Protection Against Embolism for Non-valvular AF Subjects: Investigational Device Evaluation of the WATCHMAN FLX™ LAA Closure Technology
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Boston Scientific Corporation

Form/Template 90702637 Rev/Ver AI 
PINNACLE FLX Protocol #91081206, Rev/Ver AF 
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THESE DOCUMENTS ARE THE PROPERTY OF BOSTON SCIENTIFIC CORPORATION AND SHALL NOT BE REPRODUCED, 
DISTRIBUTED, DISCLOSED OR USED FOR MANUFACTURE OR SALE OF APPARATUS WITHOUT THE EXPRESS WRITTEN 
CONSENT OF BOSTON SCIENTIFIC CORPORATION. 
 
 
Protection against Embolism for non-valvular AF Patients: Investigational 
Device Evaluation of the WATCHMAN FLX™ LAA Closure Technology 
 
CLINICAL INVESTIGATION PLAN 
 
G150200 
 
Sponsored By 
Boston Scientific Corporation 
300 Boston Scientific Way 
Marlborough, MA 01752 
 
 
 
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 
Robert Shipley, Ph.D. 
Fellow, Clinical Science 
Boston Scientific WATCHMAN 
300 Boston Scientific Way 
Marlborough, MA 01752 
(508) 683-4000 
 
 
Coordinating Principal 
Investigators 
Dr. Saibal Kar 
Cedars Sinai Medical Center 
(310) 423-3977 
8631 West Third Street 
Room 415E 
Los Angeles, CA  90048 
karsk@cshs.org 
 
Dr. Shephal Doshi 
Pacific Heart 
(310) 829-7678 
2001 Santa Monica Blvd Suite 280 West 
Santa Monica, CA  90404 
skdoshi@pacificheart.com 
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.  
 
 
 
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Original Release: August 17, 2015 
Current Version: April 12, 2018 
Revision History 
Revision Number 
Release Date 
Section 
Change 
Reason for Change 
AA 
14-Dec-2015 
All 
Revised the document 
to alpha 
IDE approval 
AB 
18-Dec, 2015 
12 
Change method of 
calculation for the rate 
of the Primary 
Effectiveness Endpoint 
to exclude implant 
failures from rate 
denominator. 
FDA input.  
 
 
9 
Changed the echo 
exclusion criteria of 
pericardial effusion > 
2mm to > 5mm (and/or 
other criteria listed in 
9.4) 
National PI feedback 
based on experience in 
previous WATCHMAN 
trials.  The change will 
avoid unnecessarily 
excluding subjects in 
the trial 
 
 
20 
Clarifications 
Editorial 
 
 
25 
Added a section for 
CMS 
Required for IDE 
coverage 
 
 
8 
Decreased sites 
participating from up to 
40 to up to 35 
Site selection complete 
AC 
12-Jan-2016 
8 
Increased the number of 
sites from up to 35 to up 
to 40 
Align with IDE 
approval 
 
13-Jan-2016 
12 
Corrected secondary 
endpoint hypothesis 
Typo 
AD 
27-Jan-2016 
9 
Added exclusion for 
pregnant subjects 
Clarification 
AE 
7-MAR-2016 
9 
Added CHADS2 score 
and Increased 
CHA2DS2-VASc 
score to 3 
Based on the national 
coverage decision 
(NCD) 
 
 
2 
Added Access system as 
test device for Japan 
only 
Clarification 
 
 
11 
Updated medication 
regimen section 
 
Clarification 
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Revision History 
Revision Number 
Release Date 
Section 
Change 
Reason for Change 
AF 
12-APR-2018 
11 
Added DOAC as the 
post implant drug 
regimen 
Study WM with most 
widely used 
anticoagulants 
 
 
All 
Removed Japan and 
made minor 
clarifications throughout 
US only trial 
 
 
8 
Increased number of 
sites to 45 and roll-ins 
to 90 
Requirement of 2 roll-
ins per site 
 
 
9 
Inclusion criteria 
changed from 
CHA2DS2-VASc 3 or 
greater to CHA2DS2-
VASc 2 or greater for 
males or CHA2DS2-
VASc 3 or greater for 
female 
Align with IDE 
approval Study Design 
Consideration 
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2. Protocol Synopsis 
PINNACLE FLX: Protection against Embolism for non-valvular AF 
Subjects: Investigational Device Evaluation of the WATCHMAN FLX™ 
LAA Closure Technology 
Objective(s) 
The primary objective of this study is to establish the safety and 
effectiveness of the WATCHMAN FLX™ Left Atrial Appendage 
Closure (LAAC) Device for subjects with non-valvular atrial fibrillation 
who are eligible for anticoagulation therapy to reduce the risk of stroke.  
Planned 
Indication(s) for 
Use  
The WATCHMAN FLX Device is indicated to reduce the risk of 
thromboembolism from the left atrial appendage in subjects with non-
valvular atrial fibrillation who: 
• Are at increased risk for stroke and systemic embolism based on 
CHADS2 or CHA2DS2-VASc scores and are recommended for 
anticoagulation therapy; 
• Are deemed by their physicians to be suitable for anticoagulation 
therapy; and 
• Have an appropriate rationale to seek a non-pharmacologic alternative 
to anticoagulation therapy, taking into account the safety and 
effectiveness of the device compared to anticoagulation therapy.  
Test 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 investigation 
to establish the safety and effectiveness of the WATCHMAN FLX 
LAAC Device for subjects with non-valvular atrial fibrillation who are 
eligible for long-term anticoagulation therapy to reduce the risk of 
stroke but who have a rationale to seek a non-pharmacologic alternative.  
Planned 
Number of 
Subjects 
A maximum of 490 subjects will be enrolled in the study. 
Planned 
Number of 
Up to 45 investigational centers in the United States. 
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PINNACLE FLX: Protection against Embolism for non-valvular AF 
Subjects: Investigational Device Evaluation of the WATCHMAN FLX™ 
LAA Closure Technology 
Centers / 
Countries 
Primary 
Effectiveness 
Endpoint 
The rate of effective LAA closure defined as any peri-device flow < 
5mm demonstrated by TEE at 12 months. 
 
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. 
Secondary 
Effectiveness 
Endpoint 
The occurrence of ischemic stroke or systemic embolism at 24 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. 
Method of 
Assigning 
Subjects to 
Treatment 
A subject who signs informed consent is considered enrolled in the 
study. 
Follow-up 
Schedule 
Study procedures and follow-up visits will occur as follows: 
• Enrollment Visit  
• WATCHMAN FLXTM Implant (within 3 calendar days of 
Enrollment TEE)  
• 45-day Follow-up (45 ± 15 days) 
• 6-Month Follow-up (180 ± 30 days) 
• 12-Month Follow-up (365 ± 30 days) 
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PINNACLE FLX: Protection against Embolism for non-valvular AF 
Subjects: Investigational Device Evaluation of the WATCHMAN FLX™ 
LAA Closure Technology 
• 18-Month Follow-up (540 ± 30 days) 
• 24-Month Follow-up (730 ± 60 days) 
The study will be considered complete with regards to the primary 
efficacy endpoint after at least 50% of enrolled subjects complete the 18 
month visit. 
Study Duration The duration of the study is expected to last approximately 38 months.  
The duration of individual subject participation is expected to last 
approximately 24 months but may vary per subject (withdrawal, death, 
etc.). 
Required 
Medication 
Therapy 
Direct oral anticoagulant (DOAC), aspirin, clopidogrel , heparin, and 
antibiotics, as applicable and outlined within the Directions for Use 
(DFU), this protocol, and institutional procedure. 
Key Inclusion 
Criteria 
1. The subject is 18 years of age or older. 
2. The subject has documented paroxysmal, persistent, permanent 
or long-term/longstanding persistent non-valvular atrial 
fibrillation (i.e., the subject has not been diagnosed with 
rheumatic mitral valvular heart disease). 
3. The subject is eligible for the defined protocol pharmacologic 
regimen of anticoagulation and antiplatelet therapy following 
WATCHMAN FLX Device implant. 
4. The subject is eligible to come off of anticoagulation therapy if 
the LAA is sealed (i.e. the subject has no other conditions that 
would require long-term anticoagulation therapy suggested by 
current standard medical practice). 
5. The subject has a calculated CHA2DS2-VASc score of 2 or 
greater for males or 3 or greater for females. 
6. The subject is able to understand and willing to provide written 
informed consent to participate in the trial. 
7. The subject is able and willing to return for required follow-up 
visits and examinations. 
Key Exclusion 
Criteria 
1. Subjects who are currently enrolled in another investigational study 
or registry that would directly interfere with the current study, except 
when the subject is participating in a mandatory governmental 
registry, or a purely observational registry with no associated 
treatments. Each instance must be brought to the attention of the 
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PINNACLE FLX: Protection against Embolism for non-valvular AF 
Subjects: Investigational Device Evaluation of the WATCHMAN FLX™ 
LAA Closure Technology 
sponsor to determine eligibility, regardless of type of co-enrollment 
being proposed. 
2. The subject requires long-term anticoagulation therapy for reasons 
other than AF-related stroke risk reduction, for example due to an 
underlying hypercoagulable state (i.e., even if the device is 
implanted, the subjects would not be eligible to discontinue 
anticoagulation due to other medical conditions requiring chronic 
anticoagulation therapy). 
3. The subject is contraindicated for short-term anticoagulant therapy 
with DOAC post-implant.  
4. The subject is contraindicated to aspirin and/or clopidogrel.  
5. The subject is indicated for long-term clopidogrel therapy or has 
taken clopidogrel within 7 days prior to the WATCHMAN FLXTM 
Device implant.  
6. The subject had or is planning to have any cardiac or non-cardiac 
invasive or surgical procedure within 30 days prior to or 60 days 
after the WATCHMAN FLX Device implant (including, but not 
limited to: cardioversion, coronary angiogram with or without 
percutaneous coronary intervention (PCI), cardiac ablation, cataract 
surgery, endoscopy, etc.).  
7. The subject had a prior stroke (of any cause, whether ischemic or 
hemorrhagic) or transient ischemic attack (TIA) within the 90 days 
prior to enrollment.  
8. The subject has had a myocardial infarction (MI) documented in the 
clinical record as either a non-ST elevation MI (NSTEMI) or as an 
ST-elevation MI (STEMI), with or without intervention, within 90 
days prior to enrollment. 
9. The subject has a history of atrial septal repair or has an ASD/PFO 
device.  
10. The subject has implanted mechanical valve prosthesis in any 
position. 
11. The subject has New York Heart Association Class IV Congestive 
Heart Failure at the time of enrollment.  
12. The subject is of childbearing potential and is, or plans to become 
pregnant during the time of the study (method of assessment upon 
study physician’s discretion). 
13. The subject has a documented life expectancy of less than two years. 
ECHO 
Exclusion 
Criteria 
1. The subject has LVEF < 30%. 
2. The subject has intracardiac thrombus, LAA sludge (gelatinous, non-
adherent, intracavitary echo-density more layered than dense 
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PINNACLE FLX: Protection against Embolism for non-valvular AF 
Subjects: Investigational Device Evaluation of the WATCHMAN FLX™ 
LAA Closure Technology 
 
spontaneous echo contrast (SEC) seen continuously throughout 
cardiac cycle) or dense SEC visualized by TEE within 3 calendar 
days prior to implant. 
3. The subject has an existing pericardial effusion with a 
circumferential echo-free space > 5mm, and/or the subject has 
signs/symptoms of acute or chronic pericarditis, and/or there is 
evidence (clinically or echocardiographically) of tamponade 
physiology.  
4. The subject has a high- risk patent foramen ovale (PFO) with an 
atrial septal aneurysm excursion > 15mm or length > 15mm. 
5. The subject has a high-risk PFO with a large shunt defined as early, 
within 3 beats and/or substantial passage of bubbles. 
6. The subject has significant mitral valve stenosis (i.e., MV <1.5 cm2). 
7. The subject has complex atheroma with mobile plaque of the 
descending aorta and/or aortic arch. 
8. The subject has a cardiac tumor. 
Multiple 
Interventions 
During Index 
Procedure 
No concomitant procedures are to be performed at the time of the 
WATCHMAN FLXTM implant procedure. This includes, but is not 
limited to, cardiac ablation procedures, transcutaneous valve procedures, 
cardioversions, pacemaker or ICD generator change, etc. 
 
 
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Statistical Test 
Method 
Hypotheses testing in this study will use standard statistical 
methodology. Each primary endpoint will be assessed vs. a performance 
goal.  To declare success, the two primary endpoints must be met. The 
details of each endpoint analysis are listed in the table below.  
Endpoint 
Assessment 
period 
Expected Rate 
Delta 
Performance 
Goal 
Min/Max 
Observable rate 
Test 
(α=5%) 
Expected 
Primary 
Effectiveness 
12-month 
follow-up 
visit 
99.3% 
2.3% 
97.0% 
98.8% 
One-sided exact 
test 
20% 
Primary 
Safety 
7 days or 
hospital 
discharge, 
whichever 
is later 
1.68% 
2.53%  
4.21% 
2.5% 
One-sided exact 
test 
0% 
Secondary 
Effectiveness 
0 to 2 yrs. 
4.7%  
4.0% 
8.7% 
6.2% 
Pointwise log-log 
upper confidence 
limit of Kaplan-
Meier rate 
20% 
 
 
 
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3. Table of Contents 
1. 
TITLE PAGE  .......................................................................................................................1 
2. 
PROTOCOL SYNOPSIS .........................................................................................................5 
3. 
TABLE OF CONTENTS .......................................................................................................11 
3.1. Table of Figures .....................................................................................................15 
3.2. Table of Tables ......................................................................................................15 
4. 
INTRODUCTION ................................................................................................................16 
4.1. Background ............................................................................................................16 
4.2. WATCHMAN Therapy ........................................................................................17 
5. 
DEVICE DESCRIPTION ......................................................................................................22 
 
STUDY ...............................................................................................................................26 
6. 
OBJECTIVES .....................................................................................................................26 
7. 
STUDY ENDPOINTS ...........................................................................................................26 
7.1. Primary Effectiveness Endpoint ..........................................................................26 
7.2. Primary Safety Endpoint ......................................................................................26 
7.3. Secondary Effectiveness Endpoint ......................................................................26 
7.4. Additional analysis ................................................................................................26 
8. 
STUDY DESIGN .................................................................................................................27 
8.1. Scale and Duration ................................................................................................27 
8.2. Treatment Assignment .........................................................................................27 
8.3. Justification for the Study Design ........................................................................27 
9. 
SUBJECT SELECTION ........................................................................................................28 
9.1. Study Population and Eligibility ..........................................................................28 
9.2. Inclusion Criteria ..................................................................................................28 
9.3. Exclusion Criteria .................................................................................................29 
9.4. Echo Exclusion Criteria ........................................................................................30 
10. SUBJECT ACCOUNTABILITY .............................................................................................30 
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10.1. Point of Enrollment ...............................................................................................30 
10.2. Withdrawal (point of study exit) ..........................................................................30 
10.3. Subject Status and Classification .........................................................................31 
10.3.1. Screen Failure ...........................................................................................31 
10.3.2. Intent .........................................................................................................31 
10.3.3. Attempt .....................................................................................................32 
10.3.4. Implant ......................................................................................................33 
10.4. Enrollment Controls .............................................................................................33 
11. STUDY METHODS .............................................................................................................33 
11.1. Data Collection ......................................................................................................33 
12. INFORMED CONSENT ........................................................................................................35 
12.1. Informed Consent .................................................................................................35 
12.2. Enrollment Visit ....................................................................................................35 
12.3. Stroke Assessments ...............................................................................................36 
12.4. LAA Imaging (e.g. Fluoro/TEE/TTE) .................................................................36 
i) 
Transthoracic Echocardiogram (TTE) ...............................................................37 
ii) 
Transesophageal Echocardiogram (TEE)...........................................................37 
a. 
Stroke or Systemic Embolism TEE .....................................................................37 
b. 
Device Thrombus TEE .........................................................................................38 
12.5. Implant Procedure ................................................................................................38 
12.6. Study Medication Regimen (for subjects classified as Implant) .......................39 
12.7. Follow-up Procedures ...........................................................................................41 
12.7.1. Follow-Up (45-Days) ................................................................................41 
12.7.1.1. For Subjects classified as Intent or Attempts ...........................41 
12.7.1.2. For Subjects classified as Implants ..........................................42 
12.7.2. Office Visit Follow-up (6-month+/- 15 days) ..........................................42 
12.7.3. Office Visit Follow-up (12-month+/- 30 days) ........................................43 
12.7.4. Office Visit Follow-Up (18-months+/- 30 days) ......................................43 
12.7.5. Office visit Follow-Up (24-months) .........................................................43 
12.8. Study Exit ...............................................................................................................44 
13. STATISTICAL CONSIDERATIONS ......................................................................................45 
13.1. Endpoints ...............................................................................................................45 
13.1.1. Primary Effectiveness Endpoint ...............................................................45 
13.1.1.1. Hypotheses ...............................................................................45 
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13.1.1.2. Sample Size ..............................................................................45 
13.1.1.3. Statistical Methods ...................................................................45 
13.1.2. Primary Safety Endpoint ...........................................................................46 
13.1.2.1. Sample Size ..............................................................................46 
13.1.2.2. Statistical Methods ...................................................................46 
13.1.3. Secondary Effectiveness Endpoint ...........................................................47 
13.1.3.1. Hypotheses ...............................................................................47 
13.1.3.2. Sample Size ..............................................................................47 
13.1.3.3. Statistical Methods ...................................................................48 
13.2. General Statistical Methods .................................................................................49 
13.2.1. Analysis Sets .............................................................................................49 
13.2.2. Control of Systematic Error/Bias ..............................................................49 
13.2.3. Control of Type-I Error ............................................................................49 
13.2.4. Number of Subjects per Investigative Site ...............................................49 
13.3. Additional Data Analyses .....................................................................................49 
13.3.1. Justification of Pooling .............................................................................49 
13.3.2. Subgroup Analyses ...................................................................................50 
13.3.3. Multivariable Analyses .............................................................................50 
13.3.4. Other Analyses ..........................................................................................51 
13.3.5. Changes to Planned Analyses ...................................................................51 
14. DATA MANAGEMENT .......................................................................................................51 
14.1. Data Collection, Processing, and Review ............................................................51 
14.2. Data Retention .......................................................................................................52 
14.3. Core Laboratories .................................................................................................52 
15. AMENDMENTS ..................................................................................................................52 
16. DEVIATIONS .....................................................................................................................53 
17. DEVICE/EQUIPMENT ACCOUNTABILITY .........................................................................53 
18. COMPLIANCE ....................................................................................................................54 
18.1. Statement of Compliance ......................................................................................54 
18.2. Investigator Responsibilities ................................................................................54 
18.2.1. Delegation of Responsibility ....................................................................56 
18.3. Institutional Review Board/ Ethics Committee ..................................................56 
18.4. Sponsor Responsibilities .......................................................................................56 
18.4.1. Role of Boston Scientific Representatives ...............................................57 
18.5. Insurance ................................................................................................................57 
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19. MONITORING ....................................................................................................................58 
20. POTENTIAL RISKS AND BENEFITS ...................................................................................58 
20.1. Anticipated Adverse Events .................................................................................58 
20.2. Anticipated Adverse Device Effects .....................................................................59 
20.3. Possible Interactions with Concomitant Medical Treatments ..........................59 
20.4. Risk Minimization Actions ...................................................................................60 
20.5. Anticipated Benefits ..............................................................................................60 
20.6. Risk to Benefit Rationale ......................................................................................60 
21. SAFETY REPORTING .........................................................................................................61 
21.1. Reportable Events by investigational site to Boston Scientific .........................61 
21.2. Definitions and Classification ..............................................................................61 
21.3. Relationship to Study Device ...............................................................................65 
21.4. Investigator Reporting Requirements .................................................................67 
21.5. Boston Scientific Device Deficiencies (DDs) ........................................................69 
21.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators ...................69 
21.7. Clinical Event Committee Events (CEC) – Documentation ..............................69 
21.7.1. Stroke Reporting Documentation Recommendations ..............................70 
21.8. Device Related Thrombus ....................................................................................70 
21.9. Death Reporting ....................................................................................................71 
22. INFORMED CONSENT ........................................................................................................72 
23. COMMITTEES ...................................................................................................................73 
23.1. Safety Monitoring Process ....................................................................................73 
23.2. Clinical Events Committee ...................................................................................73 
23.3. Data Monitoring Committee ................................................................................74 
24. SUSPENSION OR TERMINATION ........................................................................................74 
23.1 Premature Termination of the Study ..................................................................74 
23.1.1 
Criteria for Premature Termination of the Study ......................................74 
23.2 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/ EC Approval .................................................................................................74 
23.3 Requirements for Documentation and Subject Follow-up ................................75 
23.4 Criteria for Suspending/Terminating a Study Site ............................................75 
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25. PUBLICATION POLICY ......................................................................................................75 
26. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS .................................................76 
26.1. Subject Reimbursement .......................................................................................76 
26.2. Compensation for Subject’s Health Injury ........................................................76 
27. BIBLIOGRAPHY .................................................................................................................76 
28. ABBREVIATIONS AND DEFINITIONS .................................................................................78 
28.1. Definitions ..............................................................................................................78 
28.1.1. Stroke/TIA definitions ..............................................................................78 
28.1.2. Classification of Bleeding events .............................................................79 
 
 
3.1. Table of Figures 
Figure 1: WATCHMAN Delivery System (Delivery Catheter & LAA Closure Device) ...... 23 
Figure 2: Subject Status and Data Collection Flow Chart ...................................................... 33 
Figure 3: WATCHMAN FLX Device Implant Pharmacologic Regimen .............................. 41 
 
3.2. Table of Tables 
Table 4.1: Description of WATCHMAN Products ................................................................ 17 
Table 4.2: Clinical Studies of the WATCHMANTM Device .................................................. 17 
Table 9-1: Inclusion Criteria ................................................................................................... 28 
Table 9-2: Exclusion Criteria .................................................................................................. 29 
Table 9-3: Echo Exclusion Criteria......................................................................................... 30 
Table 11-1: Data Collection Schedule .................................................................................... 34 
• 
Table 19-1: Anticipated Adverse Events ............................................................. 58 
Table 20.2-1: Definitions ........................................................................................................ 61 
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event .................................................................................................................... 66 
Table 20.4-1: Investigator Reporting Requirements ............................................................... 67 
 
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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. 
4.2. WATCHMAN Therapy 
Two generations of the WATCHMAN Closure Device with Delivery System, as identified in 
the Table 4.1, 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 4.1: 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 4.2 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 4.2: Clinical Studies of the WATCHMANTM Device 
Study 
Dates of Enrollment 
Enrolled 
Sites 
Follow-Up 
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Subjects 
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, 
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cardiovascular or unexplained death and systemic embolism (for Bayesian analysis, posterior 
probabilities are used to determine superiority; > 95% represents superiority). 
•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_ENREF_8 (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 
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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 
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. 
 
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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 CHA2DS2-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 
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 
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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. 
4.2.1. Initial WATCHMAN FLX EU LMR Experience 
The first iteration of the WATCHMAN FLX Device began a limited market release (LMR) 
in Europe on November 11, 2015. This LMR continued until March 29, 2016. During this 
period, WATCHMAN FLX was implanted in 213 patients at 23 European centers. The LMR 
was not a clinical trial so clinical results were generated by survey and case review.  The 
WATCHMAN FLX implant success rate was 94.0% (213/227) during the LMR and the 
adverse event rate was relatively low at 5.8% when accounting for all potential adverse 
events and the learning curve associated with a new device. Of interest was the overall device 
embolization rate of 3.8% (8/210). All embolized devices were retrieved percutaneously.  
The rate of embolization (3.8%) for this initial FLX iteration was greater than anticipated 
based on prospective risk assessment, as well as the historical rate experienced with the 
WATCHMAN (Gen 2.5) Device.  The rate of device embolizations in the PREVAIL 
randomized clinical study was <0.7%. 
 
Based on the European LMR experience with the earlier iteration of WATCHMAN FLX, 
Boston Scientific elected to make design enhancements to the device. These design 
enhancements were incorporated into the current WATCHMAN FLX Device (i.e., the device 
included the PINNACLE FLX trial). 
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.  
 
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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. 
5.2.Indications for Use 
The WATCHMAN FLX Device is indicated to reduce the risk of thromboembolism from the 
left atrial appendage (LAA) in patients with non-valvular atrial fibrillation who: 
• Are at increased risk for stroke and systemic embolism based on CHADS2 or 
CHA2DS2-VASc scores and are recommended for anticoagulation therapy; 
• Are deemed by their physicians to be suitable for anticoagulation therapy; and 
• Have an appropriate rationale to seek a non-pharmacologic alternative to 
anticoagulation therapy, taking into account the safety and effectiveness of the device 
compared to anticoagulation therapy. 
Contraindications 
Do not use the WATCHMAN FLX Device if: 
1. 
Intracardiac thrombus is visualized by TEE echocardiographic imaging. 
2. 
An atrial septal defect repair or closure device or a patent foramen ovale 
repair or closure device is present. 
3. 
The LAA anatomy will not accommodate a Closure Device (refer to the 
WATCHMAN FLX Device Selection guide in the WATCHMAN FLX DFU).  
4. 
The patient has a known hypersensitivity to any portion of the device material 
or the individual components (see Device Description in the WATCHMAN 
FLX DFU) such that use of the WATCHMAN FLX Device is contraindicated.  
5. 
Any of the customary contraindications for other percutaneous catheterization 
procedure (e.g. patient size too small for TEE probe or required catheters) or 
conditions (e.g., active infection, bleeding disorder) is present. 
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6. 
There are contraindications to the use of anticoagulation, aspirin, or 
clopidogrel . 
6. Study Objectives 
The primary objective of this study is to establish the safety and effectiveness of the 
WATCHMAN FLX™ Left Atrial Appendage Closure Device for patients with non-valvular 
atrial fibrillation who require treatment for potential thrombus formation. The WATCHMAN 
FLX™ Device is intended 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 who are eligible for anticoagulation therapy. 
7. Study Endpoints 
7.1. Primary Effectiveness Endpoint 
The rate of effective closure defined as any peri-device flow < 5mm demonstrated by TEE at 
12 months.  
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. 
7.3. Secondary Effectiveness Endpoint 
The occurrence of ischemic stroke or systemic embolism at 24 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. 
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8. Study Design 
This study is a prospective, non-randomized, multi-center investigation to establish the safety 
and effectiveness of the WATCHMAN FLX™ LAA Closure Device for subjects with non-
valvular atrial fibrillation who require treatment for potential thrombus formation. 
This study will be conducted at up to 45 centers in the United States.  Of the potential 490 
subjects, 400 will be enrolled in the main cohort.  The remaining 90 subjects will be Roll-in 
subjects. 
Investigators will include physicians with WATCHMAN (Gen 2.5) implant experience.  
Sites will be limited to two implanting investigators per institution.  All sites are required to 
enroll two Roll-in subjects prior to enrollment in the main cohort of subjects. The use of 
Roll-in subjects will allow physicians to gain experience with the WATCHMAN FLX 
implant procedure prior to beginning enrollment in the main study cohort. 
8.1. Scale and Duration 
Subjects will be followed through the enrollment period, at device implant, then at intervals 
of 45 days, 6 months, 12 months, 18 months and 24 months,  
It is anticipated that enrollment will be conducted over a period of 12 months.  
8.2. Treatment Assignment 
The study is designed to enroll subjects that meet all inclusion and no exclusion criteria. 
8.3. Justification for the Study Design 
The WATCHMAN LAA Closure Device with Delivery System and WATCHMAN Access 
System received FDA approval on March 13, 2015 and received CE mark on October 5, 
2005.  WATCHMAN FLX was chartered to enhance the user experience and acute safety 
profile for the WATCHMAN LAA Closure Technology compared to the current 
WATCHMAN LAAC Device (also called WATCHMAN Gen 2.5).  The PINNACLE FLX 
investigational device exemption (IDE) study is designed to collect safety and effectiveness 
data on the next-generation WATCHMAN Device (called WATCHMAN FLX). The implant 
of the Closure Device will be done according to the current indications and under direction of 
the WATCHMAN FLX DFU. Acute procedure-related information will be collected to 
assess safety; long-term follow-up visits at 12, 18, and 24 months will be used to assess long-
term safety and effectiveness. 
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9. Subject Selection  
9.1. Study Population and Eligibility  
Any subject who provides written informed consent is enrolled in the study. The subjects 
selected for participation will be from the investigators’ general subject population. The 
investigator has the responsibility for screening all potential subjects and selecting those who 
meet study inclusion criteria and do not meet any of the exclusion criteria as described in 
sections 9.2 and 9.3.  There are additional Echo exclusion criteria (section 9.4) that must be 
met.  All subjects will have their screening criteria assessed such that the baseline TEE is the 
final determination of eligibility. 
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (Table 9-1) will be given consideration for 
inclusion in this clinical investigation, provided no exclusion criterion (see Section 9.3) is 
met.  
Table 9-1: Inclusion Criteria 
Clinical 
Inclusion 
Criteria 
1. The subject is 18 years of age or older. 
2. The subject has documented paroxysmal, persistent, permanent or 
long-term/longstanding persistent non-valvular atrial fibrillation 
(i.e., the subject has not been diagnosed with rheumatic mitral 
valvular heart disease). 
3. The subject is eligible for the defined protocol pharmacologic 
regimen of anticoagulation and antiplatelet therapy following 
WATCHMAN FLX Device implant. 
4. The subject is eligible to come off of anticoagulation therapy if the 
LAA is sealed (i.e. the subject has no other conditions that would 
require long-term anticoagulation therapy suggested by current 
standard medical practice). 
5. The subject has a calculated CHA2DS2-VASc score of 2 or greater 
for males or 3 or greater for females. 
6. The subject is able to understand and willing to provide written 
informed consent to participate in the trial. 
7. The subject is able and willing to return for required follow-up 
visits and examinations. 
 
 
 
 
 
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9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9-2) will be excluded from this 
clinical study. 
Table 9-2: Exclusion Criteria 
Clinical 
Exclusion 
Criteria 
1. Subjects who are currently enrolled in another investigational study or 
registry that would directly interfere with the current study, except when 
the subject is participating in a mandatory governmental registry, or a 
purely observational registry with no associated treatments. Each 
instance must be brought to the attention of the sponsor to determine 
eligibility, regardless of type of co-enrollment being proposed. 
2. The subject requires long-term anticoagulation therapy for reasons other 
than AF-related stroke risk reduction, for example due to an underlying 
hypercoagulable state (i.e., even if the device is implanted, the subjects 
would not be eligible to discontinue anticoagulation due to other 
medical conditions requiring chronic anticoagulation therapy). 
3. The subject is contraindicated for short-term anticoagulant therapy with 
DOAC post-implant.  
4. The subject is contraindicated to aspirin and/or clopidogrel.  
5. The subject is indicated for long-term clopidogrel therapy or has taken 
clopidogrel within 7 days prior to the WATCHMAN FLX Device 
implant.  
6. The subject had or is planning to have any cardiac or non-cardiac 
invasive or surgical procedure within 30 days prior to or 60 days after 
the WATCHMAN FLX Device implant (including, but not limited to: 
cardioversion, coronary angiogram with or without percutaneous 
coronary intervention (PCI), cardiac ablation, cataract surgery, 
endoscopy, etc.).  
7. The subject had a prior stroke (of any cause, whether ischemic or 
hemorrhagic) or transient ischemic attack (TIA) within the 90 days prior 
to enrollment.  
8. The subject has had a myocardial infarction (MI) documented in the 
clinical record as either a non-ST elevation MI (NSTEMI) or as an ST-
elevation MI (STEMI), with or without intervention, within 90 days 
prior to enrollment. 
9. The subject has a history of atrial septal repair or has an ASD/PFO 
device.  
10. The subject has implanted mechanical valve prosthesis in any position. 
11. The subject has New York Heart Association Class IV Congestive Heart 
Failure at the time of enrollment.  
12. The subject is of childbearing potential and is, or plans to become 
pregnant during the time of the study (method of assessment upon study 
physician’s discretion). 
13. The subject has a documented life expectancy of less than two years. 
 
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9.4. Echo Exclusion Criteria 
After informed consent and prior to or at the onset of procedure a TTE/TEE is performed.  
These additional exclusion criteria must be evaluated for each subject.  If any of the Echo 
exclusion criteria are met, then the subject will be withdrawn from the study and will be 
classified as “INTENT” subject. 
Table 9-3: Echo Exclusion Criteria 
Echo 
Exclusion 
Criteria 
1. The subject has LVEF < 30%. 
2. The subject has intracardiac thrombus, LAA sludge (gelatinous, non-
adherent, intracavitary echo-density more layered than dense 
spontaneous echo contrast (SEC) seen continuously throughout cardiac 
cycle) or dense SEC visualized by TEE within 3 calendar days prior to 
implant. 
3. The subject has an existing pericardial effusion with a circumferential 
echo-free space > 5mm, and/or the subject has signs/symptoms of acute 
or chronic pericarditis, and/or there is evidence (clinically or 
echocardiographically) of tamponade physiology.  
4. The subject has a high- risk patent foramen ovale (PFO) with an atrial 
septal aneurysm excursion > 15mm or length > 15mm. 
5. The subject has a high-risk PFO with a large shunt defined as early, 
within 3 beats and/or substantial passage of bubbles. 
6. The subject has significant mitral valve stenosis (i.e., MV <1.5 cm2). 
7. The subject has complex atheroma with mobile plaque of the descending 
aorta and/or aortic arch. 
8. The subject has a cardiac tumor 
 
10. Subject Accountability 
10.1. Point of Enrollment 
Subjects who have signed and dated the Informed Consent Form are considered enrolled in 
the study.   The implant visit must occur within 30 days of informed consent and within 3 
days of LAA imaging. 
10.2. Withdrawal (point of study exit) 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study 
or lost to follow-up) shall be accounted for and documented. 
If a subject withdraws from the clinical investigation, the reason(s) must be reported. If such 
withdrawal is due to problems related to the WATCHMAN FLX device safety or 
performance, the investigator must ask for the subject’s permission to follow his/her 
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status/condition outside of the clinical study. This request needs to be documented in the 
subject file. 
Reasons for study exit include, but are not limited to, physician discretion, subject choice to 
withdraw consent, lost to follow-up, or death. While study exit is discouraged, subjects may 
withdraw from the study at any time, with reason, and without prejudice to further treatment. 
The sponsor may ask that withdrawn subjects be followed for information related to the 
safety of the WATCHMAN FLXTM device if available. If such withdrawal is due to 
problems related to investigational device safety or performance, the investigator shall ask 
for the subject’s permission to follow his/her status/condition outside of the clinical study. 
Study subjects may also complete the study per protocol requirements.  When that has 
occurred, their participation in the study is considered as complete, and they will have exited 
the study. 
All applicable case report forms must be completed at study exit (i.e., withdrawal, death, 
study completion) and an “End of Study” form must be completed. Subjects who are “lost-to-
follow-up” must have three documented attempts to contact them prior to completion of the 
“End of Study” form.  Data collected up to the point of subject withdrawal may be used for 
study analysis, unless local regulations prohibit its use. 
At the point of study completion and/or withdrawal, all open adverse events must be assessed 
by the investigator. These events must be closed or documented as chronic. For those events 
that have been assessed as related to the investigational device, these should be followed 
through resolution. 
10.3. Subject Status and Classification 
10.3.1. Screen Failure 
A subject who signs informed consent, but does not meet clinical eligibility criteria is 
considered a screen failure.  These subjects do not count towards the enrollment ceiling and 
will not be used for the primary analysis. Screen failure subjects should be withdrawn 
immediately upon determining ineligibility. The original signed Informed Consent must be 
maintained in the center’s subject file and the following forms must be completed: 
• Enrollment forms such as, but not limited to: informed consent, enrollment 
information and other related forms 
10.3.2. Intent 
A subject who signs informed consent, meets clinical 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 LAA imaging eligibility criteria for a 
WATCHMAN FLX Device at the implant TEE/CT evaluation (e.g. a thrombus has 
developed in the LAA, inappropriate LAA size).  This definition also includes subjects in 
which anticoagulation has been changed or interrupted prior to the WATCHMAN FLX 
implant (prior to the WATCHMAN Access Sheath being inserted into the body for implant), 
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but ultimately do not undergo an implant.  Intent subjects must be followed until the 45 day 
visit from the time of intervention.  Adverse events (AE) related to the protocol required 
interventions (e.g. TEE and/or protocol required medication change) must be recorded on the 
AE form. For these subjects, the follow-up may occur via phone or in-office visit. TEE and 
NIHSS is not required for INTENT subjects at the 45-day follow-up. 
Intent subjects do not count towards the enrollment ceiling and will not be used for the 
primary analysis.  They will be included in a sensitivity analysis. 
The original signed Informed Consent must be maintained in the center’s subject file and the 
following forms must be completed: 
• Enrollment forms such as, but not limited to: informed consent, enrollment 
information and other related forms 
• “Adverse Event” form(s) for any reportable event, as defined in Section 20 for any 
adverse event that occurs after signing the Informed Consent, up to the point of 
subject withdrawal  
• 45 Day Visit Form(s); 
• An “End of Study” form must be completed following the 45 day visit 
10.3.3. Attempt 
A subject who signs informed consent and has had the WATCHMAN Access Sheath inserted 
into the body in order to implant the device, but eventually does not receive a WATCHMAN 
FLX Device will be classified as “Attempt.”  Attempt subjects will be followed until the 45 
day visit and adverse events will be collected up to the point of subject withdrawal.  This 
information can be collected via a phone or in-office visit. Attempt subjects count towards 
the enrolment 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: TEE and NIHSS is not required for ATTEMPT subjects at the 45-day follow-
up. 
• Enrollment forms such as, but not limited to: informed consent, screening, Enrollment 
information and other related forms;  
• Implant forms, such as, but not limited to: device information, procedure information 
and other related forms;  
• 45 Day Visit Form(s); 
• Adverse Event and/or Device Deficiency form(s) for any reportable event(s), as 
defined in Section 20; and 
• “End of Study” form for withdrawal, when applicable. 
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The date at which the “End of Study” form has been completed will be considered as the 
point of subject withdrawal.  
10.3.4. Implant 
A subject who is successfully implanted with the WATCHMAN FLX Device will be 
classified as an “Implant.” These subjects are followed in accordance with the follow-up 
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 subject file. 
Figure 2: Subject Status and Data Collection Flow Chart 
10.4. Enrollment Controls 
Subject enrollment into the WATCHMAN FLX Study will be discontinued upon attempting 
400 non-roll-in subjects with the WATCHMAN FLX Device. Investigational sites will be 
notified when the enrollment goal is close to being reached and once enrollment is complete. 
11. Study Methods 
11.1. Data Collection 
For subjects classified as INTENT or ATTEMPT (underwent the testing or implant 
procedure but DID NOT receive the WATCHMAN FLX Device), all visits up to and 
Informed consent 
obtained 
LAA echo 
criteria met? 
Implant of WATCHMAN 
FLX 
NO 
YES 
Device implanted 
Device not implanted 
Follow-up according to 
protocol schedule 
Withdrawal 
(Attempt) 
Withdrawal 
(Intent) 
All clinical criteria met? 
YES 
NO 
Duration not 
to exceed 30 
calendar days 
Withdrawal 
(Screen Failure) 
Not to 
exceed 3 
calendar 
days
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including the 45 day visit are required.  All AE reporting should also be completed. LAA 
imaging or NIHSS is not required for these subjects. 
For all IMPLANT subjects (successfully received the WATCHMAN FLX Device) all visits 
are required, as defined in Table 11-1. 
Table 11-1: Data Collection Schedule 
Procedure/Assessment 
Enrollmen
t 
Implan
t 
Follow-up Visits 
45-Day 
(± 15 Days) 
Office or 
Phone Visite 
6-Month ( 180 
days ± 
15 Days) 
Office Visit 
12 months 
(365 days 
± 30 Days) 
Office 
Visit 
18 months 
(540 days 
± 30 Days) 
Office Visit 
24 Month 
(730 days ± 
60 Days) 
Office Visit 
Informed consent form, 
including informed consent 
signature date 
X 
 
 
 
 
 
 
Demographics, including 
age, gender, and race and 
ethnicity 
X 
 
 
 
 
 
 
Physical exam including 
vital signs 
X 
 
Xc 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
Transthoracic 
echocardiogram (TTE)a 
X 
 
 
 
 
 
 
Transesophageal 
echocardiogram (TEE) 
Xb 
X 
Xc 
Xg 
X 
 
 
Brain Imaging (MRI/CT) 
Xd 
 
As requiredf 
As requiredf 
As requiredf 
As requiredf 
As requiredf 
Anticoagulant and 
antiplatelet medications 
X 
 
X 
X 
X 
X 
X 
Modified Rankin Scale 
X 
 
Xc 
X 
X 
X 
X 
NIH Stroke Scale 
X 
 
Xc 
 
X 
 
X 
Device and implant details 
 
X 
 
 
 
 
 
Adverse event/ Device 
Deficiency monitoring 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin, eGFRh, and 
proteinuria 
X 
 
 
 
 
 
 
aAn LVEF value obtained from a TTE performed within 90 days prior to enrollment may be used.  If a 
significant cardiac event occurs after the TTE which causes a change in cardiac status [i.e., major Congestive 
Heart Failure (CHF) decompensation] the enrollment TTE must be repeated at enrollment 
b Within 3 calendar days prior to implant 
c For Intent and Attempt not  required 
d Obtain MRI/CT required at baseline if subject had prior stroke or TIA. A MRI or CT performed within in 90 
days prior to enrollment may be used. 
eFor Intent and Attempt subjects the visit can be performed in office or via phone.  For subjects classified as 
implant an office visit is required 
f Brain MRI or CT required if subject suffers stroke or TIA 
g Only required for subjects that did not have a seal at the 45-day visit 
heGFR obtained up to 6 months prior to enrollment may be used 
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12. Informed Consent 
12.1. Informed Consent 
In order to determine eligibility of a subject, the investigator needs to implement the consent 
process and verify and document that the subject meets the inclusion/exclusion criteria. 
Informed consent is required from all subjects prior to the subject’s participation in the study. 
The subject should be given ample time to consider participation and ask questions if 
necessary. An IRB-approved informed consent form must be signed and personally dated by 
the subject or his/her legal representative. The original, signed document is to be kept with 
the subject’s file and a copy must be provided to the subject. The informed consent process 
must be documented by the person obtaining consent and the documentation must be placed 
in the subject’s file. The implant visit must occur within 30 calendar days of informed 
consent for study participation. 
12.2. Enrollment Visit 
Subjects selected for participation in this study should be from the investigator’s general non-
valvular atrial fibrillation population.  Each investigator is responsible for screening all non-
valvular atrial fibrillation potential subjects and selecting those who are appropriate for 
inclusion. 
Subjects who have signed and dated the Informed Consent Form are considered enrolled. The 
implant visit must occur within 30 calendar days of enrollment. Once LAA imaging 
eligibility is confirmed, the implant visit must occur within 3 calendar days. 
The following will be assessed at the Enrollment visit and documented on the case report 
forms for enrolled subjects: 
• Demographics and medical history 
• Physical exam including vital signs 
• Current medication regimen for the use of antiplatelet and anticoagulation 
medications 
• Modified Rankin Scale (MRS) and NIH Stroke Scale (NIHSS) 
• Subjects with prior history of ischemic stroke, hemorrhagic stroke or TIA are 
required to have a Baseline MRI or CT obtained (up to 90 days prior to consent or at 
the enrollment visit if no prior measurement is available) 
• Transesophageal echocardiogram (TEE) within three calendar days of implant (can 
occur at the time of implant). 
• Transthoracic Echocardiogram (TTE) (up to 90 days prior to consent or at enrollment 
if no prior measurement is available) 
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• Hemoglobin 
• eGFR (serum creatinine up to 6 months before enrollment or at enrollment if no prior 
measurement is available) 
• Proteinuria (dichotomized as protein none/trace vs. 1+ or higher) 
12.3. Stroke Assessments 
The Modified Rankin Scale (MRS) score will be routinely collected at Enrollment and office 
follow-up visits for all subjects and should be collected at 90 (+/- 10) days following a stroke 
or TIA event.  This scale assesses the severity of stroke disability and functional dependence 
of subjects. This test will be collected at baseline and all office follow-up visits.  The 
assessment must be performed by either a neurologist or personnel who have completed a 
certification for the MRS. 
The NIH Stroke Scale (NIHSS) is an assessment tool which quantifies stroke related 
neurological deficit.  This assessment must be conducted in person to provide valuable 
information on stroke severity.  This test will be performed at baseline, at 45 days, 12 
months, 24 months and if possible, following stroke. It must be conducted by a neurologist or 
personnel who have a current certification to conduct the NIHSS. 
12.4. LAA Imaging (e.g. Fluoro/TEE/TTE) 
TEE imaging and fluoroscopy are required during the WATCHMAN implant procedure to 
assist the investigator to appropriately guide the WATCHMAN System Access Sheath into 
the LAA, obtain proper measurements of the LAA to correctly size the device, and to ensure 
appropriate device position. CT imaging of the LA is occasionally performed for pre-
planning of LAAC with WATCHMAN.  This is not required for this study and does not 
replace the need for the enrollment/implant TEE.  However, if CT is performed, sites must 
note this on the data collection form and the image should be saved to disk and available to 
the sponsor upon request. 
After informed consent, all subjects will undergo an enrollment TEE and TTE.  For subjects 
successfully implanted with the WATCHMAN FLX Device, follow-up TEE’s at the 45-day 
visit, 6-month visit (if applicable), and 12 month visit are also required. All study required 
TEEs will be performed by protocol trained individuals and in accordance with the Imaging 
Manual.  Copies of the TEE’s will be sent to the Echo Core Lab per the Imaging Manual. 
Fluoroscopy recordings and images may be recorded and made available to the sponsor upon 
request. 
Copies of all protocol required TEE imaging will be saved to disk and available to the 
sponsor upon request.  Certain information from TEEs conducted during the course of the 
study, including any non-protocol required TEEs, will be captured on the study case report 
forms.  The site and subject identification number should be clearly identified on the disks. 
Copies of the Enrollment TTE imaging will be saved to disk and available to the sponsor 
upon request.   Certain information from TTEs conducted during the course of the study will 
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be captured on the study case report forms. The site and subject identification number should 
be clearly identified on the disks. 
i) 
Transthoracic Echocardiogram (TTE) 
All TTEs will be conducted according to the Imaging Manual if required.  The Enrollment 
TTE will be done to evaluate LVEF to confirm subject eligibility.  An LVEF value obtained 
from a TTE performed within 90 days prior to enrollment may be used.  If a significant 
cardiac event occurs after the TTE which causes a change in cardiac status [i.e., major 
Congestive Heart Failure (CHF) decompensation] the enrollment TTE must be repeated after 
informed consent and prior to implant. 
ii) 
Transesophageal Echocardiogram (TEE) 
All protocol required TEEs will be performed by protocol trained individuals and in 
accordance with the Imaging Manual.  The Enrollment TEE will determine that all inclusion 
and exclusion criteria are met.  The implant must occur within three calendar days of the 
enrollment TEE.  The enrollment TEE may occur on the same day as implant. The implant 
TEE will 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 confirm 
adverse events have not occurred during the implant procedure (i.e., pericardial effusion). 
The 45-day, 6-month (if applicable) and 12-month TEEs are conducted to assess flow 
through and around the WATCHMAN FLX Device and to verify there is no thrombus on the 
surface of the device.  Adequate LAA seal is defined as little or no visible residual blood 
flow around the margins of the WATCHMAN FLX Device in either a retrograde or 
antegrade fashion, with jet size ≤ 5mm.  
As required by protocol, some subjects may also have a 6-month TEE if the 45-day TEE 
demonstrates inadequate seal around the device or device thrombus.  
a. Stroke or Systemic Embolism TEE 
In the event that a subject experiences a stroke or systemic embolism (SE) during the course 
of the study (see section 20.8), supporting TEE documentation will be requested by the sponsor 
in an attempt to search for causes of stroke or embolic event.  If a stroke or SE occurs, a TEE 
is strongly encouraged to help better ascertain the mechanism of the stroke or SE. An optimal 
TEE evaluation includes, where feasible based on subject status and technical considerations, 
evaluation of:  
i. 
LA thrombus – size, location, mobility, etc. 
ii. 
WATCHMAN FLX Device seal or presence (and measurement) of peri-device flow 
iii. 
WATCHMAN FLX Device thrombus or pannus – size, location, mobility, etc. 
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iv. 
Agitated saline contrast injection to evaluate presence of residual right to left shunt at 
the atrial level (persistence of PFO or residual puncture hole from transseptal 
catheterization for device placement)  
v. 
Presence, location and grade of ascending and arch aortic atheroma 
vi. 
Presence of worsening left ventricular dysfunction, “new” regional wall motion 
abnormality or presence of LV thrombus (LVEF data may be supplemented/substituted 
by TTE where appropriate, in addition to TEE parameters above) 
b. Device Thrombus TEE 
The most accurate determination of whether thrombus has formed on the surface of the 
WATCHMAN FLXTM Device is through TEE evaluation.  In the case of thrombus on the atrial 
facing side of the device, anticoagulation therapy should be initiated for approximately 12 
weeks, or a longer period of time per hospital standard of care, for treatment of thrombus.  
After the course of anticoagulation therapy, a repeat TEE evaluation should be performed to 
confirm the thrombus has resolved. Cessation of anticoagulation after this timepoint is at the 
discretion of the investigator. 
12.5. Implant Procedure 
The implant visit must occur within 30 calendar days of consent and within 3 calendar days 
of enrollment/implant LAA imaging.  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 Device should only 
be performed by physicians trained in percutaneous and transseptal procedures who have 
completed the WATCHMAN physician training program and WATCHMAN FLX implant 
training. Refer to the WATCHMAN FLX Directions for Use (DFU) for detailed instructions 
regarding the implantation and use of the WATCHMAN FLX Device. 
Information collected during the implant procedure includes the following: 
• WATCHMAN FLX Device usage information 
• Access System(s) usage information 
• Device Release Criteria 
• Device Deficiencies 
• Device-, procedure- and/or study-related adverse events experienced since previous 
visit 
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12.6. Study Medication Regimen (for subjects classified as Implant) 
Protocol-required concomitant medications must be reported in the eCRF from the time of 
the enrollment visit through the 2 year follow-up. Information pertaining to the use of oral 
anticoagulants, clopidogrel, and aspirin, including dose changes, medication interruptions, 
and medication cessation, must be documented. 
 Implant through 45-Day TEE 
Following device placement, anticoagulation with a direct oral anticoagulant (DOAC) must 
be started and should be administered in accordance with the Directions for Use per the specific 
DOAC prescribed.. Implanted subjects should be on DOAC therapy through at least the 45-
day follow-up.  Use of apixaban or rivaroxaban is strongly recommended though other FDA 
approved DOACs can be used if necessary.  While on DOAC therapy, subjects should also 
be prescribed aspirin (81-100mg).  Aspirin is necessary post device placement to mitigate 
platelet aggregation.  Subjects should remain on DOAC and aspirin until the 45-day TEE 
evaluation has shown adequate seal of the LAA. 
 45-Day Visit 
A TEE will be conducted at the 45-day visit to assess position and the seal around the 
perimeter of the WATCHMAN FLX Device within the LAA ostium.  Adequate LAA seal is 
defined as little or no visible residual blood flow around the margins of the WATCHMAN 
FLX Device in either a retrograde or antegrade fashion, with jet size < 5mm.  
If the 45-day TEE shows adequate seal of the LAA with a jet around the device < 5mm:  
• DOAC therapy should be discontinued, 
• Aspirin (81-100 mg) should be continued indefinitely, and 
• Clopidogrel (75mg)  should be initiated, taken for 6-months post-implant, and then 
discontinued.  
If the 45-day TEE shows inadequate seal of residual LAA blood flow with a jet size > 5mm 
around the margins of device, the subject should remain on anticoagulation therapy and 
aspirin and a future TEE (i.e. 6 months post-implant) should be conducted to assess LAA 
seal as determined by the investigator.  
 
Cessation of OAC therapy is at physician discretion provided that any peri-device flow 
demonstrated by TEE is ≤ 5 mm. If adequate seal is not demonstrated, subsequent OAC 
therapy cessation decisions are contingent on demonstrating flow ≤ 5 mm. At the time the 
patient ceases OAC therapy, the patient should continue aspirin and begin clopidogrel daily. 
This regimen should continue until 6 months have elapsed after implantation. Patients should 
then remain on aspirin indefinitely. If a patient remains on OAC therapy and aspirin (81 mg-
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100 mg) for at least 6 months after implantation, and then ceases OAC therapy, the patient 
should not require clopidogrel, but should continue aspirin daily. 
Clopidogrel may be substituted with ticagrelor or prasugrel if the subject requires the 
medication for other indications (e.g. acute coronary syndromes treated with drug eluting 
stents) or if the subject cannot take clopidogrel.  Prasugrel should only be used if neither 
clopidogrel nor ticagrelor can be used due to potential for increased bleeding risk. 
Notes: 
• 
Do not use prasugrel in patients with active pathological bleeding or a history of transient 
ischemic attack or stroke.  
• 
In patients ≥75 years of age, prasugrel is generally not recommended, except in high-risk 
patients (diabetes or prior MI), where its use may be considered.  
• 
Additional risk factors for bleeding with prasugrel include: body weight <60 kg; 
propensity to bleed; concomitant use of medications that increase the risk of bleeding.  
• Do not use ticagrelor in patients with a history of intracranial bleeding 
 
 
 
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Figure 3: WATCHMAN FLX Device Implant Pharmacologic Regimen   
 
12.7. Follow-up Procedures 
12.7.1. Follow-Up (45-Days) 
12.7.1.1. For Subjects classified as Intent or Attempts 
Subjects who were NOT successfully implanted with the WATCHMAN FLX Device will 
complete an office or phone visit 45-days post procedure/intervention (i.e. TEE and/or 
NIHSS for Intent or Attempt not required). Information collected during the 45-day visit for 
“INTENT” or “ATTEMPT” subjects includes the following: 
Device, procedure and/or study related adverse events experienced since previous 
visit 
TEE, MRS, physical exam, vital signs, or NIHSS is not required for these subjects 
 
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12.7.1.2. For Subjects classified as Implants 
Subjects successfully implanted with the WATCHMAN FLX Device will complete an office 
visit 45-days post-implant with a TEE evaluation. Information collected during the 45-day 
visit includes the following: 
TEE (as described in Section 11.5) 
Modified Rankin Score and NIH Stroke Scale (NIHSS) 
Current medication regimen for the use of antiplatelet and anticoagulation 
medications (as described in Section 11.7)  
Physical exam including vital signs   
Device-, procedure- and/or study-related serious adverse events, including 
device deficiencies experienced since previous visit 
Stroke, SE and/or Thrombus TEE, if needed and not available from time of last 
event 
Brain MRI or CT follow-up if needed and not available from time of last event  
 
A TEE will be conducted at the 45-day visit to assess position and the seal around the 
perimeter of the WATCHMAN FLX Device within the LAA ostium.  Adequate LAA seal is 
defined as little or no visible residual blood flow around the margins of the WATCHMAN 
FLX Device in either a retrograde or antegrade fashion, with jet size < 5mm.  
12.7.2. Office Visit Follow-up (6-month+/- 15 days) 
All subjects classified as Implant should complete the 6 month visit.  Subjects whose 45-day 
TEE demonstrates inadequate seal around the device or device thrombus should have an 
additional TEE at 6-months to assess position and the seal around the perimeter of the 
WATCHMAN FLX Device within the LAA ostium.  Adequate LAA seal is defined as little 
or no visible residual blood flow around the margins of the WATCHMAN FLX Device in 
either a retrograde or antegrade fashion, with jet size < 5mm 
Information collected during the 6-month visit includes the following: 
TEE (as described in Section 11.5) for subjects who do not have a device seal at 
45 days.  Subjects who had a device seal at 45 days do not require at TEE at 6 
months. 
Modified Rankin Score 
Current medication regimen for the use of antiplatelet and anticoagulation 
medications ( as described in Section 11.7)  
Physical exam including vital signs   
Device-, procedure- and/or study-related adverse events, including device 
deficiencies experienced since previous visit 
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Stroke, SE and/or Thrombus TEE, if needed and not available from time of last 
event 
Brain MRI or CT follow-up if needed and not available from time of last event  
 
12.7.3. Office Visit Follow-up (12-month+/- 30 days) 
Subjects will complete an office visit 12-months post-implant. Information collected during 
this visit includes the following: 
TEE (as described in Section 11.5) 
Modified Rankin Score and NIH Stroke Scale (NIHSS) 
Current medication regimen for the use of antiplatelet and anticoagulation 
medications (as described in Section 11.7) 
Physical exam including vital signs 
Device-,, procedure- and/or study-related adverse events, including device 
deficiencies experienced since previous visit 
Stroke, SE and/or Thrombus TEE, if needed and not available from time of last 
event 
Brain MRI or CT follow-up if needed and not available from time of last event  
12.7.4. Office Visit Follow-Up (18-months+/- 30 days) 
Subjects will complete an office visit 18-months post-implant.  Information collected during 
this visit includes: 
Modified Rankin Scale 
Current medication regimen for the use of antiplatelet and anticoagulation 
medications 
Physical exam including vital signs   
Device, procedure and/or study related adverse events, including device 
deficiencies experienced since previous visit 
Stroke, SE and/or Thrombus TEE, if needed and not available from time of last 
event 
Brain MRI or CT follow-up if needed and not available from time of last event  
12.7.5. Office visit Follow-Up (24-months) 
Subjects will complete an office visit 24 months post implant.  Information collected during 
this visit includes: 
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Modified Rankin Score and NIH Stroke Scale (NIHSS) 
Current medication regimen for the use of antiplatelet and anticoagulation 
medications 
Physical assessment including vital signs 
Device-, procedure- and/or study-related serious adverse events, including 
device deficiencies experienced since previous visit 
Stroke, SE and/or Thrombus TEE, if needed and not available from time of last 
event 
Brain MRI or CT follow-up if needed and not available from time of last event  
 
12.8. Study Exit 
Once a study subject has exited the study, their participation in the study has ended.  
Appropriate eCRFs are completed indicating the status of the subject (i.e., end of study 
form).  The table below provides information on the appropriate eCRF’s to complete. 
 
Type of Study Exit 
Date to Use 
Form(s) to complete 
Subject withdrawal 
Date of subject 
withdrawal 
End of Study form 
Adverse Event  (resolve/close 
any AE’s) 
Subject Lost to Follow-
up 
The date of last attempt 
to contact the subject 
End of study form 
Adverse Event  (resolve/close 
any AE’s) 
Subject Death 
Date of Death 
End of Study Form 
Adverse Event with fatal 
outcome, resolve/close other 
AE’s (only one event to be 
recorded with outcome of fatal) 
 
Complete all protocol 
visits 
Date of last study visit 
End of Study Form 
Adverse Event (resolve/close 
any AE’s) 
   
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13. Statistical Considerations 
13.1. Endpoints 
13.1.1. Primary Effectiveness Endpoint 
The rate of effective closure defined as any peri-device flow < 5mm demonstrated by TEE at 
the 12 months visit.   
13.1.1.1. Hypotheses 
H0: Pe1 ≤ 97.0% 
H1: Pe1 > 97.0% 
where Pe1 is the Primary Effectiveness Endpoint rate.   
13.1.1.2. Sample Size  
A sample size of 400 enrolled subjects is required to evaluate the 1st Primary Effectiveness 
Endpoint, accounting for 20% attrition. This sample size was calculated employing exact 
binomial methodology using SAS version 9.4 with the following assumptions: 
Expected rate of effective LAA closure =  99.3%  
Delta = 2.3% 
Performance goal = 97.0%  
1-sided alpha = 5% 
Power = 92% 
Expected attrition rate = 20% 
Required sample size = 400 subjects 
The expected rates of effective LAA closure and attrition are based off the rates observed in 
the combined PREVAIL and CAP2 WATCHMAN subjects with a CHADS2 score ≥ 2 or a 
CHA2DS2-VASc score ≥ 3 (July 9, 2015 update), which were 99.3% and 20%, respectively.  
The attrition estimate includes all patients who do not have a 12-month TEE performed. A 
delta of 2.3% was then subtracted from the expected rate of effective LAA closure to 
establish the performance goal of 97.0%.  This represents a minimum observable rate of 
98.8%, which is similar to the rate observed in previous WATCHMAN studies. 
13.1.1.3. Statistical Methods 
All implanted subjects with a completed 12-month TEE, and who have not had any LAA 
closure procedures other than the initial FLX implant attempt, will be considered for the 
endpoint analysis.  All subjects who complete their 12-month TEE will be included in the 
denominator for the Primary Effectiveness event rate.  All subjects who complete the 12-
month TEE and demonstrate a peri-device flow of ≤ 5mm will be included in the numerator.  
A one-sided exact binomial test will be used to test the assumption that the rate of effective 
LAA closure at 12 months is > 97.0%.  The null hypothesis will be rejected if the resulting p-
value is less than 0.05.  
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13.1.2. Primary Safety Endpoint 
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. Events 
included into this endpoint will be confirmed by CEC adjudication.  Percutaneous catheter 
drainage of pericardial effusions, snaring of an embolized device, thrombin injection to treat 
femoral pseudoaneurysm and minor nonsurgical treatments of access site complications are 
excluded from this endpoint. . 
Hypotheses 
H0: Ps ≥ 4.21% 
Ha: Ps < 4.21% 
where Ps is the rate of subjects experiencing a safety endpoint event within 7 days or hospital 
discharge, whichever is later 
13.1.2.1. Sample Size  
A sample size of 400 subjects is required to evaluate the Primary Safety Endpoint.  This 
sample size was calculated employing exact binomial methodology using SAS version 9.4 
with the following assumptions: 
Expected event rate = 1.68%  
Delta = 2.53% 
Performance goal = 4.21%  
1-sided alpha = 5% 
Power = 92% 
Expected attrition rate = 0% 
Required sample size = 400 subjects 
 
The expected rate of the Primary Safety Endpoint is based off the rate observed in the 
combined PREVAIL and CAP2 WATCHMAN subjects with a CHADS2 score ≥ 2 or a 
CHA2DS2-VASc score ≥ 3 (July 9, 2015 update), which was 1.68%.. A delta of 2.53% was 
then added to this expected rate to establish the performance goal of 4.21%.  This 
performance goal corresponds to a maximum observable rate of 2.5%, and is deemed to be 
clinically acceptable based on observed rates of procedural complications in comparable 
procedures. 
13.1.2.2. Statistical Methods 
The Primary Safety event rate will be calculated as the percent of all implanted or attempted 
subjects who experience a Primary Safety event.  A one-sided exact binomial test will be 
used to test the null hypothesis that the rate of subjects experiencing a Primary Safety event 
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is ≥ to 4.21% vs the 1-sided alternative hypothesis that the rate is <4.21%.  The null 
hypothesis will be rejected if the resulting p-value is less than 0.05. 
13.1.3. Secondary Effectiveness Endpoint 
The Secondary Effectiveness End point is the occurrence of ischemic stroke or systemic 
embolism at 24 months from the time of implant. Events included into this endpoint will be 
confirmed by CEC adjudication. 
13.1.3.1. Hypotheses 
H0: Pe2 ≥ 8.7% 
H1: Pe2 < 8.7% 
where Pe2 is the 2-year Kaplan-Meier rate of the Secondary Effectiveness Endpoint. 
13.1.3.2. Sample Size  
A sample size of 400 enrolled subjects is required to evaluate the Secondary Primary 
Effectiveness Endpoint, accounting for 20% attrition. This sample size was calculated 
employing exact binomial methodology and confirmed via Monte Carlo simulations 
employing Kaplan-Meier methodology, using SAS version 9.4 with the following 
assumptions: 
Expected event rate =  4.7%  
Delta = 4.0% 
Performance goal = 8.7%  
1-sided alpha = 5% 
Power = 90% 
Expected attrition rate = 20% 
 
Required sample size = 400 subjects 
The expected rate of the Secondary Effectiveness Endpoint is based off the rate observed in  
PREVAIL-eligible subjects with a CHADS2 score ≥ 2 or a CHA2DS2-VASc score ≥ 3 from 
the combined PROTECT AF, CAP, PREVAIL and CAP2 WATCHMAN arms (July 9, 2015 
update), which was 4.7%.The 20% expected rate of attrition accounts for all subjects who 
exit the study for any reason, including death, prior to 2 years. A delta of 4.0% was added to 
the expected event rate to establish the performance goal of 8.7%.  This corresponds to a 
maximum observable rate of 6.2%.   
 
 
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The performance goal of 8.7% is considered clinically meaningful in the context of the 
expected ischemic stroke rate for a population eligible for this study but treated only with 
aspirin (ASA).  This expected rate was determined from the Swedish Atrial Fibrillation 
Cohort study of approximately 182,000 subjects 17.  The risk of ischemic stroke for a given 
subject out of a population of 1000 subjects followed for one year are tabulated below based 
on the subject’s CHA2DS2-VASc Score.  It is assumed that the annual rate would be linear 
out to two years.  Thus, the annual stroke risk per 1000 subject-years was doubled and then 
divided by 10 to convert the 2-year stroke rate.  
CHA2DS2-VASc 
Score 
Annual Stroke 
Risk/1000 
Subject-years 
2-Year 
Stroke Rate 
1 
0.6 
1.2% 
2 
25 
5.0% 
3 
37 
7.4% 
4 
55 
11.0% 
5 
84 
16.8% 
A linear regression was calculated for the two year stroke rate as a function of CHA2DS2-
VASc score to yield the following equation: 
2-year stroke rate = CHA2DS2-VASc score * 3.72 – 2.88;  r2 = 0.977 
The mean CHA2DS2-VASc score observed in PREVAIL-eligible subjects from the combined 
PROTECT AF, CAP, PREVAIL, and CAP2 studies was 4.3. Substituting a CHA2DS2-VASc 
score of 4.3 into the equation yields an expected 2-year ischemic stroke rate of 13.1% for 
subjects treated with ASA only. Therefore the performance goal of 8.7% represents an 
improvement over ASA only for the Secondary Primary Effectiveness Endpoint, which 
includes systemic embolism events in addition to ischemic stroke. 
13.1.3.3. Statistical Methods 
Data from all implanted or attempted subjects at the time of endpoint analysis will be eligible 
for inclusion in this endpoint analysis. The Secondary Effectiveness event rate from date of 
implant (or date of attempt, for devices attempted but not implanted) through 2 years post-
implant will be calculated using Kaplan-Meier methodology. Event-free subjects who exit 
the study will be censored at the time of their last follow-up. The 95% one-sided upper 
pointwise confidence limit of the event rate will be calculated via log-log methodology for all 
eligible subjects contributing to the analyses and compared to the performance goal of 8.7%. 
If the upper confidence limit is less than 8.7%, the null hypothesis will be rejected. 
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13.2. General Statistical Methods 
13.2.1. Analysis Sets 
The analysis set for the Primary Effectiveness analysis includes implanted subjects with a 
completed 12-month TEE, and who have not had any LAA closure procedures other than the 
initial FLX implant attempt. The analysis set for the Primary Safety and Secondary 
Effectiveness analyses will be the “intent-to-treat” analysis set, including all implanted or 
attempted subjects. Roll-in subjects are excluded from all Primary and Secondary endpoint 
analyses. 
13.2.2. Control of Systematic Error/Bias 
Selection of subjects for enrollment will be made from the Investigator’s usual subject load. 
All subjects meeting the eligibility criteria and having signed the ICF will be eligible for 
enrollment in the study. To control for the potential bias that could be introduced via sponsor 
classification of adverse events, a Clinical Events Committee (CEC) will adjudicate 
important endpoints and relevant adverse events. 
A tipping-point analysis may be conducted for the Primary Effectiveness Endpoint to assess 
the impact of different assumptions about the missing data on interpretation of the results. 
Specifically, for subjects who do not have evaluable 12-month TEE results, the proportion of 
those subjects assumed to have effective LAA closure will be varied until the point that 
significance compared to the performance goal no longer holds in order to assess the 
robustness of the conclusion of the Primary Effectiveness Endpoint analysis. 
13.2.3. Control of Type-I Error 
Due to the requirement that each applicable endpoint must be passed, each applicable 
endpoint can be tested at the significance level of 5% while still maintaining the overall type-
I error level at no greater than 5%. This follows the methodology of the Intersection-Union 
Test (IUT).  All study endpoints will be analyzed using one-sided significance levels of 5%. 
13.2.4. Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will not be authorized to implant or attempt 
more than 20% of the 400 subjects (n = 80) per this protocol without prior approval from 
Boston Scientific. 
13.3. Additional Data Analyses 
The following sections describe additional data analyses planned for PINNACLE FLX. 
13.3.1. Justification of Pooling 
Poolability across investigational center will be assessed for all Primary and Secondary 
Endpoints.  Poolability of the Primary Effectiveness and Safety Endpoints across 
investigations center will be assessed by adding center into a logistic regression model as a 
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random effect. Centers will be deemed to be heterogeneous if the variance of the random 
center effect is found to be significantly different from zero using a significance level of 
0.15.  Poolability of the Secondary Effectiveness Endpoint across investigations center will 
be assessed by adding center to a shared frailty model as a random effect.  Centers will be 
deemed heterogeneous with respect to the Primary Effectiveness Endpoint if the p-value 
from Wald test for the investigational center random effect is <0.15.  Regardless of the 
results of the poolability analyses, results by investigational center will be provided for each 
Primary and Secondary Endpoint.  
Poolability of the Secondary Effectiveness Endpoint will be assessed across subjects who did 
vs did not switch from Warfarin to a DOAC upon enrollment in the study.  A Cox regression 
model of time to ischemic stroke or SE will be fit on OAC history (switched from Warfarin 
to DOAC vs not) as well as CHA2DS2-VASc score. Results will be considered poolable if the 
resulting p-value for the coefficient for OAC history is ≥0.15. 
13.3.2. Subgroup Analyses 
Descriptive statistics will be presented for primary, secondary, and additional endpoints for the 
subgroups listed below: 
• Sex (Female vs. Male) 
• Age at time of consent (< 75 years vs. ≥ 75 years) 
• Full recaptures (0 vs. ≥ 1) 
• Partial recaptures (0 vs. ≥ 1) 
• Risk (CHA2DS2-VASc Score) 
•  Post-implant drug regimen  
• OAC history (i.e. did subject switch from Warfarin to DOAC or not upon enrollment 
in the study) 
13.3.3. Multivariable Analyses 
Univariate and multivariate modeling analyses will be performed to assess the effect of 
baseline covariates on the Primary Effectiveness, Secondary Effectiveness, and Primary 
Safety Endpoints.   Logistic regression will be used to assess the effects of possible 
predictors on the Primary Effectiveness and Safety Endpoints, and Cox proportional hazards 
regression will be used to assess the effects of possible predictors on the Secondary 
Effectiveness Endpoint in a time-to-event manner. The covariates to be included in this 
analysis will include, but are not limited to, the following:   
• 
Gender 
• 
Ethnicity 
• 
Age  
• 
LAA dimension  
• 
LAA shape 
• 
LVEF%  
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• 
Prior stroke 
• 
CHADS2 score 
• 
CHA2DS2-VASc score 
• 
HAS-BLED score 
• 
Medication history 
• 
Years on anticoagulation therapy 
• 
Cardiovascular Disease History (CAD, diabetes, hypertension) 
• 
Cardiac Surgery History 
• 
Significant Non-Cardiovascular Disease History 
• 
Atrial Fibrillation History 
• 
Full device recapture rate (0 vs. ≥ 1) 
• 
OAC history (i.e. did subject switch from Warfarin to DOAC or not upon enrollment 
in the study)  
13.3.4. Other Analyses 
No formal interim analyses are planned for the purpose of stopping this trial early for 
effectiveness or futility. 
 
Administrative analyses of safety data may be performed for regulatory agency review. 
 
Descriptive statistics of subject demographic and baseline characteristics will be presented 
for the overall study population.  
13.3.5. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analysis will be 
documented in an amended Statistical Analysis Plan approved prior to performing the 
analysis. Changes from the planned statistical methods after performing the analysis will be 
documented in the clinical study report along with a reason for the deviation. 
14. Data Management 
14.1. 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 EDC System. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review 
by the sponsor or its representative. The associated RAVE software and database have been 
designed to meet regulatory compliance for deployment as part of a validated system 
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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. 
14.2. Data Retention 
The Investigator or Investigational Site will maintain, securely store, 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 formal discontinuation of the clinical investigation of the product. 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. 
14.3. Core Laboratories 
An independent core laboratory will be utilized to review TEE imaging collected at protocol 
required time points during the study. All interpretations of TEE imaging for purposes of 
subject care will be conducted by each site’s investigator and/or echocardiographer. The 
Core Lab will not be utilized as a means of reference for subject management decisions. 
Imaging will be collected by each study site according to the Imaging Protocol and submitted 
to the Core Lab for review. The Core Lab will provide Boston Scientific with summary of 
results for reporting purposes and associated study endpoint analyses. 
15. 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 
/FDA) of the revised protocol must be obtained prior to implementation. 
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16. Deviations 
An Investigator must not make any changes to or deviate from this protocol, except in order 
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. Such notice shall be given as 
soon as possible, but no later than 5 working days after the emergency occurred, or per 
prevailing local requirements if sooner than 5 working days.  
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 using the appropriate 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. 
17. Device/Equipment Accountability 
The investigational devices shall be securely maintained, controlled, and used only in this 
clinical study. The sponsor shall keep records to document the physical location of all 
investigational devices from shipment of investigational devices to the investigation sites 
until return or disposal. 
Records shall be kept by the investigational site to document the physical location and 
conditions of storage of all investigational devices/equipment.  
The principal investigator or an authorized designee shall keep records documenting the 
receipt, use, return and disposal of the investigational devices/equipment, which shall include 
the following: 
• Date of receipt. 
• Identification of each investigational device/piece of equipment (batch number or unique 
code). 
• Expiry date, as applicable. 
• Date or dates of use. 
• Subject identification. 
• Date on which the investigational device/piece of equipment was returned/explanted from 
subject, if applicable. 
• Date of return to sponsor of unused, expired, or malfunctioning investigational devices, if 
applicable. 
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Please note: Written procedures may be required by local, state, and/or federal  regulations. 
Current sponsor processes will be used to track subjects and investigational device during the 
study. Upon completion of enrollment into the study, or as directed by the sponsor, all 
unused investigational devices must be returned to the sponsor. 
18. Compliance 
18.1. Statement of Compliance 
This study will be conducted in accordance with 21 CFR 814.20 part 56, part 50 and part 812 
or 813, ISO 14155: Clinical Investigation of Medical Devices for Human Subjects – Good 
Clinical Practice, 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 IRB/EC and/or regulatory authority has been obtained, if appropriate. Any 
additional requirements imposed by the IRB/EC or regulatory authority shall be followed, if 
appropriate. 
18.2. 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 
plan/protocol, 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 Clinical Study 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. 
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• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor on the eCRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) 
reportable adverse events and observed device deficiencies. 
• Report to BSC, events per the protocol requirements, and all SAEs and device 
deficiencies that could have led to a SADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that 
could have led to a SADE, 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. 
• Maintain the device accountability records and control of the device, ensuring that the 
investigational device is used only by authorized/designated users and in accordance with 
this protocol and instructions/directions for use. 
• 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. 
• 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, as needed. 
• 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). 
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• 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. 
18.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal 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.  
18.3. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational site will provide to the sponsor 
documentation verifying that their IRB/EC is registered or that registration has been 
submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
sponsor before recruitment of subjects into the study and shipment of investigational 
product/equipment. Prior approval must also be obtained for other materials related to subject 
recruitment or which will be provided to the subject. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study 
as required by local/country or IRB/EC requirements. Copies of the Investigator’s reports 
and the IRB/EC continuance of approval must be provided to the sponsor.  
18.4. 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 including, but not limited to Contract Research Organization (CRO) 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 
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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’ identifiable personal health information (PHI) 
confidential in accordance with all applicable laws and regulations.  Boston Scientific may 
use subjects’ personal health information to conduct this research, 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. 
18.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health 
care personnel (collectively HCP) as needed during implant, testing required by the protocol, 
and follow-ups. Support may include HCP training, addressing HCP questions, or providing 
clarifications to HCPs concerning the operation of BSC devices. 
In addition, BSC personnel may perform certain activities to ensure study quality. These 
activities may include the following. 
• Observing testing or medical procedures to provide information relevant to protocol 
compliance. 
• Reviewing collected data and study documentation for completeness and accuracy. 
Boston Scientific personnel will not do the following:  
• Practice medicine. 
• Provide medical diagnosis or treatment to subjects. 
• Discuss a subject’s condition or treatment with a subject without the approval and 
presence of the HCP. 
• Independently collect critical study data (defined as primary or secondary endpoint data). 
• Enter data in electronic data capture systems or on paper case report forms. 
18.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage by BSC for 
subjects in the study will be obtained. 
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19. Monitoring 
A combination of on-site, remote and central monitoring will be utilized by the sponsor 
through the duration of the study to assess participating sites’ continued compliance with the 
protocol and applicable local and federal regulations, The sponsor will assess and verify that 
study records are adequately maintained, that study data are reported in a satisfactory manner 
with respect to timeliness, adequacy, and accuracy, and that the Principal Investigator 
continues to have sufficient staff and facilities to conduct the study safely and effectively. 
The Investigator/institution guarantees access to original 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 Principal Investigator 
and relevant study personnel are available during on-site monitoring visits and audits and that 
sufficient time is devoted by the site personnel to the monitoring and inspection processes. 
20. Potential Risks and Benefits 
20.1. Anticipated Adverse Events 
Potential procedural risks associated with the WATCHMAN FLX implant procedure are 
similar to those encountered peri- and post-operatively for WATCHMAN (Gen 2.5) and 
many routine catheterization procedures.  These are included in Table 19.1, 
• Table 20-1: Anticipated Adverse Events 
• Air embolism 
• Airway trauma 
• Allergic reaction to contrast 
media/medications or device materials 
• Altered mental status 
• Anemia requiring transfusion 
• 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 
• Death 
• 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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• Decreased hemoglobin 
• Deep vein thrombosis 
• Device embolism/migration 
• Device fracture 
• Device thrombosis 
• Edema 
• Excessive bleeding 
• Fever 
• Groin pain 
• Groin puncture bleed 
• Hematuria 
• Hemoptysis 
• Respiratory insufficiency / failure  
• Surgical removal of the device 
• Stroke – Ischemic  
• Stroke – Hemorrhagic 
•    Systemic embolism 
• TEE complications (throat pain, bleeding, 
esophageal trauma) 
• Thrombocytopenia 
• Thrombosis 
• Transient ischemic attack (TIA) 
• Valvular damage 
• Vasovagal reactions 
 
20.2. Anticipated Adverse Device Effects  
From the Anticipated Adverse Events listed above, the following anticipated adverse device 
effects (ADE) have been identified for the WATCHMAN FLX Device are as follows: 
• Additional surgery if the device is not placed in the correct position 
• Allergic reaction to the implant materials 
• Device misplacement 
• Device embolization 
• Device fracture or extrusion 
• Excessive bleeding 
• Hypertrophic scarring or thrombosed veins 
• Device thrombosis 
• Inability to move or retrieve device 
• Inability to implant the device  
20.3. Possible Interactions with Concomitant Medical Treatments 
Subjects who receive the WATCHMAN FLX Device may stop anticoagulation therapy as 
early as the 45-day follow-up visit if they meet anticoagulaiton cessation guidelines; 
therefore, at that time, subjects may be at an increased risk of stroke.   Anticoagulation is the 
most frequently utilized modality for reducing the risk of stroke in atrial fibrillation.  The 
WATCHMAN FLX Device is designed to be used instead of long-term anticoagulation.  The 
absence of an anticoagulant may represent a risk, especially if the device is not effective in 
preventing stroke. 
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20.4. 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 research 
procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this protocol. 
20.5. Anticipated Benefits 
No direct subject benefit is expected from this study. Subjects enrolled in this study will 
receive the same clinical care as subjects who are routinely implanted with a WATCHMAN 
Device and not enrolled in this study. However, results from the data collected during this 
study may improve the management of WATCHMAN FLX subjects in the future; therefore, 
the subjects enrolled in this study may also benefit at a later stage.  
WATCHMAN FLX was chartered to enhance the user experience and acute safety profile for 
the WATCHMAN LAA Closure Technology compared to the current WATCHMAN LAAC 
Device (also called WATCHMAN Gen 2.5).  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 anticoagulation therapy may reduce bleeding complications, such as 
hemorrhagic stroke, associated with long-term anticoagulation.  Economic and subject 
benefits related to the elimination of life-long compliance to anticoagulation therapy and the 
frequent blood tests and lifestyle changes associated with blood thinning medications are 
numerous. 
20.6. Risk to Benefit Rationale 
Risk management activities, including Hazard Analyses (HA) and Failure Mode Effects 
Analyses (FMEA), have been performed on the WATCHMAN FLX Device to identify and 
analyze known and foreseeable hazards and reasonably foreseeable sequences or 
combinations of events that could result from using this product and the risks associated with 
each hazard.  Mitigations have been implemented in the design, processes, and/or labeling 
and directions for use of the product to reduce the residual risk of each hazard as necessary 
and practicable.  The HA has been reviewed and approved and the remaining risks are 
acceptable when weighed against the intended benefits to the subject. 
In addition, investigational teams selected to conduct the study will be experienced and 
skilled in interventional cardiology and/or electrophysiology with transseptal and left heart 
experience, will have completed the WATCHMAN Physician Training program and will 
have access to modern high technology medical facilities to conduct those procedures. 
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21. Safety Reporting 
21.1. Reportable Events by investigational site to Boston Scientific 
Any reportable event(s), experienced by the study subject after enrollment, must be recorded 
in the electronic data capture system.  It is the responsibility of the investigator to determine 
the clinical significance of the event and report the event per protocol requirements. 
For the purpose of this study, relevant reportable events are defined as: 
• WATCHMAN FLX Device procedure-related adverse events (see AE table 19.1).   
• Adverse events related to protocol required testing (i.e., TTE, TEE). 
• Adverse events where systemic embolism is suspected and/or confirmed, regardless 
of relationship to the WATCHMAN FLX Device. 
• Adverse events related to WATCHMAN FLX (device thrombus, embolization, 
erosion, etc.). 
• All bleeding events regardless of relationship to the WATCHMAN FLX Device. 
• All strokes (regardless of cause) and transient ischemic (TIA) regardless of 
relationship to the WATCHMAN FLX Device. 
• Device deficiencies  
• All serious adverse events, including: death of all cause (cardiovascular, non-
cardiovascular, and unknown)  
• Unanticipated adverse device effects/unanticipated serious adverse device effects not 
previously defined in the physician’s manuals 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device/procedure/protocol required testing, it should be submitted as an 
adverse event and/or device deficiency. 
Death should not be recorded as an AE, but should only be reflected as an outcome of ONE 
(1) specific SAE. 
Refer to Section 20 for the known risks associated with the study device(s). 
21.2. Definitions and Classification 
In order to provide clarity, the adverse event definitions are provided in Table 20.2-1. 
Administrative edits were made to the event definitions from ISO 14155-2011 and 21 CFR 
812.  
 
Table 21.2-1: Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
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Table 21.2-1: Definitions 
Term 
Definition 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3 
 
subjects, users or other persons, whether or not related to the 
investigational medical device. (see section 20.1) 
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). 
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3 
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 
 
Ref: MEDDEV 2.7/3 
Adverse event that: 
• Led to death, 
o 
Led to  serious deterioration in the health of the subject as defined 
by a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient-hospitalization  or prolongation 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 
 
• Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 
Note 1. Planned Hospitalization for pre-existing condition, or a procedure 
required by the clinical investigational plan, without a serious 
deterioration in health, is not considered a serious adverse event 
 
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
NOTE 1: This includes any adverse event resulting from insufficiencies 
or inadequacies in the 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 
intentional abnormal use of the investigational medical device. 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
 
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, 
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.   
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Table 21.2-1: Definitions 
Term 
Definition 
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in 
the risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3 
A device deficiency (DD) 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. 
 
 
 
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Term 
Definition 
Complication 
An adverse event that resulted in: death, serious injury a, correction using 
invasive intervention, or permanent loss of device functions. 
a Per 21 CFR 803.3: Serious injury means an injury or illness that: 
• 
Is life-threatening 
• 
Results in permanent impairment of a body function or 
permanent damage to a body structure, or 
• 
Necessitates medical or surgical intervention to preclude 
permanent impairment of a body function or permanent damage 
to a body structure 
Permanent means irreversible impairment or damage to a body 
structure or function, excluding trivial impairment or damage 
b Invasive interventions are those in which treatment necessary to 
correct the adverse event is delivered by cutting or piercing of the skin 
or placing an instrument in a body cavity to provide therapy. 
Examples of invasive interventions (complication) include, but are not 
limited to: 
• 
Electrophysiology study in which an ablation is performed 
• 
Angiogram in which angioplasty or stent placement is performed 
• 
Intravenous medications 
• 
Blood transfusions 
• 
Intubation to provide respiratory support 
• 
Chemical (pharmacologic) cardioversion with IV sedation (This 
is a complication due to the IV antiarrhythmic medication used 
for the cardioversion.) 
Invasive procedures that are purely diagnostic in nature should not be 
considered as a complication. Some examples of procedures that are 
invasive, but not considered to be an intervention include: 
• 
Blood draw for laboratory analysis  
• 
Cardiac catheterization in which pressures are recorded, but 
without therapeutic intervention 
• 
Electrophysiology study to map arrhythmias, but without 
therapeutic intervention  
• 
Transesophageal echo (TEE) 
Electrical (external) cardioversion with IV sedation (the IV sedation used 
is for subject comfort and not part of the treatment) 
 
 
Observation 
An adverse event that was transient or reversible and corrected with non-
invasive interventions, such as reprogramming or oral medications, or else 
resolved with no intervention or monitoring. 
 
 
 
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21.3. Relationship to Study Device 
The Investigator must assess the relationship of the AE to the study device or. See criteria in 
Table 20.3-1:  
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Table 21.3-1: Criteria for Assessing Relationship of Study Device or 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 investigational 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 investigational 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 investigational 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 investigational device seems relevant and/or 
the event cannot reasonably explained by another cause, but additional information 
may be obtained. 
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Table 21.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Causal Relationship 
The serious event is associated with the investigational 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 investigational device use/application 
or procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational 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 investigational 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. 
 
21.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 20.4-1. 
Table 21.4-1: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline pre-market studies* 
(MEDDEV 2.7/3:  
CLINICAL INVESTIGATIONS: SERIOUS 
ADVERSE EVENT REPORTING UNDER 
DIRECTIVES 90/385/EEC AND 93/42/EEC) 
Unanticipated 
Adverse Device 
Effect / 
Unanticipated 
Serious Adverse 
Device Effect  
 
Complete AE eCRF 
page with all available 
new and updated 
information.  
• Within 1 business day of first becoming aware of 
the event. 
• Terminating at the end of the study 
Provide all relevant 
source documentation 
(de-identified) for 
reported event 
• At request of the sponsor 
Serious Adverse 
Event  
Complete AE eCRF 
page with all available 
• Within 3 calendar days of first becoming aware 
of the event or sooner as per local/regional 
regulations.  
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Table 21.4-1: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline pre-market studies* 
(MEDDEV 2.7/3:  
CLINICAL INVESTIGATIONS: SERIOUS 
ADVERSE EVENT REPORTING UNDER 
DIRECTIVES 90/385/EEC AND 93/42/EEC) 
new and updated 
information.  
• Reporting required through the end of the study 
Provide all relevant 
source documentation 
(de-identified) for 
reported event upon 
request of the sponsor 
• At request of sponsor 
Serious Adverse 
Device Effects 
Complete AE eCRF 
page with all available 
new and updated 
information. 
• Within 3 calendar days of first becoming aware 
of the event or as per local/regional regulations.  
• Reporting required through the end of the study 
Provide all relevant 
source documentation 
(de-identified) for 
reported event 
• When documentation is available 
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 DD form with 
all available new and 
updated information.  
• Within 3 calendar days of first becoming aware 
of the event.  
• Reporting required through the end of the study 
Provide all relevant 
source documentation 
(de-identified) for 
reported event 
• At request of sponsor 
Adverse Event 
including Adverse 
Device Effects 
Complete AE eCRF 
page, which contains 
such information as date 
of AE, treatment of AE 
resolution, assessment 
of seriousness and 
relationship to the 
device.  
• In a timely manner  (e.g. Recommend within 10 
business days) after becoming aware of the 
information 
• Reporting required through end of study 
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Table 21.4-1: Investigator Reporting Requirements 
Event 
Classification 
Communication 
Method  
Communication Timeline pre-market studies* 
(MEDDEV 2.7/3:  
CLINICAL INVESTIGATIONS: SERIOUS 
ADVERSE EVENT REPORTING UNDER 
DIRECTIVES 90/385/EEC AND 93/42/EEC) 
Provide all relevant 
source documentation 
(de-identified) for 
reported event 
• At request of sponsor 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
* Please note that pre-market studies are clinical studies with investigational devices or with medical devices 
that bear the regulatory approval and are not being used for the same approved indications. 
 
21.5. Boston Scientific Device Deficiencies (DDs) 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and labeling errors) will be documented and reported to BSC. If 
possible, the device(s) should be returned to BSC for analysis. Instructions for returning the 
investigational device(s) will be provided. I Device deficiencies should also be documented 
in the subject’s source records. 
Device deficiencies are to be reported as Device Deficiencies not 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. 
Additionally, 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. 
21.6. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
BSC is responsible for reporting adverse event information to all participating investigators 
and regulatory authorities.  In addition, data/interim reports will be provided to regulatory 
agencies during the course of the study.  
The Principal Investigator is responsible for informing the IRB/EC, and regulatory 
authorities of UADE/USADE and SAE as required by local/regional regulations. 
21.7. Clinical Event Committee Events (CEC) – Documentation 
As an Independent CEC will be adjudicating events for this study, appropriate medical 
records from investigative sites must be sent to Boston Scientific.   
Events which require source documents include: 
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• Stroke (all causes) including TIA 
• All deaths throughout the study 
• Systemic embolism 
• Major open cardiac and/or endovascular surgery through 7 days or hospital discharge 
(whichever is later) 
• Major bleeding events (defined as BARC 3 or BARC 5 events) 
• Other adverse events, at the discretion of Boston Scientific 
21.7.1. Stroke Reporting Documentation Recommendations 
In the event that a subject experiences a stroke or SE during the course of the study, supporting 
documentation will be requested by the sponsor.  This information may include neurologist 
consultation note(s), MRI/CT imaging, radiology reports, additional NIHSS/MRS/Barthel 
Index evaluations, or statement from the investigator. In addition, a search for alternative 
causes of stroke (including hypercoagulable work-up) and TEE evaluation at the time of any 
stroke or embolic event is strongly encouraged to help better ascertain the mechanism of all 
strokes. An optimal TEE evaluation includes, where feasible based on subject status and 
technical considerations, evaluation of:  
• LA thrombus – size, location, mobility, etc. 
• WATCHMAN FLX Device Seal or presence (and measurement) of peri-device flow 
• WATCHMAN FLX Device thrombus or pannus – size, location, mobility, etc. 
• Agitated saline contrast injection to evaluate presence of residual right to left shunt at 
the atrial level (persistence of PFO or residual puncture hole from transseptal 
catheterization for device placement)  
• Presence and grade of ascending and arch aortic atheroma 
• Presence of worsening left ventricular dysfunction, “new” regional wall motion 
abnormality or presence of LV thrombus (LVEF data may be supplemented/substituted 
by TTE where appropriate, in addition to TEE parameters above)  
21.8. Device Related Thrombus 
During the course of follow-up, device-related thrombus (DRT) may be detected by cardiac 
imaging including TEE, CT scan and MRI scan. Based on clinical experience with the prior 
generation WATCHMAN Device the most accurate and reproducible determination of 
whether thrombus has formed on the surface of the WATCHMAN FLX Device is through 
TEE evaluation.  TEE findings may be augmented by other confirmatory imaging modalities 
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In the case of DRT on the atrial facing side of the device, systemic anticoagulation therapy 
should be initiated for approximately 12 weeks, or a longer period of time per hospital 
standard of care, for treatment of thrombus.  After the course of anticoagulation therapy, a 
repeat TEE evaluation should be performed to confirm the thrombus has resolved. Cessation 
of anticoagulation after this time point is at the discretion of the investigator.  
21.9. Death Reporting 
A subject death that occurs during the study should be reported to Boston Scientific as soon 
as possible and, in any event, within three working days of center notification. The center’s 
IRB must be notified of any deaths in accordance with that center’s IRB policies and 
procedures. 
Source documentation of death will include a detailed narrative (death letter) that provides 
detailed information describing the circumstances surrounding the death and is signed by the 
principal Investigator or authorized co-Investigator. For any information which may be 
unknown, the investigator must still address the relevant area in the detailed death narrative.  
A death narrative in the local language is acceptable. The death narrative must include all of 
the following, if available: 
• Date and time of death 
• Place death occurred 
• Immediate cause of death 
• Whether the death was related to the investigational device or clinical 
investigation, procedure, or subject condition 
• Whether or not the death was witnessed 
• Whether the subject had any Transient Ischemic Attack/Stroke/Bleeding prior to 
the death 
• Any other circumstances surrounding the death 
• Approximate time interval from the initiating event to death (temporal course) 
• Investigator or co-Investigator signature and date 
Any information listed above that is unavailable or unknown must be specified as 
unavailable or unknown, as applicable, in the narrative. Also submit the following 
documentation: 
• A copy of the relevant medical records from enrollment to death, this will include  
H & P, consults, test results, operative reports, and/or progress notes from the 
hospital chart and clinic chart 
• Death certificate (if available) 
• Autopsy report (if applicable) 
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22. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
each subject or his/her legally authorized representative when approved by the IRB and if 
allowed by local regulations. The Investigator is responsible for ensuring that Informed 
Consent is obtained prior to the use of any investigational devices, study-required 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, any applicable national regulations, and local Ethics 
Committee and/or Regulatory authority body, as applicable. The ICF must be accepted by 
BSC or its delegate (e.g. CRO), and approved by the site’s IRB/EC, or central IRB, if 
applicable. 
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 site’s IRB/EC.  Any modification requires acceptance from BSC prior to use of 
the form.  The ICF must be in a language understandable to the subject and if needed, BSC 
will assist the site in obtaining a written consent translation. Translated consent forms must 
also have IRB/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 at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 
• 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 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and by 
the investigator and/or an authorized designee responsible for conducting the informed 
consent process. The original signed ICF will be retained by the site and a copy of the signed 
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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 (e.g. IRB/EC), 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 applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
following annual review by the IRB/EC. The new version of the ICF must be approved by 
the IRB/EC. Acceptance by Boston Scientific is required if changes to the revised ICF are 
requested by the site’s IRB/EC. The IRB/EC will determine the subject population to be re-
consented. 
23. Committees 
23.1. Safety Monitoring Process 
To promote early detection of safety issues, Boston Scientific reviews adverse events and 
device deficiencies per the Safety Plan. Events are reviewed with BSC Medical Safety. 
Success of this program requires dynamic collection of unmonitored data as soon as the event 
is reported. This is expedited through BSC’s Safety Operations or it’s delegate, which is 
responsible for coordinating the collection of information for the subject dossier from the 
centers and core laboratories as applicable. During regularly scheduled monitoring visits, 
clinical research monitors will support the dynamic reporting process through their review of 
source document information. 
23.2. Clinical Events Committee 
A Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise that reviews and adjudicates important events for inclusion into the primary and 
secondary endpoints.  The events that the CEC will review for this study are the primary and 
secondary endpoint events and include: device and/or procedure-related events which 
resulted in open cardiac/endovascular surgery during the 7 days or hospital discharge 
(whichever is the later) period following the implant procedure.  All strokes, TIA, all cause 
deaths, systemic embolisms, and major bleeding events will be adjudicated throughout the 
study.  Any additional event which Safety  feels requires the review of an independent 
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committee may also be sent.  The CEC will review a safety event dossier, which may include 
copies of subject source documents provided by study centers and confirm inclusion of the 
event into the primary and secondary endpoints.   CEC responsibilities, qualifications, 
membership, and committee procedures are outlined in the CEC charter.  
23.3. Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established for the review of 
data and safety parameters in the study.  The DMC will develop a charter and stopping rules 
for the study.  The members will consist of at least three physicians in specialties of 
electrophysiology, interventional cardiology, or neurology.  At least one member of the 
committee will be a biostatistician.  
The DMC will function in accordance with Guidance for Clinical Trial Sponsors: 
Establishment and Operation of Clinical Trial Data Monitoring Committees.  Meeting 
frequency will be determined by the DMC to review the clinical data and assess the impact of 
adverse events. 
24. Suspension or Termination 
23.1 Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but 
intends to exercise this right only for valid scientific or administrative reasons and reasons 
related to protection of subjects.  Investigators, associated IRBs/ECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
23.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of Boston Scientific to suspend or discontinue development of the 
device. 
23.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
Approval 
Any investigator, or IRB/ EC in the PINNACLE FLX Study may discontinue participation in 
the study or withdrawal approval of the study, respectively, with suitable written notice to 
Boston Scientific. Investigators, associated IRBs/ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of these occurrences. 
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23.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating sites by Boston Scientific. The 
IRB/EC and regulatory authorities, as applicable, will be notified. Detailed information on 
how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB or EC terminates participation in the study, participating investigators, 
associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by Boston Scientific. 
In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility; detailed information on how enrolled 
subjects will be managed thereafter will be provided by Boston Scientific. 
The Principal Investigator or his/her designee must return all study-related documents and 
investigational product to Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
23.4 Criteria for Suspending/Terminating a Study Site 
Boston Scientific reserves the right to stop the inclusion of subjects at a study site at any time 
after the study initiation visit if no subjects have been enrolled for a period beyond 3 months 
after site initiation, or if the site has multiple or severe protocol violations/noncompliance 
without justification and/or fails to follow remedial actions. 
In the event of termination of investigator participation, all study devices and testing 
equipment, as applicable, will be returned to BSC unless this action would jeopardize the 
rights, safety or well-being of the subjects. The IRB/EC and regulatory authorities, as 
applicable, will be notified. All subjects enrolled in the study at the center will continue to be 
followed per the investigator’s standard of care for subjects that undergo any WATCHMAN 
procedure. The Principal Investigator at the center must make provision for these follow-up 
visits unless BSC notifies the investigational center otherwise. 
25. Publication Policy 
BSC requires disclosure of its involvement as a sponsor or financial supporter in any 
publication or presentation relating to a BSC study or its results. BSC 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, BSC 
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. 
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• 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.  
 
26. Reimbursement and Compensation for Subjects 
26.1. Subject Reimbursement 
Travel and other expenses incurred by subjects as a result of participation in the study will be 
reimbursed in accordance with pertinent country laws and regulations and per the study site’s 
regulations.   
26.2. Compensation for Subject’s Health Injury 
Boston Scientific Corporation will purchase an insurance policy to cover the cost of potential 
health injury for study subjects if required by applicable law.  
27. 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 
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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 
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 
 
 
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28. Abbreviations and Definitions  
28.1. Definitions 
28.1.1. 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;  
 
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) 
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• 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) 
28.1.2. 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 
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: 
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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, 
• 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 PINNACLE FLX trial, a BARC score of Type 3 a, b, c and 5 a and b 
will be considered a major bleed. 
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