Observe the Safety and Effectiveness of the WATCHMAN FLX™ Left Atrial Appendage Closure (LAAC) Device for Subjects With Non-valvular Atrial Fibrillation to Reduce the Risk of Stroke in Hong Kong Area
Conditions: Non-valvular Atrial Fibrillation
Sponsor: Boston Scientific Corporation

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Hong Kong WATCHMAN FLX™ Observation 
HK FLX 
Study Reference：S2461 
CLINICAL INVESTIGATION PLAN 
 
 
 
 
Sponsored By 
BSC International Medical Trading (Shanghai) Co., Ltd, (“BSC China”) 
Part A, 2nd Floor, No.68, Rijing Road, 
Free Trade Zone, 
Shanghai, China 200131 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should be 
held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Contact Information 
Role 
Contact  
Clinical Contact 
Zhao, Yifan 
Senior Clinical Research Associate 
Boston Scientific China 
16th Floor,  South Tower, China Overseas Plaza. 
No.8 Guanghuadongli, Chao Yang District, 
Beijing 100020,P.R .China 
Email: Yifan.Zhao@bsci.com 
Cell: +86 15010081369 
Tele: +86 10 85742971 
Coordinating Principal 
Investigator(s) 
Chan Chin Pang Gary,Prince of Wales Hospital 
Fung Chi Yan Raymond, Princess Margaret Hospital 
Simon Lam,Queen Mary Hospital 
Shing-fung Chui,Queen Elizabeth Hospital 
Tsui Kin Lam,Pamela Youde Nethersole Hospital 
Vendors/Labs 
A list of vendors/laboratories involved in the trial is maintained 
by the sponsor. A complete listing of applicable vendors will be 
provided to investigational sites.  
 
Original Release: September 2，2019 
Current Version: D 
 
 
 
Revision 
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number 
and 
version 
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Justification 
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name and all have 
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Revision 
Version 
Protocol 
Date 
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number 
and 
version 
Protocol 
Section 
Modified 
 
Summary of 
Changes 
 
Justification 
for 
Modification 
Investigators 
information 
D 
July 19, 
2021 
92120219
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Ver. G 
Contact 
Information 
Updated clinical 
contact 
information 
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contact 
changed 
D 
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2021 
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8.1 Scale and 
Duration 
Deleted the below 
limitations on the 
number of subjects 
enrolled per site: 
“Each site might 
enroll a maximum 
of 25 subjects.” 
Given the 
influence of 
COVID-19 on 
the progress 
of subject 
enrollment, 
delete the 
limitations on 
the enrollment 
ceiling for 
each site. It is 
estimated this 
change will 
not 
significantly 
affect the 
study results.  
D 
July 19, 
2021 
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Ver. G 
Table of 
Contents; 
11.1 Data 
Collection; 
20. Safety 
Reporting 
Updated the page 
number in table of 
content, and the 
table number 
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to protocol 
mofification 
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2. Protocol Synopsis 
Hong Kong WATCHMAN FLX™ Observation 
HK FLX 
Study 
Objective(s) 
The primary objective of this study is to observe the safety and 
effectiveness of the WATCHMAN FLX™ Left Atrial Appendage 
Closure (LAAC) Device for subjects with non-valvular atrial fibrillation 
to reduce the risk of stroke in Hong Kong area. 
Device 
The WATCHMAN FLX Left Atrial Appendage Closure Device with 
Delivery System (consisting of the Delivery Catheter with a pre-loaded 
Closure Device) 
Device Sizes 
WATCHMAN FLX is available in 20, 24, 27, 31, and 35mm models to 
fit left atrial appendage ostia widths ranging from 14.0 – 31.5mm. 
Study Design 
This study is a prospective, non-randomized, multi-center observational 
study. 
Planned 
Number of 
Subjects 
Up to 50 subjects will be enrolled in the study. 
Each investigational site might have up to 2 roll-in subjects, which is 
included in the 50 total subjects. 
Planned 
Number of Sites 
Up to 5 investigational centers in Hong Kong.  
Primary 
Effectiveness 
Endpoint 
The occurrence of non-effective LAA closure defined as any peri-device 
flow > 5mm demonstrated by TEE/CT/MRI at First Follow-up. 
Primary Safety 
Endpoint 
The occurrence of one of the following events between the time of 
implant and within 7 days following the procedure or by hospital 
discharge, whichever is later: all-cause death, ischemic stroke, systemic 
embolism, or device- or procedure-related events requiring open cardiac 
surgery or major endovascular intervention such as pseudoaneurysm 
repair, AV fistula repair, or other major endovascular repair. 
Percutaneous catheter drainage of pericardial effusions, snaring of an 
embolized device, thrombin injection to treat femoral pseudoaneurysm 
and nonsurgical treatments of access site complications are excluded 
from this endpoint. 

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Hong Kong WATCHMAN FLX™ Observation 
HK FLX 
Secondary 
Endpoint 
The occurrence of ischemic stroke or systemic embolism at 12 months 
from the time of implant. 
Additional 
Analysis 
The occurrence of stroke (including ischemic and/or hemorrhagic), 
cardiovascular death (cardiovascular and/or unexplained cause) and 
systemic embolism. 
Follow-up 
Schedule 
Study procedures and follow-up visits will occur as follows: 
• 
Enrollment Visit  
• 
WATCHMAN FLX Implant 
• 
First Follow-up (30-100 days) 
• 
12-Month Follow-up (365 ± 30 days)  
Study Duration Enrollment is expected to be completed in approximately 12 months and 
each subject is expected to be followed for approximately 12 months 
with primary endpoints collected at First Follow-up (30-100 days); 
therefore the total study duration is estimated to be approximately 24 
months. 
Participant 
Duration 
The study duration for each subject is expected to be approximately 12 
months. 
Inclusion 
Criteria 
1. Patients who are eligible for a WATCHMAN FLX device according 
to current international and local guidelines (and future revisions) 
and per physician discretion; 
2. Patients who are willing and capable of providing informed consent, 
participating in all testing associated with this clinical investigation 
at an approved clinical investigational center; 
3. Patients whose age is 18 years or above, or of legal age to give 
informed consent specific to state and national law. 
Exclusion 
Criteria 
1. Patients who are currently enrolled in another investigational study 
or registry that would directly interfere with the current study, except 
when the patient is participating in a mandatory governmental 
registry, or a purely observational registry with no associated 
treatments. Each instance should be brought to the attention of the 
sponsor to determine eligibility. 

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Hong Kong WATCHMAN FLX™ Observation 
HK FLX 
2. Women of childbearing potential who are, or plan to become, 
pregnant during the time of the study (method of assessment upon 
physician's discretion); 
3. The subject is unable or not willing to complete follow-up visits and 
examination for the duration of the study. 
Multiple 
Interventions 
During 
Treatment/Impl
ant 
Multiple interventions are allowed in the study. 
Statistical Methods  
Primary 
Statistical 
Hypothesis 
There is no hypotheses testing in this small sample size observational 
study.  
Statistical Test 
Method 
Descriptive statistics will be conducted for the endpoint events. 
For the Primary Effectiveness Endpoint, it might be considered 
reasonable if up to 3 primary effectiveness endpoint events should occur 
in this small sample size study. 
For the Primary Safety Endpoint, it might be considered reasonable if up 
to 3 primary safety endpoint events should occur in this small sample size 
study. 
Sample Size 
Parameters 
No formal sample size calculation is performed because there is no 
formal hypothesis testing in the study. The following table provides a 
95% confidence interval (exact methods) for a sample size of 50 if there 
are 0 ~ 5 events.  
Events 
Rates (n=50) 
Lower 95%CI 
Upper 95%CI 
0 
0% 
0.0% 
7.1% 
1 
2% 
0.1% 
10.6% 
2 
4% 
0.5% 
13.7% 
3 
6% 
1.3% 
16.5% 
4 
8% 
2.2% 
19.2% 
5 
10% 
3.3% 
21.8% 

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3. Table of Contents 
 
1. 
TITLE PAGE  .......................................................................................................................1 
2. 
PROTOCOL SYNOPSIS .........................................................................................................4 
3. 
TABLE OF CONTENTS .........................................................................................................7 
3.1. Table of Figures .......................................................................................................9 
3.2. Table of Tables ........................................................................................................9 
4. 
INTRODUCTION.................................................................................................................11 
4.1. Background ............................................................................................................11 
4.2. WATCHMAN Therapy ........................................................................................12 
5. 
DEVICE DESCRIPTION ......................................................................................................17 
5.1. Product Description ..............................................................................................17 
5.1.1. 
WATCHMAN FLX Delivery System and with Pre-loaded LAAC Device
 17 
6. 
STUDY OBJECTIVES .........................................................................................................19 
7. 
STUDY ENDPOINTS ...........................................................................................................19 
7.1. Primary Effectiveness Endpoint ..........................................................................19 
7.2. Primary Safety Endpoint ......................................................................................19 
7.3. Secondary Effectiveness Endpoint.......................................................................20 
7.4. Additional analysis ................................................................................................20 
8. 
STUDY DESIGN .................................................................................................................20 
8.1. Scale and Duration ................................................................................................20 
8.2. Justification for the Study Design ........................................................................20 
9. 
SUBJECT SELECTION ........................................................................................................21 
9.1. Study Population and Eligibility ..........................................................................21 
9.2. Inclusion Criteria ..................................................................................................21 
9.3. Exclusion Criteria .................................................................................................21 
10. SUBJECT ACCOUNTABILITY .............................................................................................21 

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10.1. Enrollment .............................................................................................................21 
10.2. Withdrawal ............................................................................................................22 
10.3. Subject Status and Classification .........................................................................22 
11. STUDY METHODS .............................................................................................................24 
11.1. Data Collection ......................................................................................................24 
11.2. Informed Consent..................................................................................................25 
11.3. Enrollment Visit ....................................................................................................25 
11.4. LAA Imaging (e.g. TEE/CT/MRI) .......................................................................26 
11.5. Implant Procedure ................................................................................................26 
11.6. Follow-up Procedures ...........................................................................................27 
i) 
In-Hospital Visit ....................................................................................................27 
ii) 
Subject Contact .....................................................................................................28 
11.7. Study Completion ..................................................................................................28 
11.8. Source Documents .................................................................................................28 
12. STATISTICAL CONSIDERATIONS ......................................................................................29 
12.1. Sample Size Justification ......................................................................................29 
12.2. Statistical Analysis and Data Sets ........................................................................29 
13. DATA MANAGEMENT .......................................................................................................31 
13.1. Data Collection, Processing, and Review ............................................................31 
13.2. Data Retention .......................................................................................................31 
14. AMENDMENTS ..................................................................................................................32 
15. DEVIATIONS......................................................................................................................32 
16. COMPLIANCE ....................................................................................................................32 
16.1. Statement of Compliance ......................................................................................32 
16.2. Investigator Responsibilities ................................................................................32 
16.2.1. Delegation of Responsibility ....................................................................34 
16.2.2. Investigator Records .................................................................................34 
16.3. Institutional Review Board/ Ethics Committee ..................................................35 
16.4. Sponsor Responsibilities .......................................................................................35 
16.4.1. Sponsor Records .......................................................................................35 
16.5. Insurance ................................................................................................................36 

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17. MONITORING ....................................................................................................................36 
18. POTENTIAL RISKS AND BENEFITS ...................................................................................36 
18.1. Risks Associated with the study ...........................................................................36 
18.2. Risks Associated with a standard WATCHMAN FLX Implant & Procedure
 .................................................................................................................................36 
18.3. Risk Minimization Actions ...................................................................................38 
18.4. Anticipated Benefits ..............................................................................................38 
19. INFORMED CONSENT ........................................................................................................38 
20. SAFETY REPORTING .........................................................................................................40 
20.1. Investigator Reporting Requirements .................................................................41 
20.2. Boston Scientific Device Deficiencies ...................................................................45 
20.3. Reporting to Regulatory Authorities / IRBs / ECs / Investigators ...................45 
21. COMMITTEES ...................................................................................................................45 
21.1. Safety Monitoring Process ....................................................................................45 
22. SUSPENSION OR TERMINATION........................................................................................46 
23. PUBLICATION POLICY ......................................................................................................46 
24. BIBLIOGRAPHY .................................................................................................................47 
25. ABBREVIATIONS AND DEFINITIONS .................................................................................48 
25.1. Definitions ..............................................................................................................48 
25.1.1. Stroke/TIA definitions ..............................................................................48 
25.1.2. Classification of Bleeding events .............................................................49 
 
 
3.1. Table of Figures 
Figure 1: WATCHMAN Delivery System (Delivery Catheter & LAA Closure Device) 17 
Figure 2: Subject Status and Data Collection Flow Chart ................................................ 24 
 
3.2. Table of Tables 
Table 1: Description of WATCHMAN Products ................................................................... 12 
Table 2: Clinical Studies of the WATCHMANTM Device ..................................................... 12 

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Table 3: Data Collection Overview ........................................................................................ 25 
Table 4: 95% confidence interval for 0~5 events ................................................................... 30 
Table 5: Covariates of Interest ................................................................................................ 31 
Table 6: Adverse Event Definitions ........................................................................................ 40 
Table 7: Criteria for Assessing Relationship of Study device/Procedure to Adverse event…42  
Table 8: Investigator Reporting Requirements ....................................................................... 44 
 

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4. Introduction 
4.1. Background 
Atrial fibrillation (AF) is one of the most common abnormal rhythm disturbances and affects 
approximately 5.5 million people worldwide, including 10% of people older than 75 1years. 
The most debilitating consequence of AF is thrombus formation from stagnant blood flow 
leading to thromboembolism and stroke.  As such, the rate of ischemic stroke attributed to 
non-valvular AF is estimated to average 5% per year, which is 2-7 times that of those without 
AF2. 
Treatment with warfarin therapy for the prevention of thromboemboli originating in the left 
atrial appendage has been well documented 3-5. Warfarin therapy targeting an International 
Normalized Ratio (INR) between 2.0 – 3.0 has been considered the gold standard treatment 
historically for patients with non-valvular AF for prevention of stroke.  While warfarin has 
remained the optimum treatment for many years, there are numerous challenges with the 
drug, such as frequent need for monitoring and dosage adjustments, dietary and metabolic 
interactions, and concerns of patient compliance.  Additionally, the potential for frequent and 
fatal bleeding are high concerns for patients and caregivers, and often it is found this drug is 
not well tolerated.  
Currently available alternatives to warfarin are the direct oral anticoagulants (DOACs), 
which include dabigatran, rivaroxaban, apixaban, and edoxaban. Unlike warfarin, DOACs 
can be administered without the need for monitoring, have fewer food and drug interactions, 
and provide an improved effectiveness/safety ratio. Dabigatran at the dose of 150 mg twice 
daily is shown to be superior to warfarin in prevention of stroke and systemic 
thromboembolism, has a favorable safety profile including significantly less intracranial 
bleeding and comparable extracranial bleeding, and is associated with less cardiovascular 
mortality 6-9. Rivaroxaban at a daily dose of 20 mg is shown to be noninferior to warfarin in 
prevention of stroke or systemic embolism. The risk of major bleeding is not significantly 
different for rivaroxaban versus warfarin; however, intracranial and fatal bleeding is less 
frequent with rivaroxaban 10. In comparison to warfarin, apixaban at a dose of 5 mg twice 
daily is also shown to be superior in prevention of stroke and systemic thromboembolism, 
causes less bleeding, and is associated with a lower mortality rate 11. Edoxaban is shown to 
be non-inferior to warfarin with respect to the prevention of stroke or systemic embolism, 
and is associated with significantly lower rates of bleeding and death from cardiovascular 
causes 12. While DOACs eliminate the need for frequent monitoring, dosage adjustments, and 
dietary and metabolic interactions, there are still concerns of patient compliance and bleeding 
complications with these newer agents. 
 
As the risk of stroke increases with age and the disability and tolerance concerns with 
available drug therapy persist, the need for permanent protection against thromboembolism 
in AF patients remains unmet. The sponsor developed the WATCHMANTM Left Atrial 
Appendage Closure (LAAC) Device, a permanent implantable device to seal off the left atrial 
appendage, the location where the vast majority of thrombi originate in AF patients.  This 
device has been shown to provide an alternative to warfarin therapy in non-valvular AF 
patients who require thromboembolic protection. The current study is designed to compile 

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real-world clinical outcomes data for the next-generation WATCHMANTM device, 
WATCHMAN FLXTM LAA Closure Device, in subjects with non-valvular AF in Hong 
Kong. 
4.2. WATCHMAN Therapy 
Two generations of the WATCHMAN Closure Device with Delivery System, as identified in 
the Table 1, are discussed below. The WATCHMAN Access System, required accessory for 
use in WATCHMAN procedures, and each generation of the WATCHMAN Closure Device 
with Delivery System are provided sterile and as single use devices.  
Table 1: Description of WATCHMAN Products 
Name 
Description 
WATCHMAN™ 
Access System 
The first CE-marked and FDA-approved 
generation of the WATCHMAN Access 
System. This Access System may be used 
with either the WATCHMAN (Gen 2.5) or 
WATCHMAN FLX Closure Device with 
Delivery System 
WATCHMAN™ LAA 
Closure Device with 
Delivery System 
The first commercialized generation of the 
WATCHMAN LAA Closure Device with 
Delivery System (note: also referred to 
internally as Gen 2.5).  
WATCHMAN FLX™ 
Closure Device with 
Delivery System 
Boston Scientific’s next generation 
WATCHMAN LAA Closure Device with 
Delivery System.  
 
For simplicity, the two generations of the Closure Device with Delivery System will be 
referenced as WATCHMAN (Gen 2.5) and WATCHMAN FLX and the implanted portion of 
the products will be referred to as the Closure Device.  
The implanted component of the study device, hereafter referred to as the WATCHMAN FLX 
Device, is designed to prevent the embolization of thrombi that may form in the LAA.  The 
WATCHMAN FLX Device may reduce the occurrence of ischemic stroke and systemic 
thromboembolism in patients with non-valvular AF who require treatment for potential 
thrombus formation.  It may also reduce the risk of life-threatening bleeding events such as 
hemorrhagic stroke by potentially removing the need for anticoagulation therapy. 
Various clinical trials have established the safety and performance of the WATCHMAN LAA 
Closure Technology (Access System and Delivery System) which is designed to prevent 
thrombus embolization from the left atrial appendage and reduce the risk of life-threatening 
bleeding events in patients with non-valvular atrial fibrillation. Table 2 outlines the various 
clinical trials.  All devices tested in these trials utilized the WATCHMAN (Gen 2.5) Closure 
Device except for EVOLVE.  The EVOLVE study tested safety and efficacy in what was at 
the time the next-generation WATCHMAN (Gen 4) device. 
Table 2: Clinical Studies of the WATCHMANTM Device 
Study 
Dates of Enrollment 
Enrolled 
Subjects 
Sites 
Follow-Up 

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Pilot  
(feasibility study) 
Aug 2002 – Jan 2005 
66 
8 
U.S. subjects completed 5 
years; OUS subjects 
completed up to 9 years. 
PROTECT AF  
(pivotal study) 
Feb 2005 – Jun 2008 
800 
59 
Complete through 5 years 
CAP Registry 
Aug 2008 – Jun 2010 
566 
26 
Complete 
ASAP 
(feasibility study) 
Jan 2009 – Nov 2011 
150 
4 
Complete 
EVOLVE 
(registry) 
May 2009 – June 
2011 
69 
3 
Complete 
PREVAIL  
(pivotal study) 
Nov 2010 – Jun 2012 
461 
41 
Complete 
CAP2 Registry 
Sep 2012 – Mar 2014 
579 
47 
Ongoing through 5 years 
EWOLUTION 
(EU registry) 
Oct 2013 – May 2015 
1025 
47 
Ongoing through 2 years 
WASP (Asia 
Pacific Registry) 
Jan 2014 – Oct 2015 
201 
9 
Ongoing through 2 years 
WATCHMAN 
NESTed  
(US PAS) 
Dec 2016-present 
2000 
All 
commercial 
sites 
Ongoing through 5-years 
SALUTE (Japan 
study) 
Feb 2017-July 2017 
71 
10 
Ongoing through 2 years 
ASAP-TOO 
(OAC 
contraindicated 
population) 
Feb 2017-present 
888 
Up to 100 
Ongoing through 5-years 
 
In the PILOT study, the WATCHMAN Device was successfully implanted in 66/75 (88%) 
subjects, with discontinuation of warfarin in 68% of subjects at 45 days, 92% of subjects by 
six months, and 96% of subjects by 60 months. Mean follow-up in this study was 6.1 years. 
There were no deaths, no device embolizations related to the Closure Device, and no evidence 
of long-term erosion. These results supported progression to a pivotal study.  
The first pivotal study, WATCHMAN Left Atrial Appendage System for Embolic 
PROTECTion in Patients with Atrial Fibrillation13 (PROTECT- AF), demonstrated non-
inferiority of the WATCHMAN Device to long-term warfarin therapy for the primary 
effectiveness endpoint of stroke, systemic embolism, and cardiovascular death.  
The most recent, published analysis of the PROTECT AF14 trial has shown that the 
WATCHMAN Device achieved superiority for the combined endpoint of all stroke, 
cardiovascular or unexplained death and systemic embolism (for Bayesian analysis, posterior 
probabilities are used to determine superiority; > 95% represents superiority). 

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•The observed primary effectiveness event rate was 2.3 percent and 3.8 percent in the 
WATCHMAN and control groups, respectively, demonstrating a 40% percent relative risk 
(RR) reduction in primary effectiveness in the WATCHMAN group (RR = 0.60, posterior 
probability of superiority = 96 percent%). 
Secondary analysis also showed a relative risk reduction and superiority to control for all-cause 
mortality and cardiovascular mortality.  
•All-Cause Mortality: the WATCHMAN group was superior to the control group, 3.2% 
percent to 4.8 percent % respectively, representing a 34 percent% relative risk reduction 
in all-cause mortality in the WATCHMAN group (Hazard ratios [HR] = 0.66, p=0.0379).  
•Cardiovascular Mortality: the WATCHMAN group was superior to the control group, 1.0 
percent% and 2.4 percent % respectively, representing a 60 percent% relative risk 
reduction in cardiovascular death in the WATCHMAN group (HR = 0.40, p=0.0045). 
The Continued Access to PROTECT Registry15 (CAP Registry) provided continued access of 
the WATCHMAN Device to PROTECT- AF investigators and demonstrated a decrease in 
procedural complications of pericardial effusion with tamponade, cardiac perforation, and 
device embolization (1.2%, 0.2%, 0%, respectively).  
The second pivotal study, Prospective Randomized Evaluation of the WATCHMAN LAA 
Closure Device In Patients with Atrial Fibrillation Versus Long Term Warfarin Therapy 
(PREVAIL), was conducted to provide additional information on the implant procedure and 
complication rates associated with the device. 16 In this trial, LAA occlusion was non-inferior 
to warfarin for ischemic stroke prevention or systemic embolism (SE) >7 days’ post-procedure. 
Although non-inferiority was not achieved for overall efficacy, event rates were low and 
numerically comparable in both arms. Procedural safety has significantly improved over the 
previous trials, PROTECT AF and CAP. PREVAIL only data, data from subjects enrolled in 
the PREVAIL study without the prior PROTECT AF study information used in the Bayesian 
analysis, showed that the ischemic stroke rate (2.3 vs. 0.3 per 100 pt-years) favored to the 
Control group, while the hemorrhagic stroke rate (0.4 vs. 0.7 per 100 pt-years) and death 
(cardiovascular or unexplained) rate (1.4 vs. 2.3 per 100 pt-years) favored the WATCHMAN 
group. The PREVAIL trial provides additional data that LAA occlusion is a reasonable 
alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have 
an absolute contraindication to short-term warfarin therapy. 
The Continued Access Protocol (CAP2) was a prospective, non-randomized, multicenter 
study to allow continued access to the WATCHMAN LAA Closure Technology during the 
data analysis, reporting and review of the PREVAIL pivotal study Pre-Market Application by 
FDA. The first of 578 subjects was enrolled on 25-Sep-2012.  The final subjects were 
enrolled on 21-Mar-2014, and are currently in long-term follow-up out to 5 years.  Subjects 
in this trial were at a high-risk of stroke with a mean CHA2DS2-VASc of 4.5  
(+/- 1.3).  Additionally, 98% were at moderate to high risk of bleeding.  Patients in this trial 
had an ischemic stroke rate of 2.3%, which is in line with the other WATCHMAN trials.   
The purpose of the EValuation of the Next Generation WATCHMAN LAA Closure 
TechnOLogy in Non-Valvular AF PatiEnts (EVOLVE) study was to evaluate the 
implantability of the Gen 4 WATCHMAN LAA Closure Device in patients with non-valvular 

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atrial fibrillation (AF) with a CHADS2 stroke risk stratification of 1 or greater. The primary 
objectives of the study were to assess successful delivery and release of the WATCHMAN 
(Gen 4) Closure Device, the occurrence of serious pericardial effusions and the discontinuation 
of warfarin at 45 days. Patients who had non-valvular paroxysmal, persistent or permanent AF, 
had a CHADS2 score of ≥1, and were eligible for warfarin therapy were screened as candidates 
for the study and implant. 
 
In the EVOLVE study, the successful delivery and release of the WATCHMAN Gen 4 Closure 
Device and the occurrence of serious pericardial effusions were either consistent with or an 
improvement upon the results from the PROTECT AF study. Therefore, the acute objectives 
of the study were met and demonstrate pericardial effusion and device recapture rates lower 
than that seen with the Gen 2.5 Device in PROTECT AF. This demonstrates that the Gen 4 
WATCHMAN LAA Closure Device could be safely implanted in patients with non-valvular 
atrial fibrillation (AF) with CHADS2 stroke risk score of 1 or greater. The closed distal end of 
this generation device was similar to WATCHMAN FLX, however, for business purposes, the 
commercialization of the Gen 4 device was not pursued in lieu of developing WATCHMAN 
FLX. 
 
The REgistry on WATCHMAN Outcomes in Real-Life Utilization (EWOLUTION) study is 
an observational, prospective, single-arm, multicenter clinical study (Europe, Middle East, 
Russia) that compiles real-world clinical outcome data for WATCHMAN LAA Closure 
Device in a commercial setting and collects health care usage data for reimbursement decisions 
in certain countries; EWOLUTION continues to build on the existing WATCHMAN clinical 
database.  EWOLUTION is a purely observational post-market data collection study. 
Consecutive enrollment was strongly encouraged, and achieved in most sites, to minimize 
selection bias and maintain the strengths of a large-scale, all-comers clinical registry. A total 
of 1025 patients scheduled for a WATCHMAN implant at 47 centers in 13 countries were 
enrolled, and subjects are being followed for two years after WATCHMAN implantation 
according to standard medical practice. Analyses include procedural and long-term data, 
including stroke/embolism, bleeding, and death. 
 
Preliminary baseline/implant data, the results of the peri-procedural analyses, and data 
through the 3-month visit were presented for 1020 subjects.  The EWOLUTION population 
was at high risk for stroke presenting with CHADS2 (2.8±1.3) and CHA 2DS2-VASc (4.5±1.6) 
scores. The populations had a moderate-to-high risk of bleeding with an average HAS-BLED 
score: 2.3 ± 1.2. Approximately 72% of patients in EWOLUTION were deemed unsuitable 
for OAC by their physician. The device was successfully deployed in 98.5% of patients with 
no or minimal residual flow achieved in 99.7% of implanted patients. There were twenty-six 
(2.8%, 1.6–3.6%) serious adverse events occurring in 23 subjects reported as relating to the 
procedure at 7 days.  Three patients died within 30 days of causes that appear unrelated to the 
device. These rates of procedural success and 7-day device-related SAEs were lower than 
those found in PROTECT AF, CAP, PREVAIL, and CAP2.  
 
The WATCHMAN ASia Pacific Registry (WASP) is an Asia/Pacific registry with identical 
design to EWOLUTION that compiles real-world clinical outcome data for the 

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WATCHMAN LAA Closure Device in a commercial setting and collects health care usage 
data for reimbursement decisions in certain countries. Like EWOLUTION, WASP is a purely 
observational post-market data collection study. 
 
The ASA Plavix Study with WATCHMAN Left Atrial Appendage Closure Technology 
(ASAP) study was a multi-center, prospective non-randomized study of 150 subjects enrolled 
at four sites in Europe. Subjects were followed post-implant at 3, 6, 12, 18, and 24 months. 
The primary objective of this study was to characterize the performance of the 
WATCHMAN Left Atrial Appendage (LAA) Closure Device in non-valvular atrial 
fibrillation subjects for which warfarin therapy was contraindicated. The study demonstrated 
a high procedure success with the WATCHMAN device placed in 94.0% of all procedures 
attempted. All cause death was the most prevalent adverse event, occurring in fourteen (14) 
subjects. The next most frequent event was device thrombus (8). Of the cases of device 
thrombus one (1) was associated with an ischemic stroke event. The remaining seven (7) 
events of device thrombus were treated with low molecular weight heparin until resolution. 
Ischemic stroke was reported in four (4) subjects for a rate of 1.5 per 100 pt-yrs. This rate is 
significantly lower than other trials assessing stroke rates in subjects with atrial fibrillation 
who are unable to take anticoagulant therapy 
 
SALUTE is a study to evaluate the SAfety and effectiveness of the Left atrial appendage 
closure therapy for patients with non-valvUlar atrial fibrillation at increased risk of 
ThromboEmbolism in Japanese medical environment.  Enrollment is complete and the trial is 
in long-term follow-up.   
 
The Assessment of the WATCHMANTM Device in Patients Unsuitable for Oral 
Anticoagulation (ASAP-TOO) Study is designed to establish the safety and effectiveness of 
the WATCHMANTM Left Atrial Appendage Closure Device, including the post-implant 
medication regimen, for subjects with non-valvular atrial fibrillation who are deemed not to 
be eligible for anticoagulation therapy to reduce the risk of stroke. The device is intended to 
reduce the risk of thromboembolic ischemic stroke and systemic embolism.  This trial began 
enrollment in February of 2017 and will randomize 888 subjects at up to 100 worldwide 
centers. 
 
The first iteration of the WATCHMAN FLX Device began a limited market release (LMR) 
in Europe in 2015 and was implanted in 213 patients. The rate of embolization (3.8%) for 
this initial FLX iteration was greater than anticipated. Boston Scientific elected to make 
design enhancements to the device. These design enhancements were incorporated into the 
current WATCHMAN FLX Device. The PINNACLE FLX study is designed to establish the 
safety and effectiveness of the WATCHMAN FLX™ Left Atrial Appendage Closure 
(LAAC) Device for subjects with non-valvular atrial fibrillation. The study completed the 
enrollment of 398 subjects on November 9, 2018. Each subject will be followed for 2 years. 
However, the PINNACLE FLX study is conducted exclusively in the U.S. Although it is 
assumed that ethnic difference might not play an important role in the performance of the left 
atrial appendage closure, we designed this HK FLX study to observe the safety and 
effectiveness of the WATCHMAN FLX™ LAAC Device for subjects with non-valvular 
atrial fibrillation to reduce the risk of stroke in Hong Kong area. 

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5. Device Description 
5.1. Product Description  
The WATCHMAN FLX Delivery System consists of the Delivery Catheter and the pre-loaded 
Closure Device, Figure 1. The WATCHMAN FLX Delivery System is used in conjunction 
with a WATCHMAN Access System. Together, the WATCHMAN Access System and 
WATCHMAN FLX Delivery System permit device placement in the LAA via femoral venous 
access and crossing the inter-atrial septum into the left atrium. The WATCHMAN Access 
System is commercially-available and a required accessory for use with the WATCHMAN 
FLX procedures.  
5.1.1. WATCHMAN FLX Delivery System and with Pre-loaded LAAC Device 
The Delivery Catheter for WATCHMAN FLX consists of an inner core wire with a reinforced 
braided jacket that is connected to the deployment knob at the proximal end and a screw thread 
assembly at the distal end. The outer sheath has an overall profile of 12F.  
The WATCHMAN FLX Device is pre-loaded into a Delivery Catheter and is deployed by 
loosening the valve on the Delivery System and retracting the outer sheath. The WATCHMAN 
FLX Device can be partially recaptured and redeployed if the device is too distal. If the Closure 
Device is deployed too proximal, it can be fully recaptured.  The WATCHMAN FLX Device 
has the added ability over the existing WATCHMAN (Gen 2.5) device to be redeployed after 
being fully recaptured. As with the existing WATCHMAN Device, the Closure Device is 
released by rotating the device deployment knob counter clockwise. 
The WATCHMAN FLX Device is comprised of a self-expanding nitinol frame structure with 
fixation anchors around the Closure Device perimeter and a permeable polyester fabric that 
covers the atrial facing surface of the Closure Device. The Closure Device is constrained within 
the Delivery Catheter until deployment in the LAA. The WATCHMAN FLX Device is 
available in 5 sizes, similar to the currently available WATCHMAN (Gen 2.5) Device, but 
covers a slightly larger range from 14 to 31.5 mm.  Closure Device selection is determined by 
LAA measurements using fluoroscopy (fluoro) and echocardiographic guidance. 
Figure 1: WATCHMAN Delivery System (Delivery Catheter & LAA Closure Device) 
 

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Similar to the previous WATCHMAN Devices, the WATCHMAN FLX Device is designed to 
be permanently implanted at or slightly distal to the ostium (opening) of the LAA to trap 
potential emboli before they exit the LAA. The placement procedure can be done under local 
or general anesthesia in a catheterization laboratory.  
In addition, WATCHMAN FLX incorporates the following novel features to enhance the user 
experience for the WATCHMAN LAA Closure Technology compared to the existing 
WATCHMAN Closure Device with Delivery System: 
• Closed Distal End – Provides improved deployment stability and control, with 
atraumatic distal structure. 

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• Fully Recapturable and Redeployable – Decreases the number of devices used and 
sheath exchanges per case, which may reduce procedure time and complications 
associated with sheath exchange. 
• Decreased Recapture Force – Improves user experience. 
• Increased Conformability – Creates better left atrial appendage seal due to the increased 
number of contact points around the LAA ostium, designed to promote short-term 
healing. 
• Decreased Exposed Metal Volume on Proximal Face – May promote short-term 
healing. 
• Enhanced Radiopacity – Improves visibility under fluoroscopy. 
• Shorter Device Length – Allows for treatment of shorter appendages. 
• Greater Device Use Range – Provides for treatment of a wider range of appendage sizes. 
6. Study Objectives 
The primary objective of this study is to observe the safety and effectiveness of the 
WATCHMAN FLX™ Left Atrial Appendage Closure (LAAC) Device for subjects with non-
valvular atrial fibrillation to reduce the risk of stroke in Hong Kong area. 
Compared with PINNACLE FLX study conducted in the U.S., the data collected in this study 
maybe used for product registration in other areas to show that ethnic difference might not 
play an important role in the performance of WATCHMAN FLX™. 
7. Study Endpoints 
7.1. Primary Effectiveness Endpoint 
The occurrence of non-effective LAA closure defined as any peri-device flow > 5mm 
demonstrated by TEE/CT/MRI at First Follow-up. 
7.2. Primary Safety Endpoint 
The occurrence of one of the following events between the time of implant and within 7 days 
following the procedure or by hospital discharge, whichever is later: all-cause death, 
ischemic stroke, systemic embolism, or device or procedure related events requiring open 
cardiac surgery or major endovascular intervention such as pseudoaneurysm repair, AV 
fistula repair, or other major endovascular repair.  
NOTE: Percutaneous catheter drainage of pericardial effusions, snaring of an embolized 
device, thrombin injection to treat femoral pseudoaneurysm and nonsurgical treatments of 
access site complications will be captured as adverse events (AEs), and are excluded from 
this endpoint. 

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7.3. Secondary Effectiveness Endpoint 
The occurrence of ischemic stroke or systemic embolism at 12 months from the time of 
implant. 
7.4. Additional analysis 
The occurrence of stroke (including ischemic and/or hemorrhagic), cardiovascular death 
(cardiovascular and/or unexplained cause) and systemic embolism. 
8. Study Design 
This study is a prospective, non-randomized, multi-center observational study. 
8.1. Scale and Duration 
Up to 50 subjects at up to 5 investigational centers in Hong Kong will be enrolled in the 
study. Each investigational site might have up to 2 roll-in subjects, which is included in the 
50 total subjects.  
Enrollment is expected to be completed in approximately 12 months and each subject is 
expected to be followed for approximately 12 months with primary endpoints collected at 
First Follow-up (30 ~ 100 days); therefore the total study duration is estimated to be 
approximately 24 months. 
The study duration for each subject is expected to be approximately 12 months.  
8.2. Justification for the Study Design 
WATCHMAN FLX is new generation of the WATCHMAN product, and its safety and 
effectiveness in being verified in the PINNACLE FLX study conducted in the U.S. Although 
it is assumed that ethnic difference might not play an important role in the performance of the 
left atrial appendage closure, this HK FLX study is designed to observe the safety and 
effectiveness of the WATCHMAN FLX in Hong Kong area. 
This is an observational data collection designed to compile real-world data for 
WATCHMAN FLX in Hong Kong. The implant of the device is decided according to the 
patient clinical indications, regardless of participation in the study. The post-implant TEE (or 
alternative imaging methods) is also a clinical standard after the procedure to ensure sealing 
and exclude thrombus on the device prior to stop dual platelet inhibition or warfarin. The 
patients are followed per standard of care including the 12-Month Follow-up, which is 
mainly to collect adverse events, so no additional examination or procedure is required by the 
study other than standard clinical practice. 

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9. Subject Selection  
9.1. Study Population and Eligibility  
Any patient, who meets all the inclusion criteria, does not meet any of the exclusion criteria, 
and who provides written informed consent may be enrolled in the study. The subjects selected 
for participation will be from the investigator’s general patient population. The investigator 
has the responsibility for screening all potential patients and selecting those who meet study 
inclusion/exclusion criteria as described in sections 错误!未找到引用源。 and 0. 
9.2. Inclusion Criteria 
A subject may be enrolled in the study if all of the following inclusion criteria are met, provided 
no exclusion criteria (see section 9.3) are met:  
 
1. Patients who are eligible for a WATCHMAN FLX device according to current 
international and local guidelines (and future revisions) and per physician discretion; 
2. Patients who are willing and capable of providing informed consent, participating in all 
testing associated with this clinical investigation at an approved clinical investigational 
center; 
3. Patients whose age is 18 years or above, or of legal age to give informed consent specific 
to state and national law. 
9.3. Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. Patients who are currently enrolled in another investigational study or registry that would 
directly interfere with the current study, except when the patient is participating in a 
mandatory governmental registry, or a purely observational registry with no associated 
treatments. Each instance should be brought to the attention of the sponsor to determine 
eligibility. 
2. Women of childbearing potential who are, or plan to become, pregnant during the time of 
the study (method of assessment upon physician’s discretion); 
3. The subject is unable or not willing to complete follow-up visits and examination for the 
duration of the study. 
10. Subject Accountability 
10.1. Enrollment 
Subjects who meet the eligibility criteria as per 错误!未找到引用源。 and 0, have signed and 
dated the Informed Consent Form and actually undergo a WATCHMAN FLX implant 
procedure are considered enrolled in the study. Baseline data from subjects who meet the 
eligibility criteria as per 错误!未找到引用源。 and 0, have signed and dated the Informed 
Consent Form but do not eventually undergo a WATCHMAN FLX implant procedure are 

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collected for epidemiological reasons, to better characterize the population. The start of the 
WATCHMAN FLX implant procedure is considered the insertion of the WATCHMAN FLX 
Access Sheath. 
10.2. Withdrawal 
Every effort should be made to retain subject enrollment for the duration of the study.  During 
the informed consent process subjects should be fully informed of the data collection 
requirements and duration, and should only be enrolled if willing to fully participate in it. All 
subjects enrolled in the clinical study must be accounted for and documented. Reasons for 
withdrawal may include physician discretion, subject choice to retire consent, loss to follow-
up, or death. In the event a subject does decide to withdraw from the study, every effort should 
be made to obtain full information on any on-going adverse events.   
Subjects should only be considered lost to follow-up after significant effort has been made to 
contact the subject.  At a minimum there should be 3 documented telephone contact attempts 
and one certified letter sent to the subject’s last known residence. Subject withdrawal and lost 
to follow-up will be documented on the “End of Study” CRF. For subjects who are “lost-to-
follow-up” the investigator/center should make documented attempts to contact the subject 
prior to completion of the applicable CRF. Additional data may no longer be collected after 
the point at which a subject has been withdrawn from the study or withdraws his/her consent, 
for whatever reason. All open adverse events should be closed or documented as chronic. Data 
collected up to the point of subject withdrawal may be used, unless any local regulations apply 
which require removal of the data. 
10.3. Subject Status and Classification 
Consent Ineligible 
A subject who has signed informed consent but is found to not meet eligibility criteria will be 
classified as “Consent Ineligible”. There are no FU or adverse event reporting requirements 
for consent ineligible subjects. Subjects determined to be Consent Ineligible according to 
statements above do not count towards the enrollment ceiling and will not be used for analysis 
of the endpoints. The original signed Informed Consent must be maintained in the center’s 
administrative file.   
 
Intent 
A subject who signs informed consent, meets eligibility criteria, but then does not undergo an 
implant of a WATCHMAN FLX device will be classified as “Intent”. This definition includes 
subjects that do not meet echocardiographic criteria for a WATCHMAN FLX implant at the 
implant TEE/CT/MRI evaluation (e.g. a thrombus has developed in the LAA, inappropriate 
LAA size). These patients may be withdrawn immediately, unless re-assessment of the criteria 
is planned. If subjects are re-assessed for WATCHMAN FLX implant, as per physicians’ 
discretion, then a reconsent must be obtained for participating in the registry. 
Subjects who have been consented, but not yet implanted at the time of enrollment closure will 
also be classified as Intent. There are no FU or adverse event reporting requirements for Intent 
subjects. Intent subjects do not count towards the enrollment ceiling and will not be used for 
analysis of the endpoints. The original signed Informed Consent must be maintained in the 

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center’s patient file. For these subjects, the eCRFs in the “Baseline” folder and a “Patient Status” 
form must be completed. Subjects who become Intents due to death before the implant 
procedure must have the death documented. 
 
Attempt 
A subject who signs informed consent, meets eligibility criteria and has had the WATCHMAN 
FLX Access Sheath inserted to implant the device, but eventually does not receive a 
WATCHMAN FLX device will be classified as “Attempt”. These subjects may be withdrawn, 
unless a re-implant of a study device is planned, per physician discretion. If subjects are re-
assessed for WATCHMAN FLX implant, as per physicians’ discretion, then a reconsent must 
be obtained for participating in the registry. These subjects will be handled as “Implant” (see 
next section), if the re-implant is successful. Subjects who eventually have not received a 
WATCHMAN FLX device at the time of enrollment closure will remain classified as “Attempt” 
and be withdrawn. There are no FU requirements for Attempt subjects; however, adverse 
events will be collected up to the point of subject withdrawal. Attempt subjects count towards 
the enrollment ceiling and will be used for analyses of the endpoints. The original signed 
Informed Consent must be maintained in the center’s study file and the following forms must 
be completed: 
• eCRFs in the “Baseline” and “Implant” folders 
• “Adverse Event” forms for any adverse event that occurs after signing the Informed 
Consent, up to the point of subject withdrawal. 
• “Patient Status” form for withdrawal, when applicable. 
The date at which the patient status form has been completed will be the point of subject 
withdrawal.  
 
Implant 
A subject who is successfully implanted with the WATCHMAN FLX device will be classified 
as “Implant”. These subjects are followed in accordance with the FU schedule and included 
in all study analyses.  All applicable case report forms per the protocol must be completed. The 
original signed Informed Consent and any relevant documentation must be maintained in the 
center’s patient file.  
 
Roll-in and non-roll-in 
Each site might have up to 2 roll-in subjects if the site has never implanted a WATCHMAN 
FLX before. Roll-in subjects should be decided before the implant procedure, and might be 
classified as Attempt or Implant after the procedure. Roll-in subjects are enrolled and counted 
to the ceiling of the sample size. Other enrolled subjects are defined as non-roll-in. 
 
 
 

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Figure 2: Subject Status and Data Collection Flow Chart 
 
11. Study Methods 
11.1. Data Collection 
To ensure data quality and completeness, all required data will be recorded on case report 
forms (CRFs) provided by the sponsor.  Data will be entered onto electronic case report forms 
by the investigational site or designee. Case Report Forms should be completed accurately 
during and in a timely manner after any visit in the study.  The Principal Investigator or 
appointed designee must review the case report forms and sign them, certifying their accuracy.  
Completed case report forms should be submitted to the sponsor within two weeks of 
completion of a study visit.  
Each patient will be followed for a period of 12 months after implant according to the schedule 
and standard practice at the enrolling centers. There will be no additional procedures, for 
subjects who participate in the study. Subjects are expected to be followed at implant, then at 
First Follow-up (30 ~ 100 days), and 12-Month Follow-up (365 ± 30 days)  post-implant. An 
intermediate visit may be scheduled in a number of patients, per physician discretion.  
For subjects who are not scheduled to visit the clinic for a follow-up, a subject contact (e.g. 
phone call) will ensure capture of the endpoint related information, however it is strongly 
recommended to perform an in-office visit for at least the First Follow-up visit. 
 
Informed consent 
obtained 
LAA criteria 
met? 
Implant of WATCHMAN FLX 
 
*** subject is enrolled *** 
Reassess per 
physician’s discretion 
NO 
YES 
Device implanted 
Device not implanted 
Follow-up according to 
center’s practice 
Withdrawal 
(Attempt) 
reimplant 
Withdrawal 
(Intent) 

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 Table 3 provides an overview of the data to be collected at each visit. 
 
Table 3: Data Collection Overview 
 
Data Collected 
Enrollment 
Implant 
Follow Up 
First 
(30 ~ 100 
days) 
Office 
12-Month 
(365 
± 
30 
days) 
Office/Phone 
Additional 
Office/Phone 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
LAA imaging (TEE/CT/MRI) 
Xa,b 
Xa 
X 
Xa 
Xa 
Medication Regimen 
X 
X 
X 
X 
X 
Current status and Vital Signs 
X 
X 
X 
X 
X 
Adverse Event and Device Deficiency 
Reporting 
X 
X 
X 
X 
X 
a collected only if performed 
b within 3 calendar days prior to implant 
11.2. Informed Consent 
In order to determine eligibility of a subject, the investigator needs to implement the consent 
process and verify and document the subject meets the inclusion/exclusion criteria. Informed 
consent is required from all patients (or their legal representatives) prior to the patient’s 
participation in the study. The patient should be given ample time to consider participation and 
ask questions if necessary. An approved informed consent form shall be signed and personally 
dated by the subject (or legal representative). The original, signed document is to be kept with 
the subject’s file and a copy must be provided to the subject. 
11.3. Enrollment Visit 
Only those subjects who provide consent and meet all of the study enrolment criteria may be 
enrolled and will have baseline data collected.  Subjects who provide informed consent but do 
not meet all of the study enrolment criteria will be considered Consent Ineligible.  
The data collection at Enrollment Visit includes: 
• Demographic data, including: age at time of consent, gender, and ethnic;  
• Risk factors, including those used to calculate HAS-BLED, CHADS2 and CHA2DS2-
VASc scores; 
• Medical and cardiac history, including: cardiovascular diseases; prior history of 
ischemic stroke, hemorrhagic stroke or TIA; previous cardiac procedures; history of 
bleeding; indication for LAA occlusion; 

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• Current medical status; vital signs; AF status (paroxysmal, persistent, permanent);  
• Current medication regimen for the use of antiplatelet and anticoagulation medications; 
• Adverse Events and Device Deficiency, if applicable. 
11.4. LAA Imaging (e.g. TEE/CT/MRI) 
Prior to implantation with the WATCHMAN FLX device, an Enrollment TEE (or alternative 
imaging method) is a clinical standard to confirm there is no thrombus in the LAA or left 
atrium. If an intracardiac thrombus is visualized by echocardiographic imaging, the patients 
will not be implanted. Re-assessment may be scheduled per physician’s discretion. 
The Implant LAA imaging will also allow the investigator to obtain proper measurements of 
the LAA to correctly size the device, confirm device release criteria are met prior to device 
release, and to confirm adverse events have not occurred during the implant procedure (i.e., 
pericardial effusion). If an intracardiac thrombus is visualized by echocardiographic imaging, 
the patients will not be implanted. Re-assessment may be scheduled per physician’s discretion.  
The Follow-up LAA imaging is a clinical standard after the WATCHMAN FLX procedure, it 
is conducted to assess flow through and around the WATCHMAN FLX device, to ensure 
sealing and to verify there is no thrombus on the surface of the device prior to stopping dual 
platelet inhibition or warfarin. Additional LAA imaging may be conducted at the discretion of 
the investigator and according to center’s practice.  
Certain information from TEE/CT/MRI conducted during the course of the study will be 
captured on the study case report forms, including: heart rhythm; valve status; pericardial status; 
atrial septum characteristics; LAA size and type of anatomy; thrombus assessment. 
For measurement of per-device flow: 
• Use multiple TEE views (0º, 45 º, 90 º, and 135 º) or 3D-TEE 
• Echo colour Doppler TEE: set Nyquist limit to detect low velocity flow (20–30 cm/s). 
If leak is present, measure only the mosaic (high-velocity) colour of a communicating 
flow in multiple projections 
• Use same settings during implantation and follow-up 
• Document largest measurement as size of leak and achieved angle of measurement by 
TEE or CT/MRI 
11.5. Implant Procedure 
The implant procedure should be performed using standard of care methods established by the 
investigational center (e.g. sterile technique, personnel requirements, etc.).  Implantation of the 
WATCHMAN FLX LAA Closure Device should only be performed by physicians trained in 
percutaneous and transseptal procedures who have completed the WATCHMAN FLX training 
program. Refer to the WATCHMAN FLX LAA Closure Technology Directions for Use for 
detailed instructions regarding the implantation and use of the WATCHMAN FLX technology. 
The following will be assessed during implant procedure and documented on case report forms 
for enrolled subjects: 

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• WATCHMAN FLX Device and Access System usage information, including device 
size and compression post-implant, procedure time (from first sheath inserted to last 
sheath removed); 
• LAA imaging (as described in section 11.4): LAA measurements; intracardiac 
thrombus, device position, LAA seal, thrombus on the device surface;  
• Concomitant procedures;  
• Current medical status; vital signs; AF status; 
• Current medication regimen for the use of antiplatelet and anticoagulation medications; 
• Serious adverse events,adverse events and device deficiencies during implant 
procedure. Data to be collected for peri-procedural complications include, but are not 
limited to: 
o Cardiovascular events: pericardial effusion, cardiac tamponade, bleeding, 
stroke (ischemic/non-ischemic), TIA, systemic embolism (please refer to 
Appendix A for definitions of stroke/TIA and classification of bleeding events) 
o ICU: Length of stay 
o Conventional care unit: Length of stay 
o Device/procedure related complications 
11.6. Follow-up Procedures 
Subjects are expected to be followed at First (30 ~ 100 days) and 12-Month post-implant or 
until the study is terminated. An intermediate visit may be scheduled in a number of patients, 
per physician discretion. For subjects who are not scheduled to visit the clinic for a follow-up, 
a subject contact (e.g. phone call) will ensure capture of the endpoint related information, 
however it is recommended to perform an office visit for at least the First Follow-up visit. 
i) In-Hospital Visit 
The following will be assessed during each in-hospital visit and documented on case report 
forms for enrolled subjects: 
• Current medication regimen for the use of antiplatelet and anticoagulation medications; 
• Procedures performed since last visit; 
• Current medical status; vital signs; AF status; 
• LAA imaging (as described in section 11.4): device position, LAA seal, thrombus on 
the device surface, intracardiac thrombus and residual atrial septal shunt;  
• Serious adverse events, adverse events and device deficiencies experienced since last 
visit. Data to be collected include, but are not limited to (please refer to Appendix A 
for definitions of stroke/TIA and classification of bleeding events): 
 
o ER admission due to WATCHMAN FLX implant related clinical events 
(stroke/TIA (ischemic/non-ischemic), systemic embolism, major and minor 
bleeding) 

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o Hospitalization (ICU and Ward) due to WATCHMAN FLX implant related 
clinical events (stroke/TIA (ischemic/non-ischemic), systemic embolism, major 
and minor bleeding) 
o Specialist visits due to WATCHMAN FLX implant related clinical events 
(stroke/TIA (ischemic/non-ischemic), systemic embolism, major and minor 
bleeding) 
o Diagnostic procedure following a clinical event related to WATCHMAN FLX 
(stroke/TIA (ischemic/non-ischemic), systemic embolism, major and minor 
bleeding) 
ii) Subject Contact 
For subjects who are not scheduled to visit the clinic for a follow-up, a subject contact (e.g. 
phone call) will ensure capture of the endpoint related information. The following will be 
assessed during each subject contact and documented on case report forms for enrolled subjects: 
• Current medication regimen for the use of antiplatelet and anticoagulation medications 
• Serious adverse events, adverse events and device deficiencies experienced since last 
visit. Data to be collected include, but are not limited to (please refer to Appendix A 
for definitions of stroke/TIA and classification of bleeding events): 
 
o ER admission due to WATCHMAN FLX implant related clinical events 
(stroke/TIA (ischemic/non-ischemic), systemic embolism, major and minor 
bleeding) 
o Hospitalization (ICU and Ward) due to WATCHMAN FLX implant related 
clinical events (stroke/TIA (ischemic/non-ischemic), systemic embolism, major 
and minor bleeding) 
o Specialist visits due to WATCHMAN FLX implant related clinical events 
(stroke/TIA (ischemic/non-ischemic), systemic embolism, major and minor 
bleeding) 
o Diagnostic procedure following a clinical event related to WATCHMAN FLX 
(stroke/TIA (ischemic/non-ischemic), systemic embolism, major and minor 
bleeding) 
11.7. Study Completion 
Each subject will be followed for 12 months after the implant. In case of premature termination 
of the study, data collection will stop accordingly. As this is an observational study, subjects 
will be managed according to standard of care as per centers practice following 
termination/completion of the study. 
11.8. Source Documents 
Printed, optical or electronic document containing source data shall be used; examples include 
hospital records, laboratory notes, device accountability records, radiographs, records kept at 
the investigation site, and at the laboratories involved in the clinical study. 

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Where copies of the original source document as well as printouts of original electronic source 
documents are retained, these shall be signed and dated by a member of the investigation center 
team with a statement that it is a true reproduction of the original source document.  
12. Statistical Considerations 
An overview of the study design, sample size and statistical analysis is provided below.  
12.1. Sample Size Justification 
This is a prospective, non-randomized, multi-center observational study with no formal pre-
specified hypothesis test.  All subjects will be followed for up to 12 months or until the study 
is terminated.   
A sample size of up to 50 subjects was chosen to observe the safety and effectiveness of the 
WATCHMAN FLX™ Left Atrial Appendage Closure (LAAC) Device for subjects with non-
valvular atrial fibrillation to reduce the risk of stroke in Hong Kong area.  
The ongoing PINNACLE FLX study is designed to establish the safety and effectiveness of 
the WATCHMAN FLX™ Left Atrial Appendage Closure (LAAC) Device for subjects with 
non-valvular atrial fibrillation. The study has enrolled 398 subjects, and each subject will be 
followed for 2 years. However, the PINNACLE FLX study is conducted exclusively in the U.S. 
Although it is assumed that ethnic difference might not play an important role in the 
performance of the left atrial appendage closure, a small sample size study in Hong Kong 
should be able to provide valuable information supporting this assumption. 
12.2. Statistical Analysis and Data Sets 
There is no hypotheses testing in this small sample size observational study.  
The Primary Effectiveness Endpoint is the occurrence of non-effective LAA closure defined 
as any peri-device flow > 5mm demonstrated by TEE/CT/MRI at First Follow-up. 
The Primary Safety Endpoint is the occurrence of one of the following events between the 
time of implant and within 7 days following the procedure or by hospital discharge, 
whichever is later: all-cause death, ischemic stroke, systemic embolism, or device- or 
procedure-related events requiring open cardiac surgery or major endovascular intervention 
such as pseudoaneurysm repair, AV fistula repair, or other major endovascular repair. 
Percutaneous catheter drainage of pericardial effusions, snaring of an embolized device, 
thrombin injection to treat femoral pseudoaneurysm and nonsurgical treatments of access site 
complications are excluded from this endpoint. 
Roll-in subjects are excluded from all Primary Endpoint analyses, and will be treated 
separately analysis set for the Primary Effectiveness analysis includes implanted subjects 
with a completed First Follow-up visit. The analysis set for the Primary Safety analyses will 
be the “intent-to-treat” analysis set, including implanted or attempted subjects. It is estimated 
that both Primary Effectiveness analysis and Primary Safety analysis dataset will include at 
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For the Primary Effectiveness Endpoint, it might be considered reasonable if up to 3 primary 
effectiveness endpoint events should occur in this small sample size study. 
For the Primary Safety Endpoint, it might be considered reasonable if up to 3 primary safety 
endpoint events should occur in this small sample size study. 
Missing data will not be dealt with systematically in this small sample size study. A tipping-
point analysis might be conducted for the Primary Effectiveness Endpoint to assess the impact 
of different assumptions about the missing data on interpretation of the results. 
For Secondary Endpoint and additional analysis, different data sets could be used exploratively. 
While no formal hypothesis tests will be performed, descriptive statistics will be generated for 
the data collected at enrollment, during the implant procedure and at follow-up.  For continuous 
variables, the mean, standard deviation, median, range and 95% confidence intervals will be 
reported.  Confidence intervals (95%) for the difference between means will be used to 
compare groups.  For proportions, 95% confidence intervals will be reported.  For time-to-
event analyses, all subjects not having an event or lost to follow-up will be censored at the time 
of the last documented follow-up visit.   
For a sample size of 50, the 95% CIs of the rates for 0~5 events are as follows (exact methods), 
Table 4: 
Table 4: 95% confidence interval for 0~5 events  
Events  Rates (n=50) Lower 95% CI Upper 95% CI 
0 
0% 
0.0% 
7.1% 
1 
2% 
0.1% 
10.6% 
2 
4% 
0.5% 
13.7% 
3 
6% 
1.3% 
16.5% 
4 
8% 
2.2% 
19.2% 
5 
10% 
3.3% 
21.8% 
 
Although not powered in the small sample study, explorative analyses may include, but will 
not be limited to the study endpoints. A variety of methods may be utilized in order to assess 
associations between the likelihood of each of the study endpoints and the patient and 
procedural characteristics outlined below.  Covariates will be chosen for inclusion in the 
models based on the number of patients with complete data for each outcome according to the 
prioritization in Table 5. 
 
Methods to model multivariate associations may include but are not limited to the following: 
1) Univariate analysis of individual predictors, and subsequent construction of 
multivariate logistic regression models incorporating all significant univariate 
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2) Parsimonious multivariate logistic regression models constructed through stepwise 
selection algorithm. 
3) Classification and regression tree models.   
Table 5: Covariates of Interest 
1. Age  80 years 
2. Gender 
3. Type of AF (paroxysmal; persistent; permanent) 
4. Previous Stroke/TIA 
5. Previous major bleeding event 
6. HASBLED  3 
7. CHADS2  3 
8. CHA2DS2-VASc  5 
9. Type of anticoagulation therapy (Warfarin; NOACs; antiplatelet) 
10. Multiple concomitant procedures vs watchman implant only 
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system.  
The clinical database will reside on a production server hosted by Medidata. All changes made 
to the clinical data will be captured in an electronic audit trail and available for review by 
Boston Scientific Corporation (BSC) or its representative. The associated RAVE software and 
database have been designed to meet regulatory compliance for deployment as part of a 
validated system compliant with laws and regulations applicable to the conduct of clinical 
studies pertaining to the use of electronic records and signatures. Database backups are 
performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic case report 
forms (eCRFs) in compliance with local regulations. A written signature on printouts of the 
eCRFs must also be provided if required by local regulation. Changes to data previously 
submitted to the sponsor require a new electronic signature by the Investigator acknowledging 
and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data discrepancies. 
Manual and/or automatic queries will be created in the EDC system and will be issued to the 
site for appropriate response. Site staff will be responsible for resolving all queries in the 
database in a timely manner. 
13.2. Data Retention 
The Investigator will maintain, at the investigative site, in original format all essential study 
documents and source documentation that support the data collected on the study subjects in 
compliance with ICH/GCP guidelines.  Documents must be retained for at least 2 years after 
the last approval of a marketing application or until at least 2 years have elapsed since the 

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formal discontinuation study. These documents will be retained for a longer period of time by 
agreement with BSC or in compliance with other local regulations. It is BSC’s responsibility 
to inform the Investigator when these documents no longer need to be maintained. The 
Investigator will take measures to ensure that these essential documents are not accidentally 
damaged or destroyed. If for any reason the Investigator withdraws responsibility for 
maintaining these essential documents, custody must be transferred to an individual who will 
assume responsibility and BSC must receive written notification of this custodial change.  
14. Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
15. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect the 
life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing IRB/EC of any deviation from the investigational plan to protect 
the life or physical well-being of a subject in an emergency, and those deviations which affect 
the scientific integrity of the clinical investigation.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor within 14 days using the 
appropriate EDC eCRF. Sites may also be required to report deviations to the IRB/EC, per 
local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including notification, center re-training, or discontinuation) 
will be put into place by the sponsor or its representatives. 
16. Compliance 
16.1. Statement of Compliance 
This study will be conducted in accordance with ISO 14155:2011 Clinical Investigation of 
Medical Devices for Human Subjects-Good Clinical Practice, or the relevant parts of the ICH 
Guidelines for Good Clinical Practice, ethical principles that have their origins in the 
Declaration of Helsinki, and pertinent individual country laws and regulations. The study shall 
not begin until the required approval/favorable opinion from the Ethics Committee and/or 
regulatory authority has been obtained, if appropriate. Any additional requirements imposed 
by the EC or regulatory authority shall be followed, if appropriate. 
16.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the study 
is conducted in accordance with the Clinical Study Agreement, the investigational 

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plan/protocol, ISO 14155, ethical principles that have their origins in the Declaration of 
Helsinki, any conditions of approval imposed by the reviewing IRB/EC, and prevailing local 
and/or country laws and/or regulations, whichever affords the greater protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• Prior to beginning the study, sign the Investigator Agreement and Protocol Signature page 
documenting his/her agreement to conduct the study in accordance with the protocol. 
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the center team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of interest, 
including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event and observed device deficiency. 
• Report to BSC, per the protocol requirements, all AEs,ADEs, SAEs, SADEs, UADEs, 
USADEs and device deficiencies that could have led to a SADE and potential/USADE or 
UADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE, if required by the national 
regulations or this protocol or by the IRB/EC, and supply BSC with any additional 
requested information related to the safety reporting of a particular event. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
monitor and respond to questions during monitoring visits. 
• Allow and support regulatory authorities and the IRB/EC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this protocol 
and local IRB/EC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the Informed Consent Form 
(ICF). 
• Inform the subject of the nature and possible cause of any adverse events experienced. 

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• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations related 
to the clinical study, and make the necessary arrangements for emergency treatment, ensure 
that clinical medical records are clearly marked to indicate that the subject is enrolled in 
this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided with 
some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the subject’s 
personal physician about the subject’s participation in the clinical investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature withdrawal 
from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
• Ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable. 
16.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, included but not limited to conducting 
the informed consent process, the investigator is responsible for providing appropriate training 
and adequate supervision of those to whom tasks are delegated. The investigator is accountable 
for regulatory violations resulting from failure to adequately supervise the conduct of the 
clinical study.  
16.2.2. Investigator Records 
The investigator is responsible for the preparation (review and signature) and retention of the 
records cited below.  Records are subject to inspection and must be retained for a period of at 
least two (2) years (or according to local regulatory requirements) after the investigation is 
terminated or the date that the records are no longer required for purposes of supporting 
publications or regulatory submissions. 
• All significant correspondence which pertains to the investigation 
• Subjects’ case history records, including: signed subject informed consent form; all 
relevant observations; observations of adverse device events; medical history; 
completed sponsor Case Report Forms; documentation of the dates and reasons for any 
deviation from the protocol  
• Copies of Case Report Forms and clinical data 

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• Signed Investigator Agreement and recent curriculum vitae, both of which also must 
be submitted to the sponsor 
• IRB/EC approval and discourse documentation.  A copy of the IRB/EC approval must 
be submitted to the sponsor 
16.3. Institutional Review Board/ Ethics Committee 
A copy of the protocol, proposed Informed Consent form, other written subject information, 
and any proposed advertising material must be submitted to the EC for written approval.  A 
copy of the written EC approval of the protocol and Informed Consent form must be received 
by the sponsor before recruitment of subjects into the study and shipment of investigational 
product. 
The Investigator must submit and, where necessary, obtain approval from the EC for all 
subsequent protocol amendments and changes to the Informed Consent form.  The Investigator 
must notify the EC of deviations from the protocol or SAEs and SADEs occurring at the site 
in accordance with local procedures. 
The Investigator is responsible for obtaining annual EC approval and renewal throughout the 
duration of the study.  Copies of the Investigator’s reports and the EC continuance of approval 
must be sent to the sponsor. 
16.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC. Only authorized BSC personnel or a BSC 
representative will have access to these confidential records. Authorized regulatory personnel 
have the right to inspect and copy all records pertinent to this study. Study data collected during 
this study may be used by BSC for the purposes of this study, publication, and to support future 
research and/or other business purposes. All data used in the analysis and reporting of this 
study will be without identifiable reference to specific subject name. 
Boston Scientific will keep subjects’ health information confidential in accordance with all 
applicable laws and regulations.  Boston Scientific may use subjects’ health information to 
conduct this study, as well as for additional purposes, such as overseeing and improving the 
performance of its device, new medical research and proposals for developing new medical 
products or procedures, and other business purposes. Information received during the study 
will not be used to market to subjects; subject names will not be placed on any mailing lists or 
sold to anyone for marketing purposes.  
16.4.1. Sponsor Records 
The sponsor will maintain the following records: 
• All correspondence which pertains to the investigation 
• Signed investigator agreements and curriculum vitae 
• System/procedure related Adverse Device Events  

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• All case report forms, including samples of subject informed consents, submitted by 
the investigator; investigational plan and report of prior investigations 
• Hospital staff training and study visit reports 
• The sponsor will own and store the clinical data generated under this protocol 
16.5. Insurance  
Where required by local regulation, proof and type of insurance coverage, by BSC for subjects 
in the study will be obtained. 
17. Monitoring 
Monitoring (on-site and remote) will be performed during the study to assess continued 
compliance with the protocol and applicable regulations. In addition, the monitor verifies that 
study records are adequately maintained, that data are reported in a satisfactory manner with 
respect to timeliness, adequacy, and accuracy, and that the Investigator continues to have 
sufficient staff and facilities to conduct the study safely and effectively. The 
Investigator/institution guarantees direct access to original or electronic source documents by 
BSC personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and 
relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
18. Potential Risks and Benefits 
18.1. Risks Associated with the study 
Patients enrolled in this study will not be exposed to any additional testing, procedures or risks 
as compared to patients who are routinely implanted with the WATCHMAN FLX device and 
not enrolled in this study. The study only collects data from procedures and visits that are 
performed as routine practice, based on the patient’s clinical indications  
18.2.  Risks Associated with a standard WATCHMAN FLX Implant & Procedure 
Even if the WATCHMAN FLX implant is performed as part of clinical practice, for 
completeness of information we report here the section of the WATCHMAN FLX Directions 
For Use listing the possible adverse events and possible adverse device effects associated with 
implantation of a WATCHMAN FLX device, in alphabetical order:     
• Air embolism 
• Airway trauma 
• Allergic reaction to contrast media/medications or device materials 
• Altered mental status 
• Anemia requiring transfusion 

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• Anesthesia risks 
• Angina 
• Anoxic encephalopathy 
• Arrhythmias 
• Atrial septal defect 
• AV fistula 
• Bruising, hematoma, or seroma 
• Cardiac perforation 
• Chest pain/discomfort 
• Confusion post procedure 
• Congestive heart failure 
• Contrast related nephropathy 
• Cranial bleed 
• Decreased hemoglobin 
• Deep vein thrombosis 
• Death 
• Device embolism 
• Device fracture 
• Device thrombosis 
• Edema 
• Embolism 
• Excessive bleeding 
• Fever 
• Groin pain 
• Groin puncture bleed 
• Hematuria 
• Hemoptysis 
• Hypotension 
• Hypoxia 
• Improper wound healing 
• Inability to reposition, recapture, or retrieve the device 
• Infection/pneumonia 
• Interatrial septum thrombus 
• Intratracheal bleeding 
• Major bleeding requiring transfusion 
• Misplacement of the device/improper seal of the appendage/movement of 
device from appendage wall 
• Myocardial erosion 
• Nausea 
• Oral bleeding 
• Pericardial effusion/tamponade 
• Pleural effusion 
• Prolonged bleeding from a laceration 
• Pseudoaneurysm 
• Pulmonary edema 
• Renal failure 

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• Respiratory insufficiency/failure 
• Stroke - Hemorrhagic 
• Stroke - Ischemic 
• Surgical removal of the device 
• TEE complications (throat pain, bleeding, esophageal trauma) 
• Thrombocytopenia 
• Thrombosis 
• Transient ischemic attack (TIA) 
• Valvular damage 
There may be other potential adverse events that are unforeseen at this time. 
Some additional events that may be expected in catheterization procedures include: 
• Pneumothorax 
• Pulmonary Vein Obstruction 
• Valvular or vascular damage 
18.3. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject selection 
criteria, close monitoring of the subject's physiologic status during procedures and/or follow-
ups and by promptly supplying BSC with all pertinent information required by this protocol. 
18.4. Anticipated Benefits 
No direct patient benefit is expected from this study. Patients enrolled in this study will receive 
the same clinical care as patients who are routinely implanted with WATCHMAN FLX and 
not enrolled in this study. However, results from the data collected during this study may 
improve the management of WATCHMAN FLX patients in the future, therefore the subjects 
enrolled in this study may also benefit at a later stage.  
The potential benefit of implanting the WATCHMAN FLX device is its expected ability to 
prevent thromboembolic events originating in the LAA. The WATCHMAN FLX device may 
protect against ischemic stroke and systemic thromboembolism.  In subjects implanted with 
the device, the elimination of Warfarin therapy may reduce bleeding complications, such as 
hemorrhagic stroke, associated with long-term anticoagulation.  
19. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from all 
subjects or their legally authorized representative. The Investigator is responsible for ensuring 
that Informed Consent is obtained prior to any procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local Ethics Committee and/or Regulatory authority body, as applicable. The ICF must be 
approved by the center’s IRB, or central IRB, if applicable. 

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Boston Scientific will provide a study-specific template of the ICF to investigators 
participating in this study. The ICF template may be modified to meet the requirements of the 
investigative center’s EC and local regulations. Any modification requires approval from BSC, 
or its representative, prior to use of the form.  The ICF must be in a language understandable 
to the subject and if needed, BSC will assist the center in obtaining a written consent translation. 
Translated consent forms must also have EC approval prior to their use.  Privacy language 
shall be included in the body of the form or as a separate form as applicable.   
The process of obtaining Informed Consent shall: 
• be conducted by the Principal Investigator or designee authorized to conduct the process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study. 
The ICF shall always be signed and personally dated by the subject or legal representative and 
by the investigator or an authorized designee responsible for conducting the informed consent 
process. If a legal representative signs, the subject shall be asked to provide informed consent 
for continued participation as soon as his/her medical condition allows. The original signed 
ICF will be retained by the center and a copy of the signed and dated document and any other 
written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., FDA requirement is within 5 working days of learning 
of such an event). Any violations of the informed consent process must be reported as 
deviations to the sponsor and local regulatory authorities, as appropriate. 
If new information becomes available that can significantly affect a subject's future health and 
medical care, that information shall be provided to the affected subject(s) in written form via 
a revised ICF or, in some situations, enrolled subjects may be requested to sign and date an 
addendum to the ICF. In addition to new significant information during the course of a study, 
other situations may necessitate revision of the ICF, such as if there are amendments to the 
protocol, a change in Principal Investigator, administrative changes, or following annual 
review by the IRB. The new version of the ICF must be approved by the IRB/EC. Boston 
Scientific approval is required if changes to the revised ICF are requested by the center’s 
IRB/EC. The IRB/EC will determine the subject population to be re-consented. 

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20. Safety Reporting 
Adverse event definitions are provided in Table 6.  
 
Table 6: Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the 
investigational medical device.  
NOTE 1: This includes events related to the investigational medical device 
or comparator. 
NOTE 2: This definition includes events related to the procedures 
involved (any procedure in the clinical investigation plan). 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes any adverse event resulting from 
insufficient or inadequate instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 
 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event that: 
a) Led to death, 
b) Led to serious deterioration in the health of the subject, that either 
resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization of existing hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function 
c) Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the clinical investigational plan, without serious 
deterioration in health, is not considered a serious adverse event.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, 

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Table 6: Adverse Event Definitions 
Term 
Definition 
 
Ref: 21 CFR Part 812 
 
problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or 
welfare of subjects.   
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the System Guide 
of each device model 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in 
the current version of the System Guide of each device model 
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is any inadequacy of a medical device with respect to 
its identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, 
and inadequate labeling. 
 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
 
Table 7: Criteria for Assessing Relationship of Study Device or Procedure to Adverse Event 

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Table 7: Criteria for Assessing Relationship of Study device/Procedure to Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
- the event has no temporal relationship with the use of the study device or the 
procedures; 
- the serious event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected by the 
device or procedure; the serious event can be attributed to another cause (e.g. an 
underlying 
or concurrent illness/ clinical condition, an effect of another device, drug, treatment 
or other risk factors); 
- the event does not depend on a false result given by the study device used for 
diagnosis, when applicable; harms to the subject are not clearly due to use error; 
- In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious 
event. 
Unlikely Related 
The relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be 
obtained. 
Possibly Related 
The relationship with the use of the study device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). 
Cases were relatedness cannot be assessed or no information has been obtained 
should also be classified as possible. 
Probably Related 
The relationship with the use of the study device seems relevant and/or the event 
cannot reasonably explained by another cause, but additional information may be 
obtained. 

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Table 7: Criteria for Assessing Relationship of Study device/Procedure to Adverse Event 
Causal Relationship 
The serious event is associated with the study device or with procedures beyond 
reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
- the event has a temporal relationship with study device use/application or 
procedures; 
- the event involves a body-site or organ that 
o the study device or procedures are applied to; 
o the study device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the study device used for diagnosis, 
when applicable; 
- In order to establish the relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious event. 
20.1. Investigator Reporting Requirements 
When reporting an Adverse Event the investigator will indicate the diagnosis of the event and 
correlating signs and symptoms on the adverse event case report form.  Individual signs and 
symptoms and treatment/intervention/diagnostic testing should not be reported as separate 
adverse events, instead be reported as supporting documentation on the AE CRF.  Additionally, 
it is not necessary to report an underlying disease that was present at baseline (i.e., CHF, AF, 
hypertension, chronic anemia, etc.).  However, any increase in the severity of the underlying 
disease may require reporting, if at the determination of the investigator, it is relevant to the 
study. If possible, death should not be recorded as an AE, but should only be reflected as an 
outcome of a specific SAE (see Table 66 for AE definitions).  
 
In-patient hospitalization is defined as the subjects being admitted to the hospital, with the 
following exceptions. 
• A hospitalization that is uncomplicated and elective/planned (i.e., planned prior to 
enrollment) does not have to be reported as an SAE. 
• If complications or AEs occur during an elective/planned (i.e., planned prior to enrollment) 
hospitalization after enrollment, the complications and AEs must be reported as AEs or 
SAEs if they meet the protocol-specified definitions. However, the original 
elective/planned hospitalization(s) itself should not be reported as an SAE. 
 

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Adverse experiences that require reporting by the investigator to the sponsor include any 
adverse event with clinical symptoms that could possibly be contributed to any of the following: 
• The WATCHMAN FLX device; 
• The WATCHMAN FLX implant procedure; 
• The use of medications including warfarin, or other equivalent oral anticoagulant per 
institution’s protocol, clopidogrel or aspirin (i.e., gastrointestinal bleeding due to 
warfarin or an allergic reaction to clopidogrel); 
• Any WATCHMAN FLX related procedures (i.e., clinical complications from TEE or 
other procedure required by labeling) 
The following adverse events will also be reported: 
• Neurological events including, but not limited to, stroke, TIA or seizure which are not 
pre-study conditions 
• Any events possibly related to stroke/TIA, systemic embolization, death, etc.  
• Thrombosis   
• Bleeding complications requiring intervention or transfusion of blood.  
Please refer to 错误!未找到引用源。 for definitions of stroke/TIA and classification of 
bleeding events. Each adverse event will be evaluated by the investigator for relatedness and 
seriousness.   
The communication requirements for reporting to BSC are as shown in Table : 
 
Table 8: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Unanticipated Adverse Device Effect 
/Unanticipated Serious Adverse 
Device Effect  
 
Complete AE eCRF page with 
all available new and updated 
information. 
 
Provide all relevant source 
documentation (unidentified) 
for reported event 
d) Within 24hours of first 
becoming aware of the event. 
e) Terminating at the end of the 
study 
Serious Adverse Event including 
Serious Adverse Device Effects 
Complete AE eCRF page with 
all available new and updated 
information 
f) Within 24 hours  of first 
becoming aware of the event or 
as per local/regional 
regulations. 
g) Reporting required through the 
end of the study 
Provide all relevant source 
documentation (unidentified) 
for reported event if required 
by medical reviewer. 
h) When documentation is 
available 
Adverse Event including Adverse 
Device Effects 
Complete AE eCRF page, 
which contains such 
information as date of AE, 
treatment of AE resolution, 
i) No later than 10 working days 
after becoming aware of the 
information 

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Table 8: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
assessment of seriousness and 
relationship to the device 
j) Reporting required through the 
end of the study.  
Device Deficiencies (including but 
not limited to failures, malfunctions, 
and product nonconformities) 
Note: Any Investigational Device 
Deficiency that might have led to a 
serious adverse event if a) suitable 
action had not been taken or b) 
intervention had not been made or c) 
if circumstances had been less 
fortunate is considered a reportable 
event. 
Complete applicable Device 
Deficiency CRF page with all 
available new and updated 
information. 
 
Provide all relevant source 
documentation (unidentified) 
for reported event if required 
by medical reviewer. 
k) Investigators should report 
within 24hours of first 
becoming aware of the event 
and as per local/regional 
regulations 
l) Reporting required through the 
end of the study 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
20.2. Boston Scientific Device Deficiencies 
All device deficiencies will be documented and reported to BSC on the appropriate eCRF 
within 24hours of first becoming aware of the event.  Device deficiencies are not to be reported 
as adverse events. However, if there is an adverse event that results from a device deficiency, 
that specific event would be recorded on the appropriate eCRF.  If possible, the device(s) 
should be returned to BSC for analysis. If it is not possible to return the device, the investigator 
should document why the device was not returned and the final disposition of the device. 
Device deficiencies should also be documented in the subject’s medical record. 
20.3. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
BSC is responsible for reporting serious adverse event and device deficiency information to 
all participating investigators and regulatory authorities, as applicable. The Principal 
Investigator is responsible for informing the IRB/EC, and regulatory authorities of U(S)ADE 
and SAE as per local/regional requirements. 
BSC shall notify all participating study centers if SAEs/SADEs and device deficiency occur 
which imply a possible increase in the anticipated risk of the procedure or use of the device or 
if the occurrence of certain SAEs/SADEs demands changes to the protocol or the conduct of 
the study in order to further minimize the unanticipated risks. 
21. Committees 
21.1. Safety Monitoring Process 
The BSC Medical Safety group will provide safety oversight and classify individual events. 
During regularly scheduled monitoring visits, clinical research monitors will support the 
dynamic reporting process through their review of source document information. 

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The BSC Medical Safety group includes physicians with expertise in Electrophysiology (EP), 
and/ or Cardiology, as well as other healthcare professionals with the necessary therapeutic 
and subject matter expertise to evaluate and classify the events into the categories outlined 
above. 
22. Suspension or Termination 
This study may be terminated at any time. Upon completion or termination, all data must be 
returned to the sponsor. 
23. Publication Policy 
The results of this study may be submitted in the form of abstracts to international and/or 
national congresses and/or in the form of publications to scientific journals. Publication policy 
will be, at a minimum, dependent on the number of complete patient datasets per site. Boston 
Scientific is committed to supporting publication of results of Boston Scientific-sponsored 
clinical research investigations in written or oral publications. Boston Scientific shall do its 
best to support proposals for sub-analysis and to include as many participating investigators 
despite the fact that authorship cannot be guaranteed. Therefore clinical investigators are 
encouraged to identify topics of interest and initiate publications on their own or the pooled 
data. This will be done in close cooperation with the Sponsor and with the International Study 
Chairman or/and an Executive committee, if any has been defined. No abstract(s) or article(s) 
can be submitted for publication without prior authorization from the Sponsor. In accordance 
with the Corporate Policy on the Conduct of Human Subject Research, Boston Scientific 
requires disclosure of its involvement as a sponsor or financial supporter in any publication or 
presentation relating to a Boston Scientific study or its results. In accordance with the 
Corporate Policy for the Conduct of Human Subject Research, Boston Scientific will submit 
study results for publication (regardless of study outcome) following the conclusion or 
termination of the study. Boston Scientific Corporation adheres to the Contributorship Criteria 
set forth in the Uniform Requirements of the International Committee of Medical Journal 
Editors (ICMJE; http://www.icmje.org). In order to ensure the public disclosure of study 
results in a timely manner, while maintaining an unbiased presentation of study outcomes, 
Boston Scientific personnel may assist authors and investigators in publication preparation 
provided the following guidelines are followed. 
• All authorship and contributorship requirements as described above must be followed. 
• BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  

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24. Bibliography 
1. 
Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and 
future incidence and prevalence of atrial fibrillation in the u.S. Adult population. The 
American journal of cardiology. 2013;112:1142-1147 
2. 
Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. 
Acc/aha/esc 2006 guidelines for the management of patients with atrial fibrillation--
executive summary: A report of the american college of cardiology/american heart 
association task force on practice guidelines and the european society of cardiology 
committee for practice guidelines (writing committee to revise the 2001 guidelines 
for the management of patients with atrial fibrillation). J Am Coll Cardiol. 
2006;48:854-906 
3. 
Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, et al. 
Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on 
the quality of international normalized ratio control achieved by centers and countries 
as measured by time in therapeutic range. Circulation. 2008;118:2029-2037 
4. 
Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW. Factors associated with 
ischemic stroke during aspirin therapy in atrial fibrillation: Analysis of 2012 
participants in the spaf i-iii clinical trials. The stroke prevention in atrial fibrillation 
(spaf) investigators. Stroke. 1999;30:1223-1229 
5. 
White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, et al. Comparison of 
outcomes among patients randomized to warfarin therapy according to anticoagulant 
control: Results from sportif iii and v. Arch Intern Med. 2007;167:239-245 
6. 
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. 
Dabigatran versus warfarin in patients with atrial fibrillation. The New England 
journal of medicine. 2009;361:1139-1151 
7. 
Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified 
events in the re-ly trial. The New England journal of medicine. 2010;363:1875-1876 
8. 
Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, et al. Intracranial 
hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or 
dabigatran: The re-ly trial. Stroke. 2012;43:1511-1517 
9. 
FDA Drug Safety Communication: Update on the risk for serious bleeding events 
with the anticoagulant Pradaxa (dabigatran) FDSC. 
http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm.  
10. 
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban 
versus warfarin in nonvalvular atrial fibrillation. The New England journal of 
medicine. 2011;365:883-891 
11. 
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. 
Apixaban versus warfarin in patients with atrial fibrillation. The New England journal 
of medicine. 2011;365:981-992 
12. 
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. 
Edoxaban versus warfarin in patients with atrial fibrillation. The New England 
journal of medicine. 2013;369:2093-2104 
13. 
Reddy VY, Doshi SK, Sievert H, Buchbinder M, Neuzil P, Huber K, et al. 
Percutaneous left atrial appendage closure for stroke prophylaxis in patients with 
atrial fibrillation: 2.3-year follow-up of the protect af (watchman left atrial appendage 

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system for embolic protection in patients with atrial fibrillation) trial. Circulation. 
2013;127:720-729 
14. 
Rhythm H. The heart rhythm society’s 34th annual scientific sessions. 2013  
15. 
Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial 
appendage closure: Results from the watchman left atrial appendage system for 
embolic protection in patients with af (protect af) clinical trial and the continued 
access registry. Circulation. 2011;123:417-424 
16. 
Holmes DR, Jr., Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, et al. 
Prospective randomized evaluation of the watchman left atrial appendage closure 
device in patients with atrial fibrillation versus long-term warfarin therapy: The 
prevail trial. J Am Coll Cardiol. 2014;64:1-12 
17. 
Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for 
ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: The swedish 
atrial fibrillation cohort study. Eur. Heart J. 2012;33:1500-1510 
25. Abbreviations and Definitions  
25.1. Definitions 
25.1.1. Stroke/TIA definitions 
Broad definitions: 
Neurological deficit: An acute episode of a focal or global neurological deficit with at least 
one of the following: 
• 
Change in the level of consciousness 
• 
Hemiplegia 
• 
Hemiparesis 
• 
One-sided numbness or sensory loss 
• 
Dysphasia or aphasia 
• 
Hemianopia 
• 
Amaurosis fugax 
• 
Any other neurological signs or symptoms consistent with stroke 
 
In addition, there are no other readily identifiable non-stroke cause for the clinical 
presentation (e.g., brain tumor, trauma, infection, hypoglycemia, peripheral lesion, 
pharmacologic influences), to be determined by or in conjunction with the designated 
neurologist.  
 
Stroke: Stroke is defined by either one of the following: 
• 
Duration of focal or global neurological deficit >24 h. 
• 
Duration of focal or global neurological deficit <24 h in case of imaging-documented 
new hemorrhage or infarct. 
• 
A neurological deficit resulting in death;  
 

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Transient ischemic attack: A TIA is defined by any neurological deficit not satisfying the 
above criteria for stroke, specifically a deficit lasting <24 h without imaging-documented 
new hemorrhage or infarct. 
 
 
Stroke diagnostic criteria:  
• Rapid onset of a focal or global neurological deficit with at least one of the following: 
change in level of consciousness, hemiplegia, hemiparesis, numbness or sensory loss 
affecting one side of the body, dysphasia or aphasia, haemianopia, amaurosis fugax, or 
other neurological signs or symptoms consistent with stroke;  
• Duration of a focal or global neurological deficit ≥24 h; OR, 24 h, if therapeutic 
intervention(s) were performed (e.g. thrombolytic therapy or intracranial angioplasty); 
OR available neuroimaging documents a new haemorrhage or infarct; OR the 
neurological deficit results in death  
• No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain 
tumor, trauma, infection, hypoglycaemia, peripheral lesion, pharmacological 
influences) 
• Confirmation of the diagnosis by at least one of the following: 
o Neurology or neurosurgical specialist 
o Neuroimaging procedure (MR or CT scan or cerebral angiography) 
o Lumbar puncture (i.e. spinal fluid analysis diagnostic of intracranial 
haemorrhage) 
Stroke Types: 
Ischemic: An episode of neurological dysfunction caused by focal cerebral, spinal, or retinal 
infarction 
Hemorrhagic: 
• intracerebral: rapidly developing clinical signs of neurological dysfunction attributable 
to a focal collection of blood within the brain parenchyma or ventricular system that is 
not caused by trauma. 
• subarachnoid:  rapidly developing signs of neurological dysfunction and/or headache 
because of bleeding into the subarachnoid space (the space between the arachnoid 
membrane and the pia mater of the brain or spinal cord), which is not caused by trauma. 
Silent infarction: Imaging or neuropathological evidence of CNS infarction, without a history 
of acute neurological dysfunction attributable to the lesion. 
Stroke caused by cerebral venous thrombosis: Infarction or hemorrhage in the brain, spinal 
cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs 
caused by reversible edema without infarction or hemorrhage do not qualify as stroke. 
Not otherwise specified: an episode of acute neurological dysfunction presumed to be caused 
by ischemia or hemorrhage, persisting ≥ 24 hours or until death, but without sufficient 
evidence to be classified as one of the above 
(from Kappetein, A.P., et al., J Am Coll Cardiol, 2012. 60(15): p. 1438-54) 
25.1.2. Classification of Bleeding events 
In response to the need to develop, disseminate, and ultimately adopt standardized bleeding 
end-point definitions for subjects receiving antithrombotic therapy, the Bleeding Academic 

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Research Consortium (BARC) convened in February 2010 at the US Food and Drug 
Administration (FDA) headquarters in White Oak, MD. BARC effort brought together 
representatives from academic research organizations, the FDA, the National Institutes of 
Health, and pharmaceutical and cardiovascular device manufacturers and independent 
physician thought leaders in the field of cardiovascular disease to develop consensus bleeding 
definitions that would be useful for cardiovascular clinical trials. Application of these 
definitions is recommended for both clinical trials and registries:  
 
Type 0: 
No bleeding 
Type 1: 
Bleeding that is not actionable and does not cause the subject 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 
subject 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: 
o Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided hemoglobin 
drop is related to bleed) 
o Any transfusion with overt bleeding 
Type 3b: 
o Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is 
related to bleed), 
o Cardiac tamponade, 
o Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid), 
o Bleeding requiring intravenous vasoactive agents 
Type 3c: 
o Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal), 
o Subcategories confirmed by autopsy or imaging or lumbar puncture, 
o Intraocular bleed compromising vision. 
Type 4: 
• 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, 

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• 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 
 
(from Circulation. 2011; 123(23): 2736-47) 
For the purposes of the HK FLX trial, a BARC score of Type 3 a, b, c and 5 a and b will be 
considered a major bleed.