S. Piccini, MD), 
Piedmont Hospital Atlanta, GA (PI- Sandeep Goyal, MD), Grandview Hospital Birmingham, 
AL (PI- Dr. Jose Osorio), Moeen Saleem (Advocate Health Care, Il). 
 
 


2 
 
LIST OF ABBREVIATIONS 
 
ACP- Amplatzer cardiac plug 
AF- atrial fibrillation 
ASA- aspirin 
CTA- CT angiography 
DAPT- dual anti platelet therapy 
DAT- device associated thrombus 
DEA- Dabigatran Etexilate followed by Aspirin 
DOAC- direct oral anticoagulant 
DRT- device related thrombus 
ICE- intra-cardiac echocardiography 
LAA- left atrial appendage 
LAAC- left atrial appendage closure 
OAC- oral anticoagulation 
TEE- trans-esophageal echocardiography 
WAS- Watchman access sheath 
 
 
 


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1. Background and Study Rationale:  
Two years after FDA approval of the first left atrial appendage (LAA) closure device 
for the prevention of embolic stroke in patients with non-valvular atrial fibrillation, over 
13,000 Watchman (Boston Scientific, Inc., Natick, MA) devices have been successfully 
implanted in the US. Post-approval prospective registry data in 3,822 consecutive cases 
demonstrated implantation was successful in 3,653 (95.6%), with a median procedure time 
of 50 min with the majority of operators new to the procedure (71%). Complications 
included 39 pericardial tamponades (1.02%), 3 procedure-related strokes (0.078%); 9 
device embolizations (0.24%), and 3 procedure-related deaths (0.078%) [1]. The early 
phase PROTECT-AF complications topped 10%, but clearly as expertise in trans-septal 
access, and improvements in the delivery system and technique have evolved, total 
complications post implant have dropped to <3% in the EWOLUTION registry [2].  
With proper patient selection, routine use of ultrasound to guide venous access, and 
a continued trend to implant without bridging anti-coagulation, expert centers may be able 
to reduce total acute complications below 1%. As a stroke prevention strategy, this could 
position LAA closure as a cost-effective consideration, potentially as first line therapy for 
many patients.  Several landmark clinical trials are ongoing in the LAA occlusion space and 
will provide prospective randomized trial data on over 5000 patients closed with a variety 
of methods. The Amulet (Abbott Medical, Inc.) versus Watchman IDE clinical trial (clinical 
trials.gov # NCT02879448) has rapidly enrolled since opening in 2017 with a target 
enrollment of 1400 subjects and 300 roll-in cases. Subjects eligible for a Watchman LAA 
closure device are randomized 1:1 to Amulet or Watchman and followed for a minimum of 
18 months for the endpoint of stroke or systemic embolism. Additionally, the surgical 
LAAOS-III trial is studying over 4000 patients undergoing open heart surgery with a history 
of AF, and randomized 1:1 to LAA excision, or no intervention on the LAA.  
Anti-coagulation regimen and anti-platelet therapy post Watchman implant in the 
Amulet IDE is according to the FDA labeling for Watchman subjects, with a more variable 
strategy in the Amulet arm, including even DAPT alone (ASA 81mg plus Plavix 75mg 
minimum of 6 months, followed by ASA 81mg alone). Traditional or standard of care 
anticoagulation management following Watchman LAA closure device implantation 
includes oral dose adjusted warfarin INR 2-3 for 45 days after implant (unclear if this 
requires initiation of warfarin pre-procedure in patients who were intolerant to OAC).  In 
addition, ASA 81mg is to be taken to 45 days when a follow up TEE is performed to assess 
leaks, device position or thrombus formation.  Typically (in PROTECT and PREVAIL over 
92% of subjects stopped OAC at 45 days), the FDA labeling is to initiate ASA 325mg daily 
with clopidogrel 75mg daily for up to 180 days post implant, then indefinite ASA 325mg 
daily is recommended.  
 
Referrals for LAA closure for anti-coagulation failure (formation of thrombus in the 
LAA despite medical therapy, or recurrent embolic events or stroke while on OAC) are not 


4 
 
clearly outlined in any LAA closure clinical trial inclusion criteria. In our experience, these 
may actually be the patients who stand to benefit the most from removing or occluding the 
LAA. Two separate studies have shown over a 93% LAA closure efficacy rate, including a 
2017 LAA closure study with long term CTA assessment on Atriclip (Atricure Inc., West 
Chester OH, USA) placed by thoracoscopic approach [4,5]. Prior formal studies of surgical 
methods have reached 60-70% closure rates at best, and incomplete surgical closure is 
associated with a higher rate of stroke [6].  Management immediately following LAA closure 
by an epicardial approach with Atriclip or surgical closure does not appear to require 
systemic anti-coagulation, though no prospective randomized data exists to support this 
claim.  
Several retrospective studies were published in 2017 supporting the use of NOAC 
(novel oral anti-coagulant) or DOAC (direct oral anti-coagulant) for anti-coagulation post 
LAA device implant to reduce DAT. EWOLUTION reported a 1 year device associated 
thrombus rate of 3.7% with Watchman, independent of the post implant regimen, in which 
73% of anti-coagulation ‘contra-indicated’ subjects were on anti-platelet regimens alone 
[2]. A separate study showed a 3.2% DAT rate with the Amplatzer Cardiac Plug (previous 
generation of the Amulet device under IDE trial in the US) [7]. While certainly not what the 
implanting physician hopes to see at the 45 days or 1 year follow up TEE, whether a DAT 
leads to clinical ischemic strokes as a whole has been difficult to determine. Standard 
practice has been to initiate short-term oral anti-coagulation and repeat the TEE in 6 weeks 
to ensure resolution, of a DAT, then return to anti-platelet therapy alone. 
The process of complete endothelialization of a Watchman LAA closure device is 
poorly understood. Animal models suggest complete endothelialization may be complete 
within 6 weeks. Human autopsy examples show variable endothelialization at up to 9 
months. A study in 2017 using CT angiography demonstrated contrast flow across 66% of 
LAA devices at 6 weeks, questioning if TEE at 6 weeks is really a suitable metric for ‘closure’ 
[8]. Likely this represents a slow leak through the fabric cap and not around the device, if 
the TEE shows no Doppler flow. We have seen several cases where follow up TEE missed a 
leak and an obvious gap with contrast filling a trabeculated LAA lobe was seen with CTA. 
Anti-coagulation was discontinued, but long-term studies are needed to evaluate the impact 
of this finding. 
Event rates for bleeding after Watchman versus warfarin show superiority after 6 
months when clopidogrel is discontinued.  This is where the net clinical benefit of LAAC is 
seen, leading to improved long term outcomes and ultimately the rationale for FDA 
approval of the Watchman device. The role of dual anti-platelet therapy, or the use of 
325mg ASA versus 81 mg ASA long term is not supported by any specific literature, and was 
carried over from previous trials with use of coronary stents, and PFO and ASD occluder 
devices. Once the LAA device has complete occlusion with no flow into the LAA and surface 
endothelialization, it is plausible that ASA 81mg is a sufficient recommendation long term. 
This has recently been established in European AF guidelines on LAA closure for patients 
contra-indicated to OAC, supporting single or dual anti-platelet therapy after implant. 


5 
 
However, this potentially sets up an increased risk of device associated thrombus (DAT). If 
an alternative post procedure regimen using 90 days of dabigatran plus 81mg ASA alone is 
employed, eliminating the use of clopidogrel, we may reduce both major bleeding events, 
and reduce device associated thrombus rates at 1 year follow up. It would not be expected 
to impact ischemic stroke rate, but this could be implied if fewer DAT are observed. 
 
In conclusion, LAA closure is becoming a reasonable strategy for patients at high 
risk for stroke (CHADS 2 Vasc score 3-9) and high risk for bleeding on long term OAC (HAS 
BLED score 2-6). The FDA labeled strategy for medical management after Watchman 
implant is loosely supported scientifically, and still exposes patients to increased bleed risk 
up to 6 months after implant due to the use of DAPT. A shorter and simplified use of 
dabigatran BID for 90 days post LAAC with ASA 81mg, followed by ASA 81mg daily long 
term may reduce bleeding events, and have a beneficial impact on lowering the rate of DAT. 
Praxbind is a specific monoclonal anti-body available for dabigatran reversal. All study 
centers will have Praxbind available for use in the event of a major bleed, (i.e., subdural or 
intracranial bleed, or major bleed requiring transfusion), or in case of unexpected or 
emergent surgery.  
2. Study design:  
Single arm, prospective unblinded study on post Watchman LAA closure device 
implant anti-coagulation management at a primary center (Vanderbilt Medical Center) and 
up to 5 additional high volume LAA implant centers. This trial will be designed to evaluate 
the use of dabigatran for 90 days post implantation of an LAA closure device (Watchman 
LAA Closure Device, Boston Scientific Inc.).  The drug will be initiated on the morning 
following device implantation, taken BID per package insert dosing and until follow-up 90-
day post implant TEE.  Aspirin monotherapy will be utilized in conjunction at 81 mg for up 
to 12 months, after which the patients will be exited from the study and further treatment 
decisions will be made by the following physician (see Schedule of Study Procedures at end 
of protocol). The objective of this trial is to evaluate safety and efficacy of a 90-day period of 
dabigatran etexilate following LAA closure to prevent device associated thrombus, while 
minimizing adverse bleeding by eliminating the need for clopidogrel. This is a single arm 
pilot study with the option (pending collaboration with additional funding source) to 
expand to a full single arm non-inferiority trial design with 80% power to detect a 1.4% 
difference with the non-inferiority margin 1% in absolute rate of DAT (control rate 3.9%).  
Prospective, non-randomized single arm study. Comparison will be made to 
historical controls based on published one year DAT rates from PROTECT-AF, PREVAIL 
clinical trials, and EWOLUTION, and ACP/Amulet registries.  
Echocardiography (TEE) will be performed at 90 days (3 months, +/- 2-week 
window), and again at 1-year post implant (+/- 4 weeks). Selected images will be 
interpreted by echo lab at coordinating center in an anonymous fashion (patient data de-
identified). Ideal imaging will incorporate 0, 45, 90 and 135 degree angled views on the 
device at follow up.  


6 
 
Drug will be dispensed as part of the clinical trial supplied from the sponsor and 
each patient will receive a complete 90 days’ supply up front. They will have a drug visit on 
the day of TEE with the research coordinator to hand back any remaining dabigatran, with 
clear instruction to stop the drug and only take ASA following confirmation of closure on 
TEE (no peri-device leak on Doppler of  >5mm). A decision to continue anti-coagulation post 
closure 90day TEE will be made by the physician discretion based on TEE findings. If 
thrombus is found at the 90 days TEE, anti-coagulation may be extended another 6 weeks 
with repeat TEE imaging to confirm clot resolution at the discretion of the investigator. In 
the unlikely event of embolization or Doppler leak >5mm, decision on extending anti-
coagulation, or re-implanting a device will be made by the following physician. 
Additional baseline data collection: Patient demographics, medical history, age, sex, 
and prior use of anti-coagulants or anti-platelet medications will be collected. CHADS 2 
Vasc, and HAS-BLED score calculated. Main indication for LAA closure must be documented. 
Baseline CBC and BMP required on day of implant or up to 1 week pre-procedure (typical 
standard of care labs at time of implant). This will include a recent calculation of Creatinine 
Clearance (using Cockroft Gault and using patients actual body weight) and dosing of study 
drug will be made in accordance (see below). Repeat PCV or hematocrit on the morning 
after Watchman LAAC implantation will be per hospital standard. PCV or hematocrit value 
pre-implant and at the post 90-day visit will be analyzed.  
 
Calculation for dabigatran dosing: 
CCr={ (l40–age) x weight in kg)/(72 x SCr) } x 0.85 (if female) 
 
Implant procedure variables to collect include access site, sheath used for 
deployment (WAS), device size at implant and number of implant attempts. LA pressure 
mean if available. Presence of angiography contrast or Doppler Echo leak, thrombus, or 
pericardial effusion post implant will be recorded. At 90 days, TEE report findings and 
image review (standard of care) with drug dosing visit with research coordinator and 
return of any remaining study drug. 1 year TEE (standard of care) with a research exit visit 
with MD, physician extender, or research coordinator, with documentation of ASA 
tolerance, dosing, and any late bleeding episodes or hospitalizations (typically should be 
reported as AE/SAE when first knowledge of event is determined). TEE images will be sent 
to the primary study site (Vanderbilt University Medical Center) and core TEE lab will 
review to confirm presence or absence of DAT. In cases of CTA utilized for follow up, 
similarly images will be reviewed by chest radiology team at Vanderbilt.  
Medication administration with 90 days of dabigatran to be dispensed by pharmacy 
ideally one time (180 capsules).  
 


7 
 
3. Inclusion and Exclusion Criteria: 
Patients over the age of 18 with renal function compatible with dosing of dabigatran 
and meeting all indications for watchman LAA closure device implantation as an alternative 
to long-term anticoagulation (CMS coverage criteria, CHADS 2 Vasc 3-9, and seeking 
suitable rationale for a non-pharmacologic stroke protection option). Lab testing and 
imaging will be part of standard of care for follow-up after LAA closure implantation 
including BMP, INR (when on warfarin) and baseline rhythm on day of implant, 90-day and 
1-year transesophageal echo and when indicated CT angiography (subjects unable to 
undergo TEE at follow up). Images will be interpreted by the TEE operator, and an either 
independent radiologist or echocardiographer at Vanderbilt University Medical Center, the 
coordinating center. 
 Inclusion Criteria: 
1. 
Male or female sex, age >18 years. 
2. 
CHADS2 Vascular score of 3-9 and HAS BLED score 2 or higher meeting CMS 
coverage criteria for Watchman LAA closure device implantation.  
3. 
Able to give informed consent. 
4.  
Life expectancy of > 1year in the judgment of the implanting physician and shared 
decision-making physician.  
 
To be eligible for enrollment, patients must NOT meet any of the following criteria. 
Exclusion Criteria: 
1. 
Unable to give informed consent 
2. 
History of confirmed allergy to dabigatran etexilate 
3. 
Active cerebral bleeding, or active non-cerebral bleeding requiring blood 
transfusions (any absolute contra-indications to anti-coagulation). 
4. 
History of intraocular, spinal, retroperitoneal or a traumatic intra-articular bleeding 
unless the causative factor has been permanently eliminated or repaired (e.g. by 
surgery) 
 
5. 
Gastrointestinal (GI) haemorrhage within one month prior to screening, unless, in 
the opinion of the Investigator, the cause has been permanently eliminated (e.g. by 
surgery) 
 
6. 
Major bleeding episode (reduction in the haemoglobin level of at least 2g/dL, 
transfusion of at least two units of blood, or symptomatic bleeding in a critical area 


8 
 
or organ) including life-threatening bleeding episode (symptomatic intracranial 
bleeding, bleeding with a decrease in the haemoglobin level of at least 5g/dL or 
bleeding requiring transfusion of at least 4 units of blood or inotropic agents or 
necessitating surgery) in one month prior to screening visit 
 
7. 
Intolerance to dabigatran, if medication naïve, or other contra-indications as per the 
USPI, including ESRD on hemodialysis or GFR < 15ml/min, or concomitant use of 
rifampin. 
8. 
History of non-compliance, inability to follow-up. 
9.  
Pre-menopausal women (last menstruation ≤ 1 year prior to screening) who are not 
surgically sterile.  
10.  
Ischemic stroke or hemorrhagic stroke within 90 days of LAA placement. 
11.  
Anatomy unsuitable for LAA closure (incomplete surgical LAA ligation without 
suitable anatomy for Watchman placement. LAA ostial measurements >31mm, or 
<17mm in all views).  
12.   
Requires long-term oral anticoagulation therapy for a condition other than atrial 
fibrillation. 
 
13.  
ASA allergy, or confirmed allergy to nickel. 
 
14.  
Prior PFO or ASD closure device or prosthetic or mechanical heart valve.  
 
15.  
Acute MI within 90 days. 
 
16.  
Platelets <50,000 at time of Watchman LAAC implantation. 
 
17.  
Active endocarditis. 
 
18.    
Planning for endocardial catheter AF or left atrial ablation within 90 days of 
Watchman implantation. 
 
Dosing regimen of dabigatran will be by FDA and pharmacokinetic labeling for 
dabigatran 150mg BID dosing if Creatinine clearance >30mL/min, and 75mg BID dosing if 
15-30mL/min.  This will be based on calculated CC by baseline labs performed on day of 
implant.  Additional dosing adjustments per package insert for patients taking dronedarone 
400mg BID, or ketoconazole will be made consistent with drug label. The majority of 
subjects will be expected to be on 150 mg BID for 90 days.  Subjects on 75 mg twice daily 
dosing may be enrolled if renal function is stable in the range of 15-30mL/min.  Aspirin 81 
mg a day will be taken along with oral anticoagulation for 90 days followed by longer-term 
aspirin 81 mg daily aspirin dose.  At the 90 days TEE follow up (3 months) a PCV or CBC will 
be drawn and compared to baseline PCV pre-LAA closure implant as an assessment of 


9 
 
indolent blood loss (there is expected intra-procedural blood loss from back bleed on access 
sheaths estimated 25-125mL).  
Drug required for study: Initially start with 100 subject pilot study on therapy for 90 
days, with option to expand to full non-inferiority study if collaborative funding is secured 
(IF study expands beyond pilot, estimate 262 subjects, 90 days on therapy). Estimate 80% 
or more subjects on 150mg BID dosing, and up to 20% subjects on 75mg BID dosing.  With 
either the 100-subject pilot study, or optional expanded single arm study (262 patients) the 
objective is to establish a device associated thrombus (DAT) rate at 3 months and 1 year 
within 1.5% or less deviation from published DAT rates at 3.9% (Saw, J., et al).  Comparison 
will be made to published data on Watchman LAA closure utilizing the 45-day warfarin 
after implant followed by six-month dual antiplatelet regimen, or registry data from 
European experience on Watchman and Amulet/ACP LAA closure systems. 
Patients can be consented for the trial on the day of implantation or up to one 
month prior in clinic during consultation for LAA closure.  This is an unblinded, single arm 
prospective study.  Study exit visit will be coordinated with final twelve-month follow-up 
imaging after LAA closure implantation.   
Endpoints:  
Primary endpoint: Device associated thrombus (DAT) at 1-year follow-up imaging 
by either transesophageal echocardiogram or CT angiography depending on the patient 
tolerance for TEE (TEE preferred).  
Secondary endpoints: Includes ischemic stroke, peripheral thrombo-embolic events, 
major bleeding requiring intervention (blood transfusion, or surgical or non-operative 
intervention, i.e., pericardial effusion, vascular access repair etc.). 
Statistical Methods/Calculations:  
Statistical sample size calculation to establish comparable DAT rate with the prescribed 
regimen: 
Available data for background on DAT;  
Overall incidence of DAT was 3.9% (82 DAT for 2118 implanted devices) 
Lempereur et al. Meta-Analysis [ref 19]: 30 studies describing DAT events were 
included in the analysis. The overall incidence of DAT was 3.9% (82 DAT for 2118 
implanted devices). The median time from procedure to diagnosis of DAT was 1.5 months 
(IQR: 0-2.9). Most cases were diagnosed with transesophageal echocardiogram (TEE). The 
treatment consisted of low molecular weight heparin (LMWH) in 45.5% of cases, and oral 
anticoagulation (OAC) or other treatment modalities in 54.5%. Complete thrombus 
resolution was achieved in 95.0% of cases (100% with LMWH and 89.5% with OAC). 
Treatment duration varied greatly with a median treatment duration of 45 days (IQR: 14-


10 
 
135). Clinical events related to DAT consisted of neurologic events namely two transient 
ischemic attacks (2.4%) and four ischemic strokes (4.9%). 
Saw et al [ref 7].  339 analyzable TEE in follow up. Patients' mean age was 74.4 ± 7.5 
years, and 67.3% were men. The mean CHADS2 score was 2.7 ± 1.3, the mean CHA2DS2-
VASc score was 4.3 ± 1.5, and the mean HAS-BLED score was 3.0 ± 1.2. Peri-procedural 
major adverse events occurred in 2.4%. Median clinical follow-up duration was 355 days 
(range 179 to 622 days). Follow-up transesophageal echocardiography was performed after 
a median of 134 days (range 88 to 227 days). Device-associated thrombus was observed in 
3.2% Independent predictors of device-associated thrombus were smoking (odds ratio: 
5.79; p = 0.017) and female sex (odds ratio: 4.22; p = 0.027). 
Kaneko et al. [ref 20] 78 patients (50 males, 72 ± 8 years, average CHA2DS2-VASc 
score of 4.3 + 1.8) who had undergone WATCHMAN implantation. WATCHMAN was 
successfully implanted in all patients and four (5%) developed DRT. Patients with DRT 
were more often female (75 vs. 34%, p = 0.094). CHA2DS2-VASc score was higher for 
patients with DRT (6.3 ± 2.5 vs. 4.2 ± 1.7, p = 0.022). Chronic kidney disease (100% vs. 43%, 
p = 0.024) and deep implantation of the device, which was defined as implant position 
below the LAA ostial plane (75 vs. 24%, p = 0.026), were more common in patients with 
DRT. HAS-BLED score (4.5 ± 1.0 vs. 3.5 ± 1.1, p = 0.074) was higher and oral anticoagulants 
(50 vs. 84%, p = 0.086) were less commonly prescribed for patients with DRT. Multivariable 
logistic regression analysis showed that higher CHA2DS2-VASc score (p = 0.022, OR 2.8) 
and deep implantation (p = 0.032, OR 24.7) were associated with DRT. These results suggest 
the possible role of CHA2S2-VASc scores and implantation depth in the development of DRT 
after percutaneous LAA closure using the WATCHMAN device. 
With a single arm non-inferiority trial design to show the absolute rate of DAT is 
less than the control rate of 3.9% by a non-inferiority margin of 1% having a power 80% to 
detect a 1.4% difference at 0.05 level of significance, we would need 262 total subjects 
enrolled and reaching imaging endpoint evaluation. The initial study will begin with pilot to 
100 subjects (with 46% power) with an option to expand if additional funding source is 
obtained. 
 
Data Management:  
Data will be stored in a HIPPA-compliant manner in a REDCap database accessible 
to only the PI and key study personnel at each participating center, and site coordinating 
center monitoring team (Vanderbilt University Medical Center).  Uploaded files and patient 
data will be identifiable in raw form but de-identified chart and subject ID in REDCap with 
access restricted to implant sites and coordinating center.  
 
 


11 
 
 
Safety Reporting:  
Adverse events (AE) related to the drug or the procedure during the course of the 
study will be reported in the patient’s record, and the investigator will give his or her 
opinion as to the relationship of the adverse event to study drug treatment.(i.e., the 
relationship will be reported as “related” or “unrelated” to the study  drug administration). . 
If the adverse event is serious, it will be reported to Boehringer Ingelheim Pharmaceuticals, 
Inc. (BI), and IRB by the coordinating center and trial PI. All serious adverse events will be 
followed until resolution or stabilization. Results of the follow-up will be reported to BI and 
the IRB. 
Definitions of Adverse Events: 
 “An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product” 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or a congenital anomaly/birth defect. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasia or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
Acute minor or major complications following the implant procedure will be 
reported. Intra-operative major bleeding or device related (embolization, stroke, 
hemorrhage, etc.), will be reported as a procedural complication which is not study drug 
related. After the AM dosing of dabigatran post-operative day #1, and up to 90 days post 
procedure, AE’s potentially related to study drug will need to be reported. Adverse events 
include events such as those described above that occur at any time from informed consent 
until 90 days post implant of the LAA closure Watchman device.  
Recording of Adverse Events: 


12 
 
All AEs will be documented. A description of the event, including its date of onset 
and resolution, whether it constitutes a serious adverse event (SAE) or not, any action taken 
(e.g., changes to administration), and outcome, will be provided, along with the 
investigator’s assessment of causality (i.e., the relationship to the study treatment[s]) and 
determination of severity (e.g., mild, moderate, severe). For an AE to be a suspected 
treatment-related event, there should be at least a reasonable possibility of a causal 
relationship between the protocol treatment and the AE.  
 
Bleeding events 
Patients will be carefully assessed for signs and symptoms of bleeding at each visit. 
Bleeding will be classified as major or minor using the following guidelines. Major bleeds 
will be further sub classified as either life-threatening or other major bleeds. 
Major Bleeds: 
Bleeding associated with a transfusion of at least 2 units of blood or packed cells.  
Symptomatic bleeding in a critical area or organ requiring surgical or non-operative 
intervention: Intraocular, intracranial, intraspinal or intramuscular with compartment 
syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding. 
Minor Bleeds: 
Minor bleeds are clinical bleeds that do not fulfill the criteria for major bleeds. 
Minor bleeds are classified as associated with study medication discontinuation (temporary 
or permanent) or not. 
 
Serious Adverse Event Reporting to BI Pharmacovigilance 
Adverse events classified by the treating investigator as serious require expeditious 
handling and reporting. Serious adverse events may occur at any time from informed 
consent until 30 days post cessation of dabigatran etexilate administration. BI must be 
notified of all SAEs containing at least one (1) fatal or immediately life-threatening event 
within five calendar days of the first knowledge of the event by the treating physician or 
research personnel. BI must be notified of all other SAEs within ten calendar days of the 
first knowledge of the event by the treating physician or research personnel. The SAE 
reports shall include all SAEs and non-serious AEs occurring in the same time and/or which 
are medically related and, in particular, the following information: 
(i) the listedness of the reported events based on BI Investigator’s Brochure for the 
dabigatran etexilate, 


13 
 
(ii) PI causal assessment as to whether the event(s) is/are related to the use of the 
dabigatran etexilate, and 
(iii) the seriousness of each AE. 
Causality should be assessed for each event as either “yes” or “no”. No other 
variation should be reported. In case, according to the physician’s causal assessment the 
association between an event and the patient’s exposure to the dabigatran etexilate is 
classified as “unknown”, the event will be considered “related” to the Study Drug for 
regulatory reporting purposes. If the SAE report forwarded to the BI was also submitted to 
a regulatory authority, this shall be indicated in the cover letter. 
Supporting documentation for each of the reported SAEs, if requested by BI, will be 
provided to BI. Supporting documentation shall include, but is not limited to, lab reports, 
autopsy reports etc. SAEs, during and after pregnancy, will be reported to BI. To report an 
SAE, a BI SAE Reporting Form will be completed with the necessary information as 
available, and faxed using the following contact information: 
Boehringer Ingelheim Pharmaceuticals, Inc.  900 Ridgebury Road.  Ridgefield, CT. 
Fax: 1-203-837-4329.  
Follow-up information for SAEs and information on non-serious AEs that become 
serious will also be reported to BI as soon as it is available; these reports will be submitted 
using the BI SAE Reporting Form. Serious adverse events occurring more than 30 days after 
study drug administration need only be reported if a relationship to the dabigatran etexilate 
administration is suspected. 
The investigator does not need to actively monitor participants for adverse events 
once the clinical trial has ended However, if the investigator becomes aware of an SAE(s) 
that occurred after the participant has completed the clinical trial (including any protocol 
specified follow-up period), it should be reported to BI if the investigator considers it as 
relevant to the use of the BI study drug dabigatran. 
SAE Reporting to Regulatory Bodies: Regardless of causality, all SAEs will be documented 
and reported to regulatory bodies, including the IRB as required by the International 
Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP). Follow-up 
information for SAEs and information for non-serious AEs that become serious will also be 
reported in the same manner. SAE’s will be reported to the Vanderbilt Human Research 
Protection Program according to their policies and procedures. 
 
Study duration and timelines:  
 
From completion of the protocol, approval of contract and site initiation at 
Vanderbilt University Medical Center, study duration would be as follows: Estimated rate of 
enrollment is 2-3 subjects per site per month. Estimated time to complete enrollment of 100 


14 
 
subjects is 12 months once all sites are open, followed by 1 year of follow up to reach 1 year 
post implant imaging. Estimate completion of study in 24 months.  
 
Publications: 
 
Target Journals for publication of American College of Cardiology, Heart Rhythm, or 
Circulation Arrhythmia and Electrophysiology. 
 
 
 
 
 
 
 


15 
 
Schedule of Study Procedures: 
 
 
Baseline 
Visit  
Procedure 
Day (+/- 3 
days) 
POD 
1 
90 Days 
Post 
Procedure 
(+/- 14 
days) 
1 Year 
Post 
Procedure 
(+/- 14 
days) 
AE/Other 
(e,g, DAT, 
study 
medication 
continued 
beyond 90 
days) 
Demographics 
X 
 
 
 
 
 
H and P (including 
vital signs, height and 
weight) 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
I/E criteria (confirm 
eligibility) 
 
X 
 
X 
 
 
 
 
 
Informed Consent (a) 
X 
X 
 
 
 
 
CBC/BMP  
 
X 
X 
X 
X 
X 
Creat Cl 
X 
X 
X 
X 
X 
X 
AE review 
X 
X 
X 
X 
X 
X 
TEE 
 
X (intra-
operative) 
 
X 
X 
X 
Dispense Study 
Medication  
 
 
X 
 
 
X (as 
needed) 
Pill Count/medication 
termination (planned) 
 
 
 
X 
 
X (as 
needed) 
Exit  
 
 
 
 
X 
 
(a)  Informed Consent may be completed anytime up to one month prior to implant.  
 
 


16 
 
 
References: 
Additional References Regarding LAA and LAA Device Associated Thrombus: 
 
1) 
Reddy VY, Gibson DN, Kar S, O'Neill W, Doshi SK, Horton RP, Buchbinder M, Gordon 
NT, Holmes DR. Post-Approval U.S. Experience With Left Atrial Appendage Closure for 
Stroke Prevention in Atrial Fibrillation. J Am Coll Cardiol. 2017 Jan 24;69(3):253-261. doi: 
10.1016/j.jacc.2016.10.010. Epub 2016 Nov 2. 
2) 
Boersma LV, Schmidt B, Betts TR, Sievert H, Tamburino C, Teiger E, Pokushalov E, 
Kische S, Schmitz T, Stein KM, Bergmann MW; EWOLUTION investigators. Implant success 
and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural 
outcomes from the EWOLUTION registry. Eur Heart J. 2016 Aug;37(31):2465-74. doi: 
10.1093/eurheartj/ehv730. Epub 2016 Jan 27. 
3) 
Whitlock R Healey J, Vincent J, Brady K, Teoh K, Royse A, Shah P, Guo Y, Alings M, 
Folkeringa RJ, Paparella D, Colli A, Meyer SR, Legare JF, Lamontagne F, Reents W, Boening A, 
Connolly S . Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III. 
Annals of Thoracic Surgery. 2014 Jan;3(1):45-54. doi: 10.3978/j.issn.2225-
319X.2013.12.06. 
4) 
Ailawadi G, Gerdisch MW, Harvey RL, Hooker RL, Damiano RJ Jr, Salamon T, Mack 
MJ. Exclusion of the left atrial appendage with a novel device: early results of a multicenter 
trial. J Thorac Cardiovasc Surg. 2011 Nov;142(5):1002-9, 1009.e1. doi: 
10.1016/j.jtcvs.2011.07.052. Epub 2011 Sep 8. PMID:21906756 
5) 
Ellis CR, Aznaurov SG, Patel NJ, Williams JR, Sandler KL, Hoff SJ, Ball SK, Whalen SP, 
Carr JJ. Angiographic Efficacy of the Atriclip Left Atrial Appendage Exclusion Device Placed 
by Minimally Invasive Thoracoscopic Approach. JACC Clin Electrophysiology, May 2017. 
DOI: 10.1016/j.jacep.2017.03.008. 
6) 
Aryana A, Singh SK, Singh SM, O'Neill PG, Bowers MR, Allen SL, Lewandowski SL, 
Vierra EC, d'Avila A. Association between incomplete surgical ligation of left atrial 
appendage and stroke and systemic embolization. Heart Rhythm. 2015 Jul;12(7):1431-7. 
doi: 10.1016/j.hrthm.2015.03.028. Epub 2015 May 18. PMID: 25998141. 
7) 
Saw J, Tzikas A, Shakir S, Gafoor S, Omran H, Nielsen-Kudsk JE, Kefer J, Aminian A, 
Berti S, Santoro G, Nietlispach F, Moschovitis A, Cruz-Gonzalez I, Stammen F, Tichelbäcker T, 
Freixa X, Ibrahim R, Schillinger W, Meier B, Sievert H, Gloekler S. Incidence and Clinical 
Impact of Device-Associated Thrombus and Peri-Device Leak Following Left Atrial 
Appendage Closure With the Amplatzer Cardiac Plug, In JACC: Cardiovascular Interventions, 
Volume 10, Issue 4, 2017, Pages 391-399, ISSN 1936-8798 
8) 
Lim YM, Kim JS, Kim TH, Uhm JS, Shim CY, Joung B, Hong GR, Lee MH, Jang YS, Pak 
HN. Delayed left atrial appendage contrast filling in computed tomograms after 
percutaneous left atrial appendage occlusion. J Cardiol. 2017 May 22. pii: S0914-
5087(17)30115-6. doi: 10.1016/j.jjcc.2017.04.007. PMID: 28546017 


17 
 
9) 
Venkataraman G, Strickberger SA, Doshi S, Ellis CR, Lakkireddy D, Whalen SP, Cuoco 
F. Short-term safety and efficacy of left atrial appendage closure with the WATCHMAN 
device in patients with small left atrial appendage Ostia. J Cardiovasc Electrophysiol. 2017 
Sep 6. doi: 10.1111/jce.13333. 
10) 
Lee RJ, Lakkireddy D, Mittal S, Ellis C, Connor JT, Saville BR, Wilber D.Percutaneous 
alternative to the Maze procedure for the treatment of persistent or long-standing 
persistent atrial fibrillation (aMAZE trial): Rationale and design. Am Heart J. 2015 
Dec;170(6):1184-94. doi: 10.1016/j.ahj.2015.09.019. Epub 2015 Oct 3. PMID: 26678640 
11)       Rillig A, Tilz RR, Lin T, Fink T, Heeger CH, Arya A, Metzner A, Mathew S, Wissner E, 
Makimoto H, Wohlmuth P, Kuck KH, Ouyang F. Unexpectedly High Incidence of Stroke and 
Left Atrial Appendage Thrombus Formation After Electrical Isolation of the Left Atrial 
Appendage for the Treatment of Atrial Tachyarrhythmias. Circ Arrhythm Electrophysiol. 
2016 May;9(5):e003461. doi: 10.1161/CIRCEP.115.003461. 
12) Predictors of thrombus formation after percutaneous left atrial appendage closure 
using the WATCHMAN device. Kaneko H, Neuss M, Weissenborn J, Butter C. Heart Vessels. 
2017 May 5. doi: 10.1007/s00380-017-0971-x. [Epub ahead of print] PMID: 28477098  
13) Retrieval of embolized left atrial appendage devices. Fahmy P, Eng L, Saw J. Catheter 
Cardiovasc Interv. 2016 Sep 28. doi: 10.1002/ccd.26800. [Epub ahead of print] PMID: 
27679417  
14) Short and long-term outcomes of percutaneous left atrial appendage suture ligation: 
Results from a US multicenter evaluation. Lakkireddy D, Afzal MR, Lee RJ, Nagaraj H, 
Tschopp D, Gidney B, Ellis C, Altman E, Lee B, Kar S, Bhadwar N, Sanchez M, Gadiyaram V, 
Evonich R, Rasekh A, Cheng J, Cuoco F, Chandhok S, Gunda S, Reddy M, Atkins D, Bommana 
S, Cuculich P, Gibson D, Nath J, Ferrell R, Matthew E, Wilber D. Heart Rhythm. 2016 
May;13(5):1030-6. doi: 10.1016/j.hrthm.2016.01.022. Epub 2016 Feb 9. PMID: 26872554 
15) Left atrial appendage closure using the Amulet device: an initial experience with the 
second generation amplatzer cardiac plug. Lam SC, Bertog S, Gafoor S, Vaskelyte L, Boehm P, 
Ho RW, Franke J, Hofmann I, Sievert H. Catheter Cardiovasc Interv. 2015 Feb 1;85(2):297-
303. doi: 10.1002/ccd.25644. Epub 2014 Sep 5. PMID: 25158644  
16) Left atrial appendage occlusion with the WATCHMAN™ for stroke prevention in atrial 
fibrillation. Price MJ. Rev Cardiovasc Med. 2014;15(2):142-51. Review. PMID: 25051131  
17) Prevention and Management of Complications of Left Atrial Appendage Closure Devices. 
Price MJ. Interv Cardiol Clin. 2014 Apr;3(2):301-311. doi: 10.1016/j.iccl.2013.12.001. Epub 
2014 Jan 21. Review. PMID: 28582173 
18) Incomplete left atrial appendage occlusion and thrombus formation after Watchman 
implantation treated with anticoagulation followed by further transcatheter closure with a 
second-generation Amplatzer Cardiac Plug (Amulet device). Lam SC, Bertog S, Sievert H. 
Catheter Cardiovasc Interv. 2015 Feb 1;85(2):321-7. doi: 10.1002/ccd.25456. Epub 2014 
Mar 26. 


18 
 
19) Lempereur M, Aminian A, Freixa X, Gafoor S, Kefer J, Tzikas A, Legrand V, Saw J.  Device-
associated thrombus formation after left atrial appendage occlusion: A systematic review of 
events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet. Catheter 
Cardiovasc Interv. 2017 Feb 1. doi: 10.1002/ccd.26903. [Epub ahead of print] 
20) Kaneko H, Neuss M, Weissenborn J, Butter C. Predictors of thrombus formation after 
percutaneous left atrial appendage closure using the WATCHMAN device. Heart Vessels. 
2017 May 5. doi: 10.1007/s00380-017-0971-x. [Epub ahead of print]