Comparison of Amplatzer Amulet vs Watchman Device in Patients Undergoing Left Atrial Appendage Closure: the SWISS-APERO Randomized Clinical Trial
Phase: NA
Conditions: Left Atrial Appendage Closure
Sponsor: Insel Gruppe AG, University Hospital Bern

Protocol SWISS APERO Version 5 /29.05.2020 
1/42 
Comparison of Amplatzer Amulet vs Watchman device 
in patients undergoing left atrial appendage closure: 
the SWISS-APERO randomized clinical trial 
 
Clinical Study Protocol 
 
Study Type: 
Clinical trial of medical device 
Study Categorisation: 
Risk category A 
Study Registration: 
www.clinicaltrials.gov  NCT03399851 
Sponsor,  
Sponsor-Investigator: 
InselgruppeAG -Bern University Hospital, 3010 Bern, Switzerland 
Prof. Dr. med. Lorenz Räber, 
Lorenz.Raeber@insel.ch 
 
Coordinating-Investigator 
Prof. Marco Valgimigli MD PhD 
Cardiocentro Ticino Via Tesserete 48 ,CH-6900 Lugano 
marco.valgimigli@cardiocentro.org 
InvestigationalProducts: 
Amplatzer Amulet St. Jude-Abbott; Watchman/FLX Boston Scientific. 
Protocol Version and Date: 
Version 5 /29.05.2020 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of the InselspitalUniversity 
Hospital Bern. The information may not - in full or in part - be transmitted, reproduced, published, or 
disclosed to others than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) 
without prior written authorisation from the sponsor except to the extent necessary to obtain informed 
consent from those who will participate in the study. 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
2/42 
Signature Page(s)  
 
Project number 
www.clinicaltrials.gov NCT03399851 
Project Title 
Comparison of Amplatzer Amulet vs Watchman device in patients undergoing left atrial 
appendage closure: the SWISS-APERO randomized clinical trial 
 
 
 
 
The Sponsor-Investigator and trial statistician have approved the protocol Version 5 /29.05.2020, and 
confirm hereby to conduct the study according to the protocol, current version of the World Medical 
Association Declaration of Helsinki1, ICH-GCP guidelines2,3 or ISO 141554 norm if applicable and the 
local legally applicable requirements. 
 
Sponsor-Investigator: 
Prof.Dr.med. Räber, Lorenz, Department of Cardiology, Bern University Hospital, Bern, Switzerland 
 
 
 
Place/Date 
 
Signature 
 
 
 
 
 
 
The Coordinating-Investigator has approved this trial protocol and agrees to coordinate and conduct the 
trial as set out in this study protocol, the current version of the World Medical Association Declaration of 
Helsinki, ICH-GCP guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
 
 
Coordinating-Investigator: 
 
Prof. Marco Valgimigli, MD PhD, Cardiocentro Ticino Via Tesserete 48 ,CH-6900 Lugano; Switzerland 
 
 
 
 
Place/Date 
 
Signature 
 
 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
3/42 
Local Principal Investigator at study site*: 
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
Site 
 
Principal investigator 
 
 
 
 
Place/Date 
 
Signature 
 
*Note: In multicentre studies, this page must be individually signed by all participating Local Principal 
Investigators. 
 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
4/42 
Table of Contents 
STUDY SYNOPSIS ................................................................................................................................. 7 
ABBREVIATIONS .................................................................................................................................. 10 
STUDY SCHEDULE .............................................................................................................................. 12 
1. 
STUDY ADMINISTRATIVE STRUCTURE .................................................................................... 13 
1.1 
Sponsor ....................................................................................................................................... 13 
1.2 
Principal Investigator(s) ............................................................................................................... 13 
1.3 
Statistician ................................................................................................................................... 13 
1.4 
Any other relevant Committee, Person, Organisation, Institution ............................................... 13 
2. 
ETHICAL AND REGULATORY ASPECTS .................................................................................... 13 
2.1 
Study registration ........................................................................................................................ 13 
2.2 
Categorisation of study ............................................................................................................... 13 
2.3 
Ethical Conduct of the Study and declaration of interests .......................................................... 13 
2.4 
Patient Information and Informed Consent ................................................................................. 13 
2.5 
Participant privacy and confidentiality ......................................................................................... 14 
2.6 
Early termination of the study ...................................................................................................... 14 
2.7 
Protocol amendments ................................................................................................................. 14 
3. 
BACKGROUND AND RATIONALE ............................................................................................... 14 
3.1 
Background and Rationale .......................................................................................................... 14 
3.2 
Medical Devices and Indication ................................................................................................... 16 
3.3 
Preclinical Evidence .................................................................................................................... 17 
3.4 
Clinical Evidence to Date ............................................................................................................ 17 
3.5 
Explanation for choice of comparator.......................................................................................... 17 
3.6 
Risks / Benefits ............................................................................................................................ 17 
3.7 
Justification of choice of study population ................................................................................... 17 
4. 
STUDY OBJECTIVES .................................................................................................................... 18 
4.1 
Overall Objective ......................................................................................................................... 18 
4.2 
Primary Objective ........................................................................................................................ 18 
4.3 
Secondary Objectives ................................................................................................................. 18 
4.4 
Safety Objectives ........................................................................................................................ 18 
5. 
STUDY OUTCOMES ..................................................................................................................... 18 
5.1 
Primary Outcome ........................................................................................................................ 18 
5.2 
Secondary Outcomes .................................................................................................................. 18 
5.3 
Procedure-related complications1 ............................................................................................... 18 
5.4 
Other Outcomes of Interest ......................................................................................................... 19 
5.5 
Safety Outcomes ......................................................................................................................... 19 
5.6 
Feasibility Outcomes ................................................................................................................... 19 
6. 
STUDY DESIGN ............................................................................................................................ 19 
6.1 
General study design and justification of design ......................................................................... 19 
6.2 
Randomization ............................................................................................................................ 20 
6.3 
Other methods of minimising bias ............................................................................................... 20 
7. 
STUDY POPULATION ................................................................................................................... 20 
7.1 
Eligibility criteria ........................................................................................................................... 20 
7.2 
Recruitment and screening ......................................................................................................... 20 
7.3 
Assignment to study groups ........................................................................................................ 20 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................... 20 

Protocol SWISS APERO Version 5 /29.05.2020 
5/42 
8. 
STUDY INTERVENTION ............................................................................................................... 21 
8.1 
Identity of Investigational Medicinal Devices .............................................................................. 21 
8.2 
Procedural intervention ............................................................................................................... 21 
8.3 
Device sizing ............................................................................................................................... 22 
8.4 
Crossover .................................................................................................................................... 22 
8.5 
Compliance with study procedures ............................................................................................. 22 
8.6 
Data Collection and Follow-up for withdrawn participants .......................................................... 22 
 
. .................................................................................................................................................... 22 
8.7 
Concomitant medicaments .......................................................................................................... 22 
8.8 
Study Device Accountability ........................................................................................................ 23 
8.9 
Return or Destruction of Study device ........................................................................................ 23 
9. 
STUDY ASSESSMENTS ............................................................................................................... 23 
9.1 
Study flow chart(s) / table of study procedures and assessments .............................................. 23 
9.2 
Assessments of outcomes .......................................................................................................... 27 
Assessment of primary outcome .................................................................................................... 27 
Assessment of secondary outcomes ............................................................................................. 27 
Assessment of safety outcomes .................................................................................................... 27 
Assessments in participants who prematurely stop the study ....................................................... 27 
10. CARDIAC COMPUTER TOMOGRAPHY ANGIOGRAPHY .......................................................... 27 
10.1 CCTA PROTOCOL 19 .................................................................................................................. 27 
10.2 Adjunctive CCTA analyses .......................................................................................................... 28 
11. SAFETYREPORTING .................................................................................................................... 29 
11.1 Definitions .................................................................................................................................... 29 
11.2 Reporting of serious adverse events (SAE) and other safety related events ............................. 29 
11.3 Follow up of (Serious) Adverse Events ....................................................................................... 29 
12. STATISTICAL METHODS ............................................................................................................. 30 
12.1 Hypothesis ................................................................................................................................... 30 
12.2 Determination of Sample Size ..................................................................................................... 30 
12.3 Statistical criteria of termination of trial ....................................................................................... 30 
12.4 Planned Analyses ........................................................................................................................ 30 
Datasets to be analysed, analysis populations .............................................................................. 30 
Primary and secondary Analysis .................................................................................................... 30 
Interim analyses ............................................................................................................................. 30 
Safety analysis ............................................................................................................................... 30 
Deviation(s) from the original statistical plan ................................................................................. 30 
12.5 Handling of missing data and drop-outs...................................................................................... 30 
13. QUALITY ASSURANCE AND CONTROL ..................................................................................... 30 
13.1 Data handling and record keeping / archiving ............................................................................. 30 
13.2 Specification of source documents ............................................................................................. 31 
13.3 Data management ....................................................................................................................... 31 
13.4 Monitoring .................................................................................................................................... 31 
13.5 Audits and Inspections ................................................................................................................ 31 
13.6 Confidentiality, Data Protection ................................................................................................... 31 

Protocol SWISS APERO Version 5 /29.05.2020 
6/42 
14. PUBLICATION AND DISSEMINATION POLICY ........................................................................... 32 
15. FUNDING AND SUPPORT ............................................................................................................ 32 
16. INSURANCE .................................................................................................................................. 32 
17. REFERENCE ................................................................................................................................. 33 
APPENDIX 1: ENDPOINT AND ADVERSE CLINICAL EVENT DEFINITIONS 24 ................................ 35 
17.1 INDICATIONS FOR LAAC THERAPY ........................................................................................ 35 
17.2 MORTALITY DEFINITIONS ........................................................................................................ 35 
17.3 DIAGNOSTIC CRITERIA FOR STROKE AND TIA .................................................................... 37 
17.4 DEFINITION OF SYSTEMIC EMBOLISM .................................................................................. 38 
17.5 PULMONARY EMBOLISM ......................................................................................................... 38 
17.6 DEFINITIONS FOR SEVERITY AND TIME OF OCCURRENCE OF PERICARDIAL 
EFFUSION ............................................................................................................................................ 38 
17.7 BLEEDING DEFINITIONS .......................................................................................................... 38 
17.8 DEFINITION OF VASCULAR ACCESS-RELATED COMPLICATIONS ..................................... 39 
17.9 DEFINITION OF EPICARDIAL OR MINIMAL INVASIVE SURGICAL ACCESS-RELATED 
COMPLICATIONS ................................................................................................................................. 40 
17.10 DEVICE-RELATED COMPLICATIONS ...................................................................................... 40 
17.11 DEVICE RELATED THROMBOSIS ............................................................................................ 40 
17.12 SUCCESS DEFINITIONS ........................................................................................................... 40 
17.13 LAA PATENCY ASSESSED BY TEE ......................................................................................... 41 
17.14 FEASIBILITY OUTCOMES ......................................................................................................... 41 
17.15 STAGING SYSTEM FOR ACUTE RENAL INJURY ................................................................... 41 
18. APPENDIX 2: ISTRUCTIONS FOR USE ...................................................................................... 42 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
7/42 
STUDY SYNOPSIS 
Sponsor / Sponsor-
Investigator 
Inselgruppe AG - Inselspital - Bern University Hospital, 3010 Bern, Switzerland /  
Prof. Dr. med. Lorenz Räber, Cardiology, Bern University Hospital, Bern, 
Switzerland 
Coordinating 
Investigator 
Prof. Marco Valgimigli, MD PhD, Cardiocentro Ticino Via Tesserete 48 ,CH-6900 
Lugano; Switzerland 
Study Title: 
Comparison of Amplatzer Amulet vs Watchman device in patients undergoing left 
atrial appendage closure: a randomized clinical trial 
Short Title: 
SWISS-APEROrandomized clinical trial 
Protocol Version and 
Date: 
Version 5 /29.05.2020 
Trial registration: 
www.clinicaltrials.gov NCT03399851 
Study category and 
Rationale 
Clinical trial of device products, risk category A: all products are authorized in 
Switzerland and their use is according to the instructions for use. 
Clinical Phase: 
Phase 4 
Background and 
Rationale: 
Non-valvular Atrial fibrillation (NVAF) is the most common cardiac arrhythmia and a major 
cause of morbidity and mortality because of cardioembolic stroke. Cardiac embolism due to 
AF causes up to 25% of all ischemic strokes, which makes it socioeconomically highly 
relevant. Oral anticoagulation (OAC) with vitamin K antagonists (VKA) or Non-vitamin K 
antagonist anticoagulant (NOAC) is the most effective prophylaxis for stroke in AF. Yet, 
(N)OAC therapy is associated with a significant bleeding liability and long-term (N)OAC 
therapy in patients with NVAF and concomitant high bleeding risk poses safety issues in a 
sizable and growing population in clinical practice. Post-mortem and echocardiographic 
studies have shown that the vast majority of all cardiac thrombi in patients with NVAF form 
in the left atrial appendage (LAA). Thus, a new and emerging therapeutic option in this high-
risk patient population is the exclusion of the LAA cavity from the circulation via percutaneous 
intervention.  
Currently, the Amplatzer ACP/Amulet ™ (St. Jude Medical-Abbott), and the Watchman ™ 
(Boston Scientific, Natick, MA, USA)  are the devices with most clinical experience reported 
to date for percutaneous closure of LAA. The Watchman was tested in the setting of two 
randomized control trials, which demonstrated the safety of the procedure and the non-
inferiority in terms of stroke reduction compared to OAC. A second-generation device, the 
Watchman FLX was developed and released for simplified implantation to fit a wider range 
of patients and to enhance sealing within the left atrial appendage. It gained the CE mark at 
the begin of 2019. 
Until a few years ago in Europe the device most frequently utilized for LAA closure was the 
Amplatzer Cardiac Plug™ (ACP, St. Jude Medical-Abbott), which gained CE approval in late 
2008. There is no RCT comparing ACP with OAC, but many prospective and retrospective 
studies had shown the same safety profile and the non-inferiority with the OAC. A second-
generation device, the Amulet™, was developed and released in 2013 for easier delivery, 
better coverage, and reduction of complications. 
A critical step for each LAA closure procedure is the appraisal of LAA residual or new 
patency/leaks after device implantation. In the setting of available randomized trials (currently 
only limited to the Watchman device), successful closure was defined by the presence of a 
peridevice flow  5 mm assessed with TEE 45 days after the procedure. In these trials, as 
well as according to the current instruction for use of Watchman, the appraisal of residual 
leaks 45 days after LAAC was/is considered mandatory for a correct postprocedural 
management of pharmacotherapy (in terms of continuation or reinstitution of OAC therapy). 
Furthermore, there is a growing attention to the natural history of peridevice leaks given their 
unpredictable evolution.  
Currently the gold standard for the assessment of LAA patency after closure is the TEE. 
However it is an invasive and operator dependent examination, and replacing it with an 
alternative non-invasive exam is also desirable for patient’s comfort 
In the last years, several groups (including ours) assessed the value of CCTA as non-
invasive post-procedural surveillance imaging modality after endovascular LAA closure to 
evaluate residual leak and reported higher sensitivity for CCTA as compared to TEE in the 
identification of LAA residual patency. 
There are currently no randomized controlled trials assessing the degree of LAA closure 
between Amulet and Watchman/FLX. 
Primary Objective: 
To assess whether Amplatzer Amulet is superior to Watchman/FLX in terms of degree of 
LAA occlusion as evaluated by CCTA 45 days after implantation.   

Protocol SWISS APERO Version 5 /29.05.2020 
8/42 
Outcome(s): 
The primary outcome is the composite of LAA patency at 45 day CCTA or the crossover from 
one device to the other device based on morphological/anatomical considerations during 
device implantation.  
Secondary outcome include: 
 
LAA patency (arterial and/or venous phase) at 45 day CCTA and 13-month 
CCTA in the per protocol and as treated populations 
 
All cause of death, stroke, systemic or pulmonary embolism and spontaneous MI 
 
Cardiovascular death 
 
Ischemic stroke 
 
Hemorrhagic stroke 
 
Bleeding events according to the BARC classification at each follow-up. 
 
Procedure-related complications 
 
Rate of patients on (N)OAC at 45 days and 6 months 
 
Device related thrombosis (DRT) at 45 day TEE/CCTA and 13-month CCTA in 
the per protocol and as treated populations 
 
Feasibility outcome (number of device implantation attempts, total time 
procedure, x-ray dose and total contrast dose used in the procedure) 
 
LAA patency at 45 day TEE in the per protocol and as treated populations 
Study design: 
Randomized open-label multicentre trial. 
Inclusion / Exclusion 
criteria: 
 
Inclusion criteria 
 
Written informed consent 
 
Male or female subject aged 18 years or more with no upper age limit and willing 
to comply with the protocol 
 
Indication to a LAA closure as indicated in study population (HAS BLEED ≥3 or 
High bleeding risk as defined by Munich consensus document and CHA2DS2-
VASc≥2). 
Exclusion criteria: 
• 
New York Heart Association class IV congestive heart failure 
• 
ASD or atrial septal repair or closure device 
• 
Single occurrence of AF 
• 
Cardioversion or ablation procedure planned within 30 days 
• 
Implanted mechanical valve prosthesis 
• 
Heart transplantation 
• 
Enrolled in another IDE or IND investigation of a cardiovascular device or an 
investigational drug 
• 
Female of childbearing potential (age < 50 years and last menstruation within the 
last 12 months), who did not undergo tubal ligation, ovariectomy or hysterectomy 
• 
Active infection of any kind 
• 
Severe chronic kidney insufficiency (CrCl< 30 ml/min) 
• 
Terminal illness with life expectancy < 1 yr 
• 
Echocardiographic exclusion criteria 
• 
LVEF < 20% 
• 
Intra-cardiac thrombus or dense spontaneous echo contrast as visualized by 
TEE within 2 days before implant 
• 
Significant mitral valve stenosis (ie, MV <1.5 cm2) 
• 
Complex aortic atheroma with mobile plaque of the descending aorta and/or 
aortic arch 
• 
Cardiac tumor. 

Protocol SWISS APERO Version 5 /29.05.2020 
9/42 
Measurements and 
procedures: 
Patients with indication to LAA closure will be randomly assigned in a 1:1 ratio to Amulet or 
Watchman/FLX device implantation. In the event that the patient is randomized to the 
Watchman/FLX arm, the operator will be able to choose, on the basis of clinical reasons, if 
implant Watchman or the new generation Watchman FLX (if available in the center).Study 
procedures will be as follows:  
 
A CCTA will be performed before the procedure as per standard of care in order 
to obtain the morphological features of LAA (useful for the procedure planning)  
and to exclude the presence of LAA thrombus. 
 
Implantation will be performed according to device specific instruction for use and 
latest consensus document5, based on preprocedural CCTA images, TEE 
guidance and angiography.  
 
After the procedure, patients will receive acetylsalicylic acid (ASA) and 
clopidogrelor (N)OAC at discretion of the treating physician(according to the 
bleeding risk, the stroke risk and intra-procedural TEE evaluation) for 45 days 
and then will undergo TEE as well as CCTA) assessment. 
o 
If a residual peridevice leak flow > 5 mm or a an intra-cardiacthrombus 
is detected, treatment with ASA and (N)OAC should be considered up 
a sequential TEE evaluation at 6 months. Final decision to implement 
an OAC regimen with or without ASA will eventually be left to the 
discretion of the treating physician taking the ischemic ad bleeding risk 
into account; 
o 
If residual peridevice leak flow  5 mm, patients will receive ASA and 
clopidogrel or (N)OAC (at discretion of the treating physician according 
to the bleeding and stroke risks)up until 3 months after procedure. 
Thereafter, monotherapy with ASA will be continued until 12 months 
after procedure. 
Further follow-ups will take place at 13months and yearly until 5 years. 
Study Product / 
Intervention:  
The WATCHMAN (Atritech, Boston Scientific, Natick, MA, USA) LAAC technology consists 
of the Access System (Access Sheath and Dilator) and Delivery System (Delivery Catheter 
and WATCHMAN Device). The Access System and Delivery System permit Device 
placement in the left atrial appendage (LAA) via femoral venous access and inter-atrial 
septum crossing into the left atrium. WATCHMAN device is a self-expanding nitinol structure 
with a porous covering on the proximal face. The device is constrained within the Delivery 
System until deployment in the LAA. The Device is available in 5 sizes from 21 to 33 mm. 
The new generation Watchman FLX has a shorter device length and a less taper angle  to 
simplify implantation and to fit a wider range of patients, Furthermore, the frame of the new 
device is designed to enhance sealing within the left atrial appendage. 
 
The AMPLATZER Amulet (St. Jude Medical-Abbott) is a self-expanding device made of 
nitinol that has a distal lobe and a proximal disc, connected by an articulated waist. The 
device lobe has six to 10 pairs of stabilising wires and is meant to be implanted in the proximal 
10-15 mm of the left atrial appendage (LAA), whereas the device disc is intended to cover 
the ostium at the left atrial side. The proximal female screw is recessed to minimise thrombus 
formation on the disc and potentially facilitate re-attachment of the device to the pusher 
screw. The lobe sizes range from 16 to 34 mm.  
Number of 
Participants with 
Rationale: 
Total number of patients with primary endpoint assessment: 200 
100 patients in the Watchman/FLX group 
100 patients in the Amplatzer Amulet group 
Sample size is calculated to state superiority of Amplatzer Amulet compared with 
Watchman/FLX 
Study Duration: 
8 years 
Study Schedule: 
February 2018 
February 2026 

Protocol SWISS APERO Version 5 /29.05.2020 
10/42 
Statistical 
Considerations: 
Assuming an incidence of the primary composite end-point in the range of 50% in the 
Watchman/FLX group, which is a conservative estimate based on previous reports, 200 
patients will provide greater than 80% power to prove superiority of Amulet as compared to 
Watchman/FLX assuming a 40% risk reduction (i.e. corresponding to an event rate in the 
range of 30%) and a significance level of 5% (alpha). 
Primary and secondary end points will be analysed on an intention-to-treat basis. Additional 
analyses of the primary endpoint will be also carried out in the per-protocol and as-treated 
populations. Similarly, LAA patency and DRT at 45-day and 13-month CCTA and at 45-day 
TEE as well as clinical outcomes will also be analyzed in the per-protocol and as-treated 
population.Categorical outcome measures will compared using a χ2 test or Fisher exact test 
as required. Continuous variables will be compared using a 2-sided unpaired t test or a 
Mann-Whitney test, as appropriate. Estimation of the cumulative incidence of safety and 
efficacy endpoints will be performed using the Kaplan-Meier method, and event rates will be 
compared by the log rank test The estimated relative risk (RR) is the ratio of the risk 
probabilities, and a confidence interval will constructed based on a logarithmic 
transformation. Correlations between variables will analysed with a Cox regression. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all 
national legal and regulatory requirements.  
ABBREVIATIONS 
 
AF 
Atrial fibrillation 
ACP 
Amplazer Cardiac Plug 
ACT 
Activated clotting time 
AE 
AESI 
Adverse Event  
Adverse Event of Special Interest 
ASA 
BARC 
Acetylsalicylic acid 
Bleeding Academic research Consortium 
CA 
Competent Authority (e.g. Swiss medic) 
CCTA 
Cardiac computed tomography angiography 
CEC 
Clinical Events Committee 
CTU 
Clinical Trials Unit 
CV 
Cardiovascular 
DAPT 
DRT 
Dual antiplatelet therapy 
Device related Thrombosis 
EC 
ECG 
Ethics Committee 
Electrocardiogram 
eCRF 
Electronic Case Report Form  
EMA 
EuropeanMedicines Agency 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
H1 
Alternative hypothesis 
HBR 
High bleeding risk 
Ho 
ICE 
Null hypothesis 
Intracardiac echocardiography 
ISO 
International Organisation for Standardisation 
LAA 
Left atrial appendage 
LAAC 
Left atrial appendage closure 
LUPV 
Left upper pulmonary vein 

Protocol SWISS APERO Version 5 /29.05.2020 
11/42 
NOAC 
New oral anti-coagulation 
NVAF 
Non-valvular atrial fibrillation 
OAC 
Oral anti-coagulation 
PDL 
Perideviceleak 
PI 
Principal Investigator  
PREVAIL 
Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients with 
Atrial Fibrillation Versus Long Term Warfarin Therapy 
PROTECT AF 
Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of 
stroke in patients with atrial fibrillation: a randomised non-inferiority trial 
RCT 
Randomized clinical trial 
SAE 
Serious Adverse Event 
TEE 
Transesophageal echocardiography 
TIA 
Transient Ischemic Attack 
VKA 
Vitamin K antagonist 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
12/42 
STUDY SCHEDULE 
 
Study Periods 
 
Enrol
ment 
Proce
dure 
Post 
procedural 
Hospital 
discharge 
45- day 
follow 
up 
6- month 
follow up 
13-
month 
follow up 
2- year 
follow 
up 
3- year 
follow 
up 
4-year 
follow 
up 
5-year 
follow 
up 
Time point 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Time  
-90 / 
0 d 
0 d 
up to 48 h 
45±7 d 
180±7 d 
395 
±30 d 
730±30 
d 
1095 
±30 d 
1460 
±30 d 
1825 
±30 d 
Type of follow 
up1 
 
 
 
Medica
l 
contact  
Medical 
contact 
orphone2 
Medical 
contact 
or 
phone2 
Medica
l 
contact 
or 
phone2 
Medica
l 
contact 
or 
phone2 
Medica
l 
contact 
or 
phone2 
Medica
l 
contact 
or 
phone2 
Patient 
Information 
and Informed 
Consent 
 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Medical 
History 
x 
 
 
x 
 
x 
x 
x 
x 
x 
In- /Exclusion 
Criteria 
x 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
x 
 
x 
x 
 
(x) 
(x) 
(x) 
(x) 
(x) 
Vital Signs 
x 
 
x 
x 
 
x 
x 
x 
x 
x 
Laboratory 
test2 
x 
 
x 
 
 
 
 
 
 
 
Randomizatio
n 
X5 
 
 
 
 
 
 
 
 
 
12 lead ECG 
x 
x 
x 
x 
 
(x) 
(x) 
(x) 
(x) 
(x) 
TEE 
x3 
x4 
 
x4 
x3 
(x)3 
 
 
 
 
CCTA 
x4 
 
 
X5 
 
(x)5 
 
 
 
 
Concomitant 
therapy, 
Intervention 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
LAAC 
 
x 
 
 
 
 
 
 
 
 
AESI6 and 
SAE collection 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1All types of follow up will be described in Section 9.1. 
2In case of impossibility of a follow up by medical contact a telephone contact should be performed. It will consist 
of reporting vital status, adverse  events of special interest (as defined in 11.1) and pharmacotherapy.  
3Performed if clinically indicated 
4:As per standard of care 
5:Study specific intervention 
6As defined in 11.1 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
13/42 
1. STUDY ADMINISTRATIVE STRUCTURE 
1.1 Sponsor 
This is an Investigator Initiated Trial, the Sponsor is Inselgruppe AG - Bern University Hospital, 3010 Bern, 
Switzerland. 
1.2 Principal Investigator(s) 
Sponsor Investigator/CoordinatingInvestigator: 
Prof. Dr med, Lorenz Räber, InselspitalUniversitätsspital, Freiburgstrasse 8, 3010 Bern (CH). Phone: +41 31 632 
2111 
A Local Principal Investigators will be appointed at every center involved in the trial. 
 
1.3 Statistician 
Clinical Trials Unit – University of Bern - Finkenhubelweg 11, 3012 Bern, Phone +41 31 631 35 56 
1.4 Any other relevant Committee, Person, Organisation, Institution 
Clinical Event Committee for Adjudication of clinical events endpoints will be defined prior to the first patient 
enrolment. 
2. ETHICAL AND REGULATORY ASPECTS 
The decision of the competent Ethics Committee (EC) concerning the conduct of the study will be made in writing 
to the Sponsor-Investigator before commencement of this study. The clinical study can only begin once approval 
from all required authorities has been received. Any additional requirements imposed by the authorities shall be 
implemented. 
2.1 Study registration 
www.clinicaltrials.gov  NCT03399851 
www.kofam.ch 
2.2 Categorisation of study 
Category A 
This is a clinical trial of medical devices. The devices used for the study (Amplatzer Amulet and Watchman/FLX) 
are authorised in Switzerland and used in accordance with the Instructions for Use (Appendix 2). The risk 
category is A. 
Premature study end or interruption of the study will be reported to the EC within 15 days. The regular end of the 
study will be reported within 90 days, the final study report shall be submitted within one year after study end.  
2.3 Ethical Conduct of the Study and declaration of interests 
The study will be carried out in accordance to the protocol and with principles enunciated in the current version of 
the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, the European Directive 
on medical devices 93/42/EEC and the ISO Norm 14155, the Swiss Law and Swiss regulatory authority’s 
requirements. The EC will receive annual safety reports and be informed about study stop/end in agreement with 
local requirements.  
The study will be conducted with intellectual, financial and property independence. The financial support from St. 
Jude Medical-Abbott (see section 15) will be disclosed. 
2.4 Patient Information and Informed Consent 
The investigators will explain to each participant the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits and any discomfort it may entail. Each participant will be informed 
that the participation in the study is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical assistance and treatment.  
The participant must be informed that his/her medical records may be examined by authorised individuals other 
than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form describing the study 

Protocol SWISS APERO Version 5 /29.05.2020 
14/42 
and providing sufficient information for participant to make an informed decision about their participation in the study. 
The patient information sheet and the consent form will be submitted to the EC to be reviewed and approved. The 
formal consent of a participant, using the approved consent form, must be obtained before the participant is 
submitted to any study procedure.   
The participant on the procedure’s day (or on the day before) should read and consider the statement before signing 
and dating the informed consent form, and will be given a copy of the signed document. The consent form must 
also be signed and dated by the investigator (or his designee) and it will be retained as part of the study records. 
2.5 Participant privacy and confidentiality 
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall comply with 
applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when presenting the data at 
scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and disclosure to 
third parties is prohibited. Subject confidentiality will be further ensured by utilising subject identification code 
numbers to correspond to treatment data in the computer files and eCRF. 
For data verification purposes, authorised representatives of the Sponsor (-Investigator), a competent authority (e.g. 
Swissmedic), or an ethics committee may require direct access to parts of the medical records relevant to the study, 
including participants’ medical history. 
2.6 Early termination of the study 
The Sponsor-Investigator (and any competent authority) may terminate the study prematurely according to certain 
circumstances, for example: 
 
Ethical concerns, 
 
Insufficient participant recruitment, 
 
When the safety of the participants is doubtful or at risk, respectively, 
 
Alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
 
Early evidence of benefit or harm of the experimental intervention. 
2.7 Protocol amendments 
Substantial amendments are only implemented after approval of the EC. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-being of human 
subjects may proceed without prior approval of the sponsor and the EC. Such deviations shall be documented and 
reported to the sponsor and the EC as soon as possible. 
All non-substantial amendments are communicated to the EC within the Annual Safety Report (ASR).  
3. BACKGROUND AND RATIONALE 
3.1 Background and Rationale 
Atrial fibrillation (AF) is the most common cardiac arrhythmia and a major cause of morbidity and mortality because 
of cardioembolic stroke. The prevalence of AF increases with age up to 15% in high octogenarians and continues 
to grow rapidly because the proportion of the aging population is increasing just as the prevalence of predisposing 
conditions for AF such as diabetes, heart failure, hypertension, and coronary heart disease6. Cardiac embolism 
because of AF causes up to 25% of all ischemic strokes, which makes it socioeconomically highly relevant7. Oral 
anticoagulation (OAC) with vitamin K antagonists (VKA) or Non-vitamin K antagonist anticoagulant (NOAC) is the 
most effective prophylaxis for stroke in AF. Yet, (N)OAC therapy is associated with a significant bleeding liability 
and long-term (N)OAC therapy in patients with NVAF and concomitant high bleeding risk poses safety issues in a 
sizable and growing population in clinical practice. Postmortem and echocardiographic studies have shown that the 
vast majority of all cardiac thrombi in patients with AF form in the left atrial appendage (LAA)8. Thus, a reasonable 
alternative is the exclusion of the LAA cavity from the circulation.9 
Currently, the Amplatzer ACP/Amulet ™ (St. Jude Medical-Abbott), and the Watchman ™ (Boston Scientific, 
Natick, MA, USA)  are the devices with most clinical experience reported to date for percutaneous closure of LAA. 
The Watchman was tested in the setting of two randomized control trials. The PROTECT AF10 (Percutaneous 
closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial 
fibrillation: a randomised non-inferiority trial) trial was a multicentre, randomized controlled trial in NVAF patients 
comparing the Watchman device to warfarin for a composite primary endpoint of stroke, systemic embolism, and 
cardiovascular (CV) death. Noninferiority to warfarin was documented early and long term (2,621 patient-years 
[PY]), LAA closure (LAAC) demonstrated a significant (40%) relative risk reduction to warfarin for the primary 
efficacy endpoint, an 85% relative risk reduction in hemorrhagic stroke, a 60% relative reduction in CV mortality 

Protocol SWISS APERO Version 5 /29.05.2020 
15/42 
(absolute annual risk reduction of 1.4%), and a 34% relative reduction in all-cause mortality (absolute annual risk 
reduction of 1.6%). 
The PREVAIL trial11 (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With 
Atrial Fibrillation Versus Long Term Warfarin Therapy) was a confirmatory randomized trial comparing LAAC with 
the Watchman™ device to warfarin, which mandated inclusion of new operators, slight modifications in inclusion 
criteria, and elimination of 7-day clopidogrel therapy before implantation. Bayesian statistical methodology was 
agreed upon using informative prior data from the PROTECT AF trial. At the pre-defined evaluation time point, the 
PREVAIL trial demonstrated improved safety compared to the PROTECT AF trial, and non-inferiority of 1 of the 2 
co-primary efficacy endpoints; an 18-month rate ratio (RR) for primary efficacy, and an 18-month rate ratio 
difference for post-procedure ischemic stroke and systemic embolism. A second-generation device, the 
Watchman FLX was developed and released for simplified implantation to fit a wider range of patients and to 
enhance sealing within the left atrial appendage. It gained the CE mark at the begin of 2019. 
Until a few years ago, in Europe the device most frequently utilized for LAA closure was the Amplatzer Cardiac 
Plug™ (ACP, St. Jude Medical-Abbott), which gained CE approval in late 2008. The ACP study was recently 
published, including data from 1,047 consecutive patients treated in 22 centers12 It showed a favourable outcome 
for the prevention of AF-related thromboembolism with an annual reduction of 59% as compared to the rate 
predicted by the CHA2DS2-VASc score, and a 61% annual reduction in major bleeding events as compared to the 
rate predicted by the HAS- BLED score. A second-generation device, the Amulet™, was developed and released 
in 2013 for easier delivery, better coverage, and reduction of complications. Similar to the first generation ACP 
device, Amulet is engineered with a distal hook-crowned lobe for anchoring in the lumen of the LAA and a proximal 
disc for excluding the ostium of the LAA according to the pacifier principle. This plug and disc concept is different 
from the plug only design of Watchman/FLX device.  
A critical step for each LAA closure procedure is the appraisal of LAA residual or new patency/leaks after device 
implantation. Kanderian et al 13 showed a trend towards a decreased risk of post procedural cerebral embolism in 
patients with successful LAA surgical closure as compared to  patients with a perideviceleak >1cm assessed with 
trans-esophageal echocardiography (TEE) at 8 months after  intervention. In the setting of available randomized 
trials (currently only limited to the Watchman device), successful closure was defined by the presence of a 
peridevice flow  5 mm assessed with TEE 45 days after the procedure. In these trials, as well as according to the 
current instruction for use of Watchman, the appraisal of residual leaks 45 days after LAAC was/is considered 
mandatory for a correct postprocedural management of pharmacotherapy (in terms of continuation or reinstitution 
of OAC therapy). Whether a similar practice should be implemented after Amulet or other devices is still unclear 
given the lack of controlled randomized data comparing this specific device with current standard of care consisting 
of oral anticoagulation. It is relevant to emphasize here that while across pooled Watchman trials there is no clear 
evidence that the presence or the size of peridevice leaks are associated to higher risk of stroke or systemic 
embolism, the protocols have mandated the continuation or re-institution of OAC therapy in all cases where a leaks 
of 5 mm or greater was observed at the end of the procedure or at follow-up. Therefore, it remains highly probable 
that the risk associated to the presence of peridevice leaks has been mitigated by the concomitant use of this 
imaging-based pharmacological intervention.  
Furthermore there is a growing attention to the natural history of peridevice leaks. Freixa et al 14 showed that 
among twenty-five patients treated with LAAC, the two patients with major leaks after device deployment did not 
show significant leaks at follow-up (8 months after procedure) whereas the two patients with major leak at follow-
up did not show significant leaks after device deployment. Given the unpredictable evolution of peridevice leaks, it 
is becoming clear the need for a long term imaging follow-up (both short and long-term after LAAC).  
Currently the gold standard for the assessment of LAA patency after closure is the TEE. However it is an invasive 
and operator dependent examination, and replacing it with an alternative non-invasive exam is also desirable for 
patient’s comfort. Saw et al 15 reported a case series of 45 patients treated both with ACP than with Watchman, 
with a CCTA and TEE performed at follow-up. This study reported higher sensitivity for CCTA as compared to TEE 
in the identification of LAA residual patency. At TEE evaluation, only half of the patients where LAA patency was 
documented at CCTA were confirmed to have a leak as assessed by standard criteria. In particular, authors 
described a series of 23 patients treated with LAAC in whom both TEE and cardiac CT were available at follow up. 
Authors observed that cardiac CT identified as many as 52% of LAA patent after intervention as compared with 
only 34% at TEE. In patients in whom LAA was patent at CT patent LAA, only 58% were also recognized by TEE 
suggesting that CT would be able to identify patency that would be not recognized at TEE. Also, by measuring the 
HU in the LAA distal to the device and comparing the contrast density with surrounding cardiac chambers, they also 
noted that all patients with occluded LAA at TEE had a value <100 HU, suggesting this as threshold for cardiac CT 
evaluation. In addition, Jaguszewski et al 16 reported a series of 19 patients in whom both cardiac CT and TEE were 
performed after LAAC. The rates of patency were 62% and 36% identified by CT and TEE respectively. These two 
pivotal investigations have suggested a two-fold higher sensitivity for CT as compared to TEE in identifying the 
presence of device leaks both immediately after as well as during follow-up in LAAC patients. Importantly, the lower 
than expected sensitivity towards LAA leaks after closure may contribute to explain the apparently lack of 
association between presence/size of LAA leaks and increased stroke risk, in addition to the fact that (as alluded 
to above) those patients with greater LAA leaks (i.e. those also indetified at TEE) were freqneutjly concomitantly 
treated with OAC.  
Recently our group has retrospectively analyzed 56 patients who underwent LAACof whom 40 who received TEE 
as well as a clinically indicated CCTA after intervention.17 ACP Amplatzer was used in 38 (67.9%) patients, while 
Amulet in 12 (21.4%) and Watchman in 6 (10.7%) patients. TEE guidance was used in 3 cases only, all receiving 
the Watchman device. Device success was achieved in 100% of cases, while technical and procedural success 

Protocol SWISS APERO Version 5 /29.05.2020 
16/42 
was obtained in 53 cases (94.6%). The median time from LAAC to CT was 217 [86-401] days, whereas median 
time from LAAC to TTE was 90 [74-131] days. Based on 100 HU cut-off value, 24/56 (43%) patients had patent 
LAA after intervention (i.e. >100 HU measured in the LAA). The mean HU of LAA was significantly higher in patent 
LAA as compared with occluded LAA (209.0±67.3 vs. 63.8±21.8; p<0.001), whereas HU, as measured in LA, did 
not differ between the two groups. LAA/LA HU ratio was also significantly higher in patients with patent LAA 
(0.65±0.2 vs. 0.25±0.1; p<0.001). Using CT patency as gold standard, we calculated that a cutoff of 0.43 for the 
LAA/LA HU ratio provided a 92% of sensitivity and 94% specificity, with an AUC of 0.94. When the 
echocardiographic criteria recommended by the ACP/Amulet device manufacturer were applied to CT images, at 
least 2 mm separation between the lobe and the pacifier disk was identified in 46/50 (92%) of cases; the disc was 
concave at visual estimation in 47/50 (94%) of cases; the lobe was implanted at least 2/3 deeper than the circumflex 
artery crossing axis in 30/50 (60%) cases; the lobe and the disk were aligned in 36/50 (72.0%) of cases; finally > 
10 % lobe compression was present in 24/50(48%) of patients. None of the above reported criteria, either separately 
or in combination, differ between patients with or without patent LAA at CT images. Multiplanar reconstruction of 
CT images identified lack of proximity between the disk and LAA ostium as obvious reasons for LAA patency in 
22/24 cases (91.7%), of whom 15 (68%) were in the posterior quadrants.  Therefore, these three retrospective 
series of patients who underwent LAAC do consistently suggest that only CCTA can reliably indentify all patients 
with LAAC who present shortly after or at later time point peridevice leaks.  
There are currently no randomized controlled trials assessing the degree of LAA closure between Amulet and 
Watchman/FLX.  
Kim et al 18 reported in a retrospective series of 96 patients treated with both devices a similar rate of procedure 
success and complications, similar clinical outcome for two devices, but peridevice leakage was more frequent with 
the Watchman than the ACP (37% vs 14.9% p=0.015).  
 
An additional role of pre- and post-procedural CCTA is its capability to reliable detect the presence of LAA/LAA 
device thrombus as well as allowing a proper device sizing in the planning phase of the procedure.19 
Indeed, it is well recognized that a preprocedural CCTA improves proper sizing of the LAAC device and is useful to 
detect LAA thrombus before LAAC. Nowadays many centres across the world including ours, recommend CCTA 
before and frequently after the planned intervention. 
 
3.2 Medical Devices and Indication 
The WATCHMAN (Atritech, Boston Scientific, Natick, MA, USA) LAAC technology consists of the Access System 
(Access Sheath and Dilator) and Delivery System (Delivery Catheter and WATCHMAN Device). The Access 
System and Delivery System permit Device placement in the left atrial appendage (LAA) via femoral venous access 
and inter-atrial septum crossing into the left atriumWATCHMAN device is a self-expanding nitinol structure with a 
porous covering on the proximal face. The device is constrained within the Delivery System until deployment in the 
LAA. The Device is available in 5 sizes from 21 to 33 mm.The new generation Watchman FLX has a shorter device 
length and a less taper angle  to simplify implantation and to fit a wider range of patients, Furthermore, the frame 
of the new device is designed to enhance sealing within the left atrial appendage. 

Protocol SWISS APERO Version 5 /29.05.2020 
17/42 
The AMPLATZER Amulet (St. Jude Medical-Abbott) is a self-expanding device made of nitinol that has a distal lobe 
and a proximal disc, connected by an articulated waist. The device lobe has six to 10 pairs of stabilising wires and 
is meant to be implanted in the proximal 10-15 mm of the left atrial appendage (LAA), whereas the device disc is 
intended to cover the ostium at the left atrial side. The proximal female screw is recessed to minimise thrombus 
formation on the disc and potentially facilitate re-attachment of the device to the pusher screw. The lobe sizes range 
from 16 to 34 mm. 
3.3 Preclinical Evidence 
Not applicable, all the devices used in this study have been previously approved for use in humans in the context 
of LAAC. 
3.4 Clinical Evidence to Date 
Addition to the two randomized clinical trials previous reported, there are many prospective and retrospective study 
reported both for the Watchman that for the Amulet the safety and efficacy of the LAAC procedure. In a recent 
meta-analysis, Xu et al.20  reported the data of 2779 patients underwent to LAAC with the two devices. They reported 
a rate of stroke about 1.2/100 person-year, with a rate of major bleeding (that is the most important procedure 
adverse event) of 2.6%. 
3.5 Explanation for choice of comparator 
The two devices selected for this study are the two most used in Europe. No previous randomized studies are 
reported about the comparison between the two devices in terms of safety and efficacy and between the two 
evaluation techniques (CCTA and TEE). 
3.6 Risks / Benefits 
Patients will not be exposed to any adjunctive procedural hazard by participating into the present study because 
LAAC is a clinically-indicated procedure in this specific patient population. As previously described, AF patients are 
at risk of cardioembolic stroke. So it is mandatory to prescribe an anticoagulant therapy if AF is detected. The most 
important risk of this therapy is related to bleeding events. On the other side, the interventional procedure itself 
exposes the patient to the risk of possible complications, sometimes also severe such as migration/embolization of 
the device or major bleeding (pericardial effusion or pericardial tamponade) requiring an intervention. However, as 
reported in literature, these events are rare and their incidence is lower than the incidence of stroke in AF patients 
or as compared to the risk of bleeding complications inpatients taking (N)OAC. 
Patients are to receive, as per current standard of care, CCTA before LAAC and TEE both during the procedure 
and at follow-up.  As multiple reports 21 exist indicating that CCTA improves proper sizing of the LAAC device and 
is useful to detect LAA thrombus before LAAC, nowadays many centres across the world including ours, 
recommend CCTA before (and frequently after) the planned intervention. 
The only added risk in this study for the participating patients is represented by the routine performance of two 
CCTAs undertaken  after the procedure, since these diagnostic assessments are, at least partially, study-specific 
procedures.  As previously described,  we will use the CCTA performed 45 days after procedure as primary endpoint 
measure since it is more sensitive in detecting LAA leaks after LAAC as compared to TEE15, and CCTA at 13 
months after procedure as secondary endpoint measure to better charachterize the natural history of peridevic 
leak(s). Replacing TEE with CCTA is also desirable for patients as it is non-invasive and less time consuming.  
Unlike TEE however, CCTA is associated to ionizing radiation to patients and contrast exposure. With the most 
recent technology and new acquisition protocols, the radiation dose for each exam is lower than 5 mSv. In a recent 
publication,19 the median radiation dose (range) for the dual-phase protocol of patients submitted to a CCTA for 
LAA evaluation prior LAAC was 3.5 mSv (2.1–5.2 mSv), with a dose-length product (DLP) of 251 mGy cm (150–
374).  However taking all CCTAs performed before the index procedure, after 45 days and after 13±1 months into 
account, the total dose per year is projected to exceed the limit of 5mSv yearly limit and so, as required by Ordinance 
on Clinical Trials in Human Research of 20 September 2013 (Status as of 1 January 2018- Sect.2 Art. 28), an 
additional submission to the FOPH will be accomplished. 
 
Since patients with reduced kidney function (i.e. CrCl< 30 ml/h/kg) are excluded, we believe additional contrast 
exposure will not result in additional kidney injury in our patient population. 
 
3.7 Justification of choice of study population 
High bleeding risk (HBR) patients are the ones that most benefit from the LAAC, as it suppresses the need for 
chronic anticoagulation therapy. 

Protocol SWISS APERO Version 5 /29.05.2020 
18/42 
4. STUDY OBJECTIVES 
4.1 Overall Objective 
The purpose of this study is to compare the efficacy and safety of the two devices for the LAAC. 
4.2 Primary Objective 
The main objective is to evaluate the feasibility and the efficacy of the devices in terms of LAA complete occlusion 
with a non-invasive imaging technique such as CCTA. 
4.3 Secondary Objectives 
Other secondary objectives will include the incidence of adverse clinical events in the two groups, a comparison 
between the two devices in terms of  procedure feasibility, LAA patency and device thrombus over time as assessed 
with both 45-day and 13-month CCTA and with 45 day TEE. Furthermore, a secondary objective of the study will 
bethe comparison between TEE and CCTA with respect to LAA patency and device thrombus. 
4.4 Safety Objectives 
Safety objective is to show that there is no significant difference in terms of procedure complications up to 48 hours 
from randomization across the two groups. 
5. STUDY OUTCOMES 
5.1 Primary Outcome 
The study primary endpoint is the composite of LAA patency at 45 day evaluated with CCTA or the crossover from 
one device to the other device based on morphological/anatomical considerations during device implantation.  
Post-intervention LAA patency will also assessed via TEE based on the more conservative criterion of residual flow 
≥ 3 mm. 
5.2 Secondary Outcomes 
Secondary end-points include1: 
 
LAA patency (arterial and/or venous phase) at 45-day and 13-month CCTA in the per protocol and as 
treated populations 
 
All cause of death, stroke, systemic or pulmonary embolism and spontaneous MI 
 
Cardiovascular death 
 
Ischemic stroke 
 
Haemorrhagic stroke 
 
Bleeding events according to the BARC classificationat each follow up. 
 
Procedure-related complications2 
 
Rate of patients on (N)OAC at 45 days and 6 months 
 
Device related thrombosis (DRT) at 45 day TEE/CCTA and 13-month CCTA in the per protocol and as 
treated populations 
 
Feasibility outcome (number of device implantation attempts, total time procedure, x-ray dose and total 
contrast dose used in the procedure) 
 
LAA patency at 45 day TEE in the per protocol and as treated populations 
Adverse clinical events will be assessed at up to 48 hours or discharge whichever comes first,  at 45 days, and 
yearly. 
 
1 For the definitions of endpoint and adverse clinical events see the Appendix 1. 
2As defined in 5.3. 
5.3 Procedure-related complications1 
Procedure related complications are defined as adverse clinical events occurring during the procedure or within 7 
days after. In particular, the following complicationswill be adjudicated by the Clinical Events Committee (CEC) : 
death, TIA/stroke, systemic and pulmonary thromboembolic event, pericardial effusion, cardiac tamponade, air 
embolism, bleedings vascular access-related complications, epicardial or minimal invasive surgical access-related 
complications, device complications and acute renal injury. Any events potentially related to the above 
complications (“adverse events of special interests” [AESI], see the definition in the section 11)  should be reported 
into the ecrf.  
1For the definitions of endpoint and adverse clinical events see the Appendix 1. 
 

Protocol SWISS APERO Version 5 /29.05.2020 
19/42 
5.4 Other Outcomes of Interest 
A comparison between CCTA and TEE at 45 days and then at 13 months will be performed in order to obtain a 
validation of CCTA to reveal the LAA patency. 
5.5 Safety Outcomes 
Main safety outcomes are: 
 
Bleeding Academic Research Consortium (BARC) bleeding grade 2, 3 and 5 at  up to 48 hours or 
discharge whichever comes first and 45 days 
 
Net adverse clinical events (NACE) defined as the composite of death, fatal and non-fatal stroke, 
peripheral embolizationand BARC 2, 3, or 5 at  up to 48 hours or discharge whichever comes first and 
45 days 
 
Device related thrombosis at 45 day TEE/CCTA and 13-month CCTA in the per protocol and as treated 
populations 
5.6 Feasibility Outcomes 
A composite of following outcomes will be analysed in order to assess the feasibility of two devices: 
 
Number of attempts of LAA closure with a single device. 
 
Number of same type device used in a procedure. 
 
Total time procedure, x-ray dose and total contrast dose used in the procedure. 
6. STUDY DESIGN 
6.1 General study design and justification of design 
This will be a multicentre, open-label, prospective, randomized study in patients with AF and an indication for 
anticoagulant therapy with high bleeding risk, that agree to the LAAC procedure. Patients will be submitted to a 
screening protocol in a period not greater than 90 days before procedure, including medical and drug history, 
physical examination, 12-lead ECG, CCTA(as per standard of care) and TEE if clinically indicated. 
Once the patient is judged eligible and the informed consent has been signed, the patient will be randomly assigned 
in a 1:1 to receive a LAAC with Amplatzer Amulet or Watchman/FLX device. In the event that the patient is 
randomized to the Watchman/FLX arm, the operator will be able to choose, on the basis of clinical reasons, if to 
implant Watchman or the new generation Watchman FLX (if available in the center). 
Sizing device and implantation will be performed according to common practice guidelines5 (and so based on both 
preprocedural CCTA and intraprocedural TEE-angiography images). Furthermore, as recommended by the recent 
consensus document,5 the first operator will be able to choose if use intracardiac echocardiography (ICE) instead 
of TEE to guide the procedure, on condition that a  TEE evaluation is performed within 2 days before the procedure 
(in order to exclude LAA thrombus, to confirm the LAA suitability for both devices and to make the device sizing). 
Angiography at the end of the procedure is recommended to assess PDL. In case of concomitant procedure during 
LAAC, it will be reported separately in term of duration time, contrast dose and x-ray dose. 
At the end of procedure, a measure of PDL must be provided. 
A transthoracic echocardiogramis encouraged (but not mandatory) before the hospital discharge in order to detect 
pericardial effusion. 
All patients randomly allocated to the Watchman/FLX or Amulet arm will receive acetylsalicylic acid (ASA) and 
clopidogrel or (N)OAC (at discretion of the treating physicianand according to the bleeding risk,stroke risk as well 
as based on  post-procedural TEE evaluation) for 45 days and then will undergo TEE assessment(as well as CCTA): 
o 
If a residual peri-device leak flow at 45 days> 5 mm or a intra-cardiac thrombus is detected, a 
therapy with ASA and (N)OACcould be consideredup a sequential TEE evaluation at 6 months.  
o 
If a residual peri-device leak flow at 45 days 5 mm is detected, patients will continue to receive 
ASA and clopidogrelor(N)OAC (at discretion of the treating physician according to the bleeding 
and stroke risk)up until 3 months after procedure. Thereafter, monotherapy with ASA will be 
continued until 12 months after procedure. 
 
These drug regimensare strongly recommended according the actually evidence and the instruction for use of the 
two devices (Appendix 2). Nevertheless, if a clinical condition lead to prescribe other drugs regimen, it will be 
permitted given an exhaustive explanation by physician.   
Further procedures, such as physical examination or blood sampling will be done according the study schedule and 
Section 9, in particular visits or phone calls will take place after 6 and 13 month as well as 2/ 3/ 4/ 5 years. 
 

Protocol SWISS APERO Version 5 /29.05.2020 
20/42 
6.2 Randomization 
Balanced (1:1) randomization will be performed via a web-based interactive randomization system (ICE-Advice 
Pharma), based on a computer-generated random sequence with a random block size stratified according to site 
and a allocation to either Amulet Amplatzer device or Watchman/FLX. In the event that the patient is randomized 
to the Watchman/FLX arm, the operator will be able to choose, on the basis of clinical reasons, if to implant 
Watchman or the new generation Watchman FLX (if available in the center). Randomization will occur as close as 
possible to but always before the procedure and once the patient is judged eligible and the informed consent has 
been signed.  
 
6.3 
Other methods of minimising bias 
Not applicable. 
7. STUDY POPULATION 
7.1 Eligibility criteria 
Participants fulfilling all the following inclusion criteria are eligible for the study: 
 
Written informed consent 
 
Male or female subject aged 18 years or more with no upper age limit and willing to comply with the 
protocol 
 
Indication to a LAA closure as indicated in study population (HAS BLEED ≥3 or High bleeding risk as 
defined by Munich consensus document and CHA2DS2-VASc≥2). 
 
1 For the definitions of high bleeding risk (HBR) see Appendix 1. 
 
The presence of anyone of the following exclusion criteria will lead to exclusion of the participant: 
 
New York Heart Association class IV congestive heart failure 
 
ASD or atrial septal repair or closure device 
 
Single occurrence of AF 
 
Cardioversion or ablation procedure planned within 30 days 
 
Implanted mechanical valve prosthesis 
 
Heart transplantation 
 
Enrolled in another IDE or IND investigation of a cardiovascular device or an investigational drug 
 
Female of childbearing potential (age < 50 years and last menstruation within the last 12 months), who 
did not undergo tubal ligation, ovariectomy or hysterectomy.  
 
Active infection of any kind 
 
Severe chronic kidney insufficiency (CrCl< 30 ml/min) 
 
Terminal illness with life expectancy < 1 year 
 
Echocardiographic exclusion criteria 
 
LVEF < 20% 
 
Intracardiac thrombus or dense spontaneous echo contrast as visualized by TEE within 2 days before 
implant 
 
Significant mitral valve stenosis (ie, MV <1.5 cm2) 
 
Complex aortic atheroma with mobile plaque of the descending aorta and/or aortic arch 
 
Cardiac tumor. 
7.2 Recruitment and screening 
Patients will be screened previous the admission index. After complete screening pre-evaluation resulting in 
eligibility for LAAC, patients will be adequate informed and those accepting to participate will sign the informed 
consent form and will be enrolled in the study by dedicated staff previously identified at each center. See 9.1.1 for 
additional details. 
Study participants will not receive any payment or compensation for participation in the study. 
7.3 Assignment to study groups 
Once the patient is judged eligible and the informed consent has been signed, patients will be randomly assigned 
1:1 to one of the study groups. Randomization is described in 6.2. 
7.4 Criteria for withdrawal / discontinuation of participants 
Patients can be withdrawn from the study at every time from the enrolment if any of the following criteria occurs: 

Protocol SWISS APERO Version 5 /29.05.2020 
21/42 
withdrawal of informed consent, non-compliance, safety issue (i.e. unexpected risk related to study procedure), 
premature interruption of the study, presence of any exclusion criteria that was not known at the time of enrolment. 
8. STUDY INTERVENTION 
8.1 Identity of Investigational Medicinal Devices 
The WATCHMAN (Atritech, Boston Scientific, Natick, MA, USA) LAAC technology consists of the Access System 
(Access Sheath and Dilator) and Delivery System (Delivery Catheter and WATCHMAN Device). The Access 
System and Delivery System permit Device placement in the left atrial appendage (LAA) via femoral venous access 
and inter-atrial septum crossing into the left atrium.WATCHMAN device is a self-expanding nitinol structure with a 
porous covering on the proximal face. The device is constrained within the Delivery System until deployment in the 
LAA. The Device is available in 5 sizes from 21 to 33 mm. The new generation Watchman FLX has a shorter device 
length and a less taper angle  to simplify implantation and to fit a wider range of patients, Furthermore, the frame 
of the new device is designed to enhance sealing within the left atrial appendage. 
The AMPLATZER Amulet (St. Jude Medical-Abbott) is a self-expanding device made of nitinol that has a distal lobe 
and a proximal disc, connected by an articulated waist. The device lobe has six to 10 pairs of stabilising wires and 
is meant to be implanted in the proximal 10-15 mm of the left atrial appendage (LAA), whereas the device disc is 
intended to cover the ostium at the left atrial side. The proximal female screw is recessed to minimise thrombus 
formation on the disc and potentially facilitate re-attachment of the device to the pusher screw. The lobe sizes range 
from 16 to 34 mm.  
8.2 Procedural intervention 
Generally, general anaesthesia or at least conscious sedation is used for the procedure, due to the discomfort 
caused by the use of intra-procedural TEE for guidance. At the beginning, TEE is performed to exclude thrombus, 
to detect any pericardial effusion prior to the procedure and to evaluate the function of the mitral valve and the 
patency of the left upper pulmonary vein (LUPV). Since cardiac tamponade is a potential complication, it may be of 
benefit to establish an invasive (femoral or radial) arterial pressure monitoring with heart rate sound in order to 
detect and remedy haemodynamic instability rapidly.  
Depending on the clinical condition of the patient (left ventricular function, mitral regurgitation, and pulmonary 
pressures), it may be advisable to administer 500-1,000 cc of saline prior to TEE measurements in order to increase 
mean left atrial pressure to >12 mmHg, reducing the likelihood of inadequate LAA filling and minimizing the risk of 
device undersizing and subsequent embolization. Then, the TEE operator obtains the baseline LAA measurements 
(or confirms the measurements obtained during patient screening). The LAA is scanned from 0° to 135° (0° - 45° - 
90° - 135°) and the maximum and minimum diameters of the ostium and the landing zone are recorded. The TEE 
operator should be familiar with the implantation technique and device characteristics. However, as recommended 
by the recent consensus document,5 the first operator will be able to choose if use ICE instead of TEE to guide the 
procedure, on condition that a  TEE evaluation is performed within 2 days before the procedure (in order to exclude 
LAA thrombus, to confirm the LAA suitability for both devices and to make the device sizing). 
Currently, real-time 3D TEE is used more frequently for assessing the LAA during the implantation procedure. Real-
time 3D TEE allows better spatial visualization of the LAA and more comprehensive evaluation of the device during 
the procedure. Furthermore, with 3D TEE the device may be visualized more completely during the tug test and 
after deployment 
For the implantation of the LAAC device, femoral venous access is obtained in the right femoral vein. A 3-4 mm 
skin incision and perhaps subcutaneous separation of the access site are done to ease advancement of the 
transseptaland delivery sheath. Some operators prefer to use a short 12-16 Fr introducer for the groin. Transseptal 
puncture (TSP) is performed under fluoroscopic and preferably TEE guidance in the infero-posterior portion of the 
fossa ovalis using, e.g., a BRK-1™ needle (St. Jude Medical-Abbott) which usually provides adequate support and 
proper angulation for accurate puncture. Other systems are available and used with excellent success. TSP at the 
optimal puncture site is important to facilitate proper orientation of the delivery sheath in relation to the LAA. In this 
respect TEE guidance of TSP is instrumental. The TEE operator initially provides a bicaval view, to show the 
superior and inferior portion of the fossa. This view allows the operator to place the transseptal needle at the inferior 
axis of the fossa. Once tenting of the atrial septum has been observed, the TEE operator switches the view to a 
short-axis aortic view to show the anterior and posterior axis of the fossa. In this view the position of the transseptal 
sheath may be corrected to ensure a posterior puncture. A 3D TEE probe may allow the use of biplanar views 
showing the inferior and posterior axes of the atrial septum at the same time (x-plane). A PFO may be used for 
LAAO. However, it may result in more challenging delivery sheath orientation due to the superior entrance into the 
left atrium. The majority of operators prefer a directed infero-posteriortransseptal approach. If the interatrial septum 

Protocol SWISS APERO Version 5 /29.05.2020 
22/42 
is thick and difficult to puncture, the needle stylet or diathermy may help. Radiofrequency puncture needles are also 
available.  
Administration of unfractionated heparin is required, targeting an activated clotting time (ACT) of 250-300 seconds. 
The initial dose is 100 IU/kg. The timing of heparinisation varies. Some operators administer the complete dosage 
before, others only half of the dosage before and the remaining half after successful TSP. Some give the full dosage 
only after TSP. The half dose approach is a good compromise as it provides some antithrombotic protection in case 
of a difficult or prolonged TSP. Once access to the LA has been attained, it is of paramount importance to ensure 
adequate anticoagulation to avoid thrombus formation on wires and on or in catheters within the thrombogenic 
environment of the fibrillating LA. Adequate and regular flushing of the catheters serves the same purpose. 
8.3 Device sizing 
Optimal device sizing is critical for the procedure in order to avoid device embolisation, incomplete LAA closure, or 
multiple recaptures and repositioning of the device, prolonging the procedure. Device sizing is customarily based 
on multimodality imaging (TEE, CCTA und LAA angiography).5 Baseline CT angiography of adequate quality is an 
emerging accurate method due to its high spatial resolution and 3D capabilities. It needs to be carried out under 
adequate volume loading of the patient. TEE, 3D TEE, and ICE have lower spatial resolution but have the advantage 
of real-time evaluation during the implantation procedure. Angiography in at least two of threesuggested views 
(RAO 30° CRA 20°; RAO 30° CAU 20°; LAO 90°) is mandatory. Calibration has to be accurate and will be based 
on preprocedural CCTA, intraprocedural TEE guidance and angiography. Noteworthy, auto-calibration or calibration 
based on catheter diameters may be imprecise, leading to miss sizing. French sizes (1 Fr=0.33 mm) of sheaths 
refer to the inner lumen, whereas those of catheters refer to the outer diameter. Finally, it is important to choose 
the frame depicting the maximum LAA distention.  
ACP Amulet sizing depends on the widest landing zone on fluoroscopy or TEE. A standard recommendation is 
to upsize the device by 3 to 6 mm for the Amulet device from the widest measured landing zone measured by 2D 
TEE. This degree of oversizing improves stability of the device and proper anchoring of the lobe. However, caution 
should be exercised if the landing zone is very elliptical to avoid dramatic oversizing (> 5 mm) in the narrowest 
dimension. 
The delivery sheath size depends on the device size and is chosen based on a relevant chart, either 12 or 14 Fr. 
Oversizing of the sheath was not recommended for the ACP but is allowed for the Amulet, allowing an approach 
using a default 14 Fr in all cases. To accommodate this, a loading catheter adapter is included with the 12 Fr 
compatible devices. The AMPLATZER™ TorqVue™ 45-45° sheath (St. Jude Medical-Abbott) is the default sheath 
for Amulet devices. 
WATCHMAN/FLX sizing is based on the maximum LAA ostium diameter, which should be 17 to 31 mm 
to accommodate available devices. Oversizing is recommended by 8-10% to 20-30% based on the widest 
measurement. 
8.4 Crossover 
In case of impossibility during the procedure to implant the randomized device, operator can be choose to implant 
another device or stop the procedure. In any case the patient will continue to be considered enrolled in the trial. 
The crossover endpoint will be centrally adjudicated by the Clinical Events Committee (CEC) as justified if there will 
be evidence that the randomly allocated device has been positioned at least once in the LAA but LAA ostium sealing 
remained suboptimal (peri-device leak ≥ 3 mm) or concerns were present over the device stability and consequent 
risk of device embolization. 
8.5 Compliance with study procedures 
Expert operators must perform all procedures, with at least 20 successful cases of implant for each device. In case 
of operators with less than 20 procedures performed, a proctoring supervisor is requested during the implantation. 
8.6 Data Collection and Follow-up for withdrawn participants 
Data of withdrawn participants will be collected and evaluated up to the time of withdrawn. However, 
withdrawn participants will be asked the permission to continue collecting and evaluate data about them 
from routine data or other sources (general practitioners, Health System Softwares available) in order 
to respect the patient choice without affecting the scientific quality of the study 
8.7 
.Concomitant medicaments 
As anticoagulant therapy with unfractionated heparin (UFH) during procedure will be administer according operator 
preference in order to maintain the ACT time more than 250 during all procedure time. No particular restriction are 

Protocol SWISS APERO Version 5 /29.05.2020 
23/42 
established for previous medicament, so it is allow both DAPT then (N)OAC. 
 
After the procedure, patients will receive ASA and clopidogrel or (N)OAC at discretion of the treating physician 
(according to the bleeding risk, the stroke risk and intra-procedural TEE evaluation) for 45 days and then will 
undergo TEE assessment. 
o 
If a residual peridevice leak flow > 5 mm or a an intracardiac thrombus is detected, treatment with ASA 
and (N)OAC should be considered up a sequential TEE evaluation at 6 months. Final decision to implement an 
OAC regimen with or without ASA will eventually be left to the discretion of the treating physician taking the 
ischemic ad bleeding risk into account; 
o 
If residual peridevice leak flow  5 mm, patients will receive ASA and clopidogrel or (N)OAC (at 
discretion of the treating physician according to the bleeding and stroke risk) up until 3 months after procedure. 
Thereafter, monotherapy with ASA will be continued until 12 months after procedure. 
 
 
These drugs regimens are recommended according the current evidence and the instructions for use of the two 
devices(Appendix 2).  
8.8 Study Device Accountability 
Watchman and Amulet used for the study are already in use at the enrolling hospitals, local standard procedures 
of products management will be applied. 
8.9 Return or Destruction of Study device 
Local standard procedures of products management will be applied. 
 
9. STUDY ASSESSMENTS 
9.1 Study flow chart(s) / table of study procedures and assessments 
The Study Procedures are summarized in table study schedule.  
 
9.1.1 
Screening and enrolment 
Screening will be performed up to 90 days prior LAAC. Potential patients will be informed about the study and asked 
for participation. Subjects are considered provisionally enrolled with the signature on the written informed consent 
form (screening phase). Formal inclusion into the study will occur after baseline eligibility is confirmed and only 
once randomization takes place as close as possible to but always before LAAC. A copy of the informed consent 
form with the patient’s information document will be given to the patient. 
 
The following evaluations will be performed at baseline/enrolment: 
 
Demographics; 
 
Relevant medical history that includes: general medical, cardiovascular, neurologic and renal history; 
cardiovascular risk factors (e.g. dyslipidaemia, hypertension, diabetes mellitus, tobacco use); history of 
peripheral vascular disease, stroke, transient ischemic attack;documentation of current cardiovascular 
and diabetic medications;Stroke and bleeding risk evaluation with CHADS2, CHA2DS2VASc, HAS-
BLEED and ABC score; 
 
Evaluation of In-/Exclusion criteria; 
 
12-lead ECG; 
 
Routine laboratory tests within 48 hours prior to the index procedure as defined in 9.1.7; 
 
CCTA according to current standard of care (useful to exclude LAA thrombus and to plan the 
procedure);5 
 
TEE if clinically indicated or if no intraprocedural TEE is performed to guide the procedure. 
 
9.1.2 Randomization and Procedure 
Patients who have signed the informed consent form and meeting all inclusion and exclusion criteria will be included 
in the study and randomized before LAAC procedure.  
After randomization, patients will receive the LAAC with the randomized device. In the event that the patient is 
randomized to the Watchman/FLX group, the operator will be able to choose, on the basis of clinical reasons, if to 
implant Watchman or the new generation Watchman FLX (if available in the center). 
In case of impossibility to implant the randomized device, the operator can change the device or stop the procedure 

Protocol SWISS APERO Version 5 /29.05.2020 
24/42 
and the patient will be considered  for crossover adjudication (see section 8.4). 
Fluoroscopy images will be digitalized and encoded for adjudication. 
 
The following evaluations will be performed before, during and after the procedure: 
 
12 lead ECG 
 
TEE or ICE to guide intervention according to the current standard of care 
 
Procedure-related data collection including duration, fluoroscopic time and overall contrast medium dose 
as well as any procedure-related complications (described in 5.3) 
 
Collection of of any Serious Adverse Event (SAE) and  adverse  events of special  interest ([AESI] as 
defined in 111 and Appendix 1) up to 48 hours or discharge whichever comes first.  
 
9.1.3 Post procedure management and hospital discharge 
After the procedure, patients will receive ASA and clopidogrel or (N)OAC at discretion of the treating physician 
(according to the bleeding risk, the stroke risk and intra-procedural TEE evaluation) for 45 days and then will 
undergo TEE assessment (as per standard of care): 
o 
If a residual peridevice leak flow > 5 mm or a an intracardiac thrombus is detected, treatment with ASA and 
(N)OAC should be considered up a sequential TEE evaluation at 6 months. Final decision to implement an 
OAC regimen with or without ASA will eventually be left to the discretion of the treating physician taking the 
ischemic ad bleeding risk into account; 
o 
If residual peridevice leak flow  5 mm is detected, patients will receive ASA and clopidogrel or (N)OAC (at 
discretion of the treating physician according to the bleeding and stroke risk) up until 3 months after 
procedure. Thereafter, monotherapy with ASA will be continued until 12 months after procedure. 
 
These drug regimens are recommended according the current evidence and the instructions for use of the two 
devices (Appendix 2).  
 
The following evaluations will be performed at up to 48 h after the procedure or at hospital discharge whichever 
comes first: 
 
Physical examination as defined in 9.1.6 
 
Measurementof vital signs as defined in 9.1.5 
 
Collection of concomitant therapy and assessment of any additional intervention, if any, which occurred 
after LAAC 
 
Assessment of SAE and AESI  as defined in 11.1 and Appendix 1 
 
12 lead ECG 
 
Routine laboratory tests within 48 hours prior to the index procedure as defined in 9.1.7  
 
A transthoracic echocardiogram is encouraged (but not mandated) before the discharge in order to 
detect pericardial effusion and for the assessment of the post-procedure positioning of the LAA device.  
 
 
9.1.4 45 days, 6month, 13 month, 2/ 3/ 4/ 5 year follow up 
Patients will be followed-up with hospital visits at after 45 days(primary endpoint assessment) and thereafter at 6 
and 13 months as well as after 2, 3, 4 and 5 years the index procedure. In case of impossibility to have an in hospital 
visit, a phone call to the patient and/or to the general practitioner will be performed (except for the 45 days visit). 
 
The following evaluations will be performed at follow up visits: 
 
Collection of medical history 
 
Physical examination as defined in 9.1.6 
 
Measurement of vital signs as defined in 9.1.5 
 
Collection of concomitant therapy  
 
Assessment of SAE and AESI as defined in 11.1 and Appendix 1 
 
 
 
12 lead ECG 
 
TEE will be performed at 45 days. TEE could be repeated at 6 and 13 months after procedure if clinically 
indicated (in case of an intra-cardiac thrombus or/and a PDL >5 mm are revealed at 45 days) according 
to current standard of care 
 
CCTA at 45 days  and at 13 months after procedure will be performed as study specific interventions.  
 
In the event of pandemic or any other condition for which the participation to follow-up visits would put at risk the 
health of the patients and/or of the medical staff, the hospital visits will be replaced by phone call. Furthermore, the 
performance of imaging follow-up outside of protocol temporal window will be allowed.  

Protocol SWISS APERO Version 5 /29.05.2020 
25/42 
 
If a phone call is performed instead of an hospital visit,the following data will be collected: 
 
 
Vital status 
 
Assessment and reporting of adverse clinical events as defined in 9.1.8 and Appendix 1 
 
Assessment and reporting of SAEs and AESI 
 
Assessmentand reporting of pharmacotherapy, and additional interventions received since last contact. 
 
 
9.1.5 Definition of measurement of vital signs 
The vital signs collected will be: heart rate and arterial blood pressure. 
The 12 lead ECG will be recorded first of procedure, at the discharge and at the follow up visits. 
 
9.1.6 
Definition of physical examination 
The physical examination will consist of measurement of weight, height, arterial blood pressure,heart rate and a 
standard physical exam. 
 
9.1.7 
Definition of laboratory parameters assessed at enrolment andat up to 48 h post procedure 
Laboratory test consist of complete blood count, creatinine, troponin T hs and NT-proBNP. These will be 
assessed at enrolment and at up to 48 h post procedure or discharge whichever comes first. 
 
 
9.1.8 
Definition of adverse clinical events: 
The Adverse clinical events are overall and CV death,  ischemic and haemorrhagic stroke, systemic or pulmonary 
embolization, spontaneous MI, periprocedure related complications (defined in the section 5.3)and BARC bleeding 
grade 2, 3, or 5 (see the definitions in Appendix 1). CEC will adjudicate these adverse clinical events.  
 

Protocol SWISS APERO Version 5 /29.05.2020 
26/42 
Figure 1. 
 
 
Patients with AF CHA2DS2-VASc ≥2, 
HAS-BLEED ≥3 or High Bleeding Risk
Watchman/FLX device
Amulet device
ASA+clopidogrel or (N)OAC for 45 days
(at discretion of the treating physician according to the 
bleeding risk, stroke risk and TEE intra-procedural 
evaluation)
45 days follow-up with TEE and CCTA.
If peridevice leak ≤ 5 mm, continued with 
ASA+Clopidogrel or (N)OAC until 3 month
(at discretion of the treating physician according to the 
bleeding and stroke risks)
Stop clopidogrel or (N)OAC and 
continue with only ASA until 12 
months after procedure. 
Stop ASA.
Drug regimen according physician decision
13month follow-up with CCTA (and TEE if clinically indicated).
Evaluation of LAA patency
Drug regimen at physician decision
45 days follow-up with TEE and CCTA.
If peridevice leak > 5 mm or intra-cardiac thrombus ASA 
and (N)OAC should be considered  until 6 months after 
intervention
TEE evaluation if clinically indicated. 
If peridevice leak > 5 mm or thrombus still present, continued with 
ASA and (N)OAC until 13 month
If peridevice leask ≤5 mm or not more thrombus, Stop (N)OAC and 
continue with ASA until 12months after procedure
1:1 randomization 
45-days 
6-months 
13-months 
3-months 
12-months 
Discharge 

Protocol SWISS APERO Version 5 /29.05.2020 
27/42 
9.2 Assessments of outcomes 
Assessment of primary outcome 
The primary outcome is the composite of LAA patency at 45 day evaluated with CCTA or the crossover from one 
device to the other device based on morphological/anatomical considerations during device implantation. 
Patency LAA will be estimated at CCTA by measurement of the linear attenuation coefficient (Hounsfield unit, HU) 
in the LAA distal to the device and comparison of contrast density to atrial chamber. LAA patency was defined with 
HU≥100 or HU ≥ 25% of the atrium, as reported in a previous publication.15 The occurrence of LAA patency will be 
centrally evaluated and adjudicated by an Imaging Core Lab (ICL) composed of three imaging experts who will 
independently score each of the studies as positive or negative for LAA patency. In the event of inconsistent primary 
end point adjudication between the three readers, a consensus between all of them will be required. Adjunctive 
CCTA criteria of complete occlusion (as described in section 10.2) will be collected in order to validate them. A TEE 
evaluation of PDL presence will be performed at 45-days in order to compare the two imaging technique. The 
crossover is defined as the switch from the randomized device to the other device based on 
morphological/anatomical considerations during device implantation. It will be centrally adjudicated by CEC as 
justified if there will be evidence that the randomly allocated device has been positioned at least once in the LAA 
but LAA ostium sealing remained suboptimal (peri-device leak ≥ 3 mm) or concerns were present over the device 
stability and consequent risk of device embolization. 
 
Assessment of secondary outcomes 
Secondary outcomes will be collected at 45 days,6 months, 13 months, 2 years, 3 years, 4 years and 5 years follow 
up. Data about adverse clinical events (listed in the section 9.1.8) will be collected by means of  electronic forms 
and related documents (medical reports, CT and other imaging report). LAA patency on arterial phase has been 
already defined in the previous section (“Assessment of primary outcome”). LAA patency on venous phase is 
defined, as reported in a previous publication,22 as a LAA density ≥ 100 HU or ≥ 150% of that measured at the 
same site on arterial phase. Leak at TEE is defined as any communication jet between LA and LAA detectable by 
means of color-Doppler (high velocity 50-60 cm/sec). The size is measured taking the narrowest flow region of the 
jet that occurs at, or just close to, the device). Of note, rate of LAA patency at 45 day CCTA will be compared with 
rate of leak at 45 day TEE. 
 
Assessment of safety outcomes 
Safety outcomes will be assessed 45 days,6 months, 13 months, 2 years, 3 years, 4 years and 5 years follow up. 
Data about adverse clinical events (listed in the section 9.1.8) will be collected by means of electronic forms (ICE-
Advice Pharma) and  related documents (medical reports, CT and other imaging report). 
 
Assessments in participants who prematurely stop the study 
Data of withdrawn participants will be collected up to the time of withdrawn. However, withdrawn participants will 
be asked the permission to continue collecting and evaluate data about them from routine data or other sources 
(general practitioners, Health System Softwares available) in order to respect the patient choice without affecting 
the scientific quality of the study. 
10. CARDIAC COMPUTER TOMOGRAPHY ANGIOGRAPHY 
10.1 CCTA PROTOCOL 19 
The CCTAs will be carried out according an identical protocol, by using a 64- to 320-detector scanner, with a 
multiphasic acquisition. Iodinated contrast medium (70–90 mL) will be administered through an antecubital vein 
(flow rate: 5 mL/s), followed by 50 mL of saline chaser bolus (sodium chloride 0.9%), administered at the same 
flow rate. Patients will receive nitroglycerin, if no contraindicated (known sensitivity to nitrate medications, 
administration of PDE5 inhibitor medications within the past 24 hours, systolic blood pressure <90mmHg, history 
of increased intracranial pressure, severe anemia), and betablockers (aimed at achieving a heart rate of <65 
beat/min) prior to the CCTA acquisition. A prospective high-pitch flash mode or broad coverage single shot/step 
and shoot ECG-gated CT acquisition technique typically at 70 % of R–R interval  or a retrospectively ECG gated 
CT-acquisition at 30–70 % of R–R interval will be used. The dose modulation will be used when 
possibleExposure parameters will be adjusted according to patient size. Images will be reconstructed using 
iterative reconstruction or filtered back-projectionat 0.75 mm slice width,0.5 mm slice increment. The standard 
scan will be performed using a a bolus tracking technique for optimal scan acquisition timing. The delayed scan 
will be performed 60 s following the beginning of the standard scan to allow contrast equilibration within the blood 
pool. The delayed scan will be planned at the level of the carina and extended 4–8 cm caudally to include the 
LAA but not the whole heart, to minimize unnecessary radiation exposure. 

Protocol SWISS APERO Version 5 /29.05.2020 
28/42 
10.2 Adjunctive CCTA analyses 
Adjunctive analyses not included among study endpoints, will be performed. 
 
10.2.1 Further LAA patency analyses 
In the event of LAA patency, two elements will be assessed: presence of PDL, presence of intradevice leak.  
PDL, defined as a visible continuity of contrast between LA and LAA along the side of the device, will be looked 
for on the lobe margins (and on the disk margins in Amulet patients as well) by using reconstructed plane parallel 
to LAA orifice.  
Intradevice leak, defined as a visible continuity of contrast through the entire length of the device, will be looked 
for by using reconstructed plane parallel to device long axis. In the event that an intradevice leak is incomplete, 
passing only through a portion of the device and then continuing at its margin (or vice versa), the leak will be 
defined as “mixed”.  
The device covering will be semiquantitatively evaluated on venous phase and scored by the ICL as one of the 
following: device completely uncovered, device covered less than 50%, device covered more than 50%, device 
completely covered. 
 
10.2.2 Adjunctive CCTA criteria for LAA closure 
In order to evaluate the complete LAA occlusion with the CCTA, we proposed following criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lobe compression (%) was calculated as: [(manufacturer device diameter - measured diameter)/manufacturer 
device diameter] × 100% 
10.2.3 Amulet subgroup 
Due to the double system of closure in Amulet device, some additional data will be collected in this subgroup. 
The HU will be measured, if possible, also in the small region between the disc and the lobe by the same method 
used to assess LAA patency. 
Furthermore, in addition to PDLs assessment, that in Amulet subgroup refer to the leak passing along the side of 
the lobe, leaks passing marginally to the disc (peridisc leaks) will be assessed as well (with the same method 
used for PDLs). Finally, in Amulet subgroup the percentage of disc covering will be assessed as well. 
 
10.2.4 Coronary artery assessment subgroup 
Circumflex artery has a close anatomical relationship with LAA and both Watchman/FLX and Amulet devices are 
implanted in a region adjacent to that vessel. Our group has recently observed some cases of subocclusive stenosis 
of proximal circumflex artery occurred few years after LAAC. In both cases, despite of the close proximity between 
the LAAC device and the stenosis, no signs of external compression have been detected. Therefore, we speculated 
that LAAC could have accelerated the local inflammatory process and the progression of coronary plaque burden 
in the circumflex artery compared to other coronary arteries. In order to test this hypothesis (with the aim to detect 
some trend), we will use the serial CCTAs, to assess the difference between the circumflex artery and the remaining 
coronary arteries in terms of coronary plaque burden progression after 1 year. The coronary plaque burden 
progression is defined as the absolute annual increase in total, calcified, and noncalcified plaque volume; therefore 
Amulet-CT criteria for LAA occlusion 
Watchman/FLX -CT criteria for LAA occlusion 
Lobe compression >10% 
Position: plane of maximum diameter of the device is at or 
just distal (<2 mm) to the orifice of the LAA, and that it 
spans the entire LAA ostium. Position of the lobe in relation 
to left lateral ridge 
Disc-lobe separation (>2 mm) 
Size: measure the plane of the maximum diameter of the 
device, ensuring the threaded insert is visible. The device 
should be 80-92% of the original size 
Device axis consistent 
with landing zone  and landing zone and 
angle between disc and lobe 
Seal: no contrast in the distal lobes 
Concave disc 
Consistency between device axis and ostium 
Width of the lobe is ≥2/3 within the circumflex 
artery  and position of the disc in relation to 
left lateral ridge 
 
Lobe’s shape 
Lobe’s shape 
 

Protocol SWISS APERO Version 5 /29.05.2020 
29/42 
it consists of the difference between of total plaque volume (in particular the non calcified component) measured 
by 13 month CCTA and that measured by the preprocedural or 45 day CCTA.  
In this subgroup analysis will be included all the patients with at least one of the first two CCTAs and the third CCTA 
with a sufficient images quality (as evaluated by the ICL) to assess coronary plaque burden. The use of nitrates 
and betablocker is aimed at obtaining CCTA images suitable not only for LAA patency but also for coronary artery 
disease assessment.23 Images reconstruction will be optimized using the most suitable cardiac cycle phase (i.e. 
diastole at 70-80% of the R-R interval).  
 
11. SAFETYREPORTING 
During the entire duration of the study, all serious adverse events (SAEs) and Adverse Events of special interest 
(AESI) are collected, fully investigated and documented in source documents and electronic case report forms 
(eCRF). The software platform selected for this study is ICE-Advice Pharma. Study duration encompassed the time 
from when the participant s is randomized until the last protocol-specific procedure has been completed, including 
a safety follow-up period.  
11.1 Definitions 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation participant 
administered a pharmaceutical/device product and which does not necessarily have a causal relationship with the 
study procedure. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a device (investigational) product, whether or 
not related to the device (investigational) product. ICH E6 1.2 
The AESI are the clinical endpoints of the study (see the list and/or any AEs potentially related to them: 
overall and CV death, cerebrovascular events (including possible events like fall, syncope, headaches, 
blurred vision, etc.), cardiovascular events (including possible events like hypotension, myocardial 
infarction, chest pain, unstable angina), bleeding events (including anemization without overt bleeding); 
procedure-related complications (any AE occurred within 7 days after LAAC and potentially related to 
the procedure). All the AESI will be evaluated by the CEC and adjudicated as clinical endpoints of the 
study according the definitions mentioned in Appendix 1.  
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
 
Results in death, 
 
Is life-threatening, 
 
Requires in-patient hospitalization or prolongation of existing hospitalisation, 
 
Results in persistent or significant disability/incapacity. 
 
In addition, important medical events that may not be immediately life-threatening or result in death, or require 
hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the other outcomes 
listed above should also usually be considered serious. ICH E2A 
11.2 Reporting of serious adverse events (SAE) and other safety related 
events 
Adverse events  (SAE and AESI) reporting will start once the patient is considered fully enrolled for the study (after 
randomization). 
All SAEs must be reported immediately and within a maximum of 24 hours of awareness to the Sponsor of the 
study. SAEs should be reported to the Sponsor using the eCRF. All SAE will be reported to the EC by the Sponsor 
in the Annual Safety Report. AESI should be reported to the Sponsor using the eCRF within a maximum of 10 days 
of awareness.  
If safety measures are required, these have to be reported to the EC by the Investigator as well as by the Sponsor 
within 2 days. 
11.3 Follow up of (Serious) Adverse Events 
SAEs will be followed until resolution or stabilisation. Participants with ongoing SAEs at study termination will be 
further followed up until recovery or until stabilisation of the disease after termination. 

Protocol SWISS APERO Version 5 /29.05.2020 
30/42 
12. STATISTICAL METHODS 
Statistical considerations 
12.1 Hypothesis 
Null hypothesis A (H0A): ACP Amulet is superior in terms of complete LAA occlusion to WATCHMAN/FLX device 
and is more feasibility. 
Null hypothesis B (H0B): there is no difference between ACP Amulet and WATCHMAN/FLX in terms safety, 
feasibility and LAA patency. 
12.2 Determination of Sample Size 
Considering an incidence of the primary composite end-point in the range of 50% in the Watchman/FLX group, 
which is a conservative estimate based on previous reports, we estimate that 200 patients will provide greater than 
80% power to prove superiority of Amulet as compared to Watchman/FLX assuming a 40% risk reduction (i.e. 
corresponding to an event rate in the range of 30%) and a significance level of 5% (alpha). 
12.3 Statistical criteria of termination of trial 
No statistical interim analyses are planned. 
12.4 Planned Analyses 
Datasets to be analysed, analysis populations 
The main analysis of the primary endpoint will be conducted on all randomized patients who have 
completed the 45-day follow-up according to the intention to treat principle, in keeping with the 
superiority prespecified study hypothesis. Additional analyses of the primary endpoint will be also carried 
out in the per-protocol and as-treated populations. Similarly, LAA patency and DRT at 45-day and 13-
month CCTA and at 45-day TEE as well as clinical outcomes will also be analyzed in the per-protocol 
and as-treated population. 
Primary and secondary Analysis 
Primary and secondary end points will be analysed on an intention-to-treat basis; as above mentioned some of 
them will be analysed also in the per-protocol and as-treated populations. Categorical outcome measures will 
compared using a χ2 test or Fisher exact test as required. Continuous variables will compared using a 2-sided 
unpaired t test or a Mann-Whitney test, as appropriate. Estimation of the cumulative incidence of safety and efficacy 
endpoints will be performed using the Kaplan-Meier method, and event rates will be compared by the log rank test 
The estimated relative risk (RR) is the ratio of the risk probabilities, and a confidence interval will constructed based 
on a logarithmic transformation. Correlations between variables will analyzed with a Cox regression. 
Interim analyses 
No statistical interim analyses planned. 
Safety analysis 
No statistical interim analyses planned. 
Deviation(s) from the original statistical plan 
Any deviation from the planned analyses will be reported in the final trial report. 
12.5 Handling of missing data and drop-outs 
Patients with missing data for the primary end-point will be excluded from the primary analysis. 
13. QUALITY ASSURANCE AND CONTROL 
13.1 Data handling and record keeping / archiving 
The Local Investigator is required to prepare and maintain adequate and accurate case histories designed to record 
all observations and other data pertinent to the investigation on each individual enrolled in the study. 
An electronic data capture (EDC) system will be developed for the study. The software platform selected for this 
study is ICE-Advice Pharma, a webbased system has an integrated audit trail fulfils the legal requirements for an 
EDC system. It will include electronic case report forms (eCRFs) designed to capture study information. The forms 

Protocol SWISS APERO Version 5 /29.05.2020 
31/42 
will be completed by trained site staff. eCRFs documenting SAEs should be submitted via the EDC system within 
24 hours after the investigator becomes aware of the event. All other eCRFs should be completed in a timely 
manner, preferably within 5-10 days of the subject’s enrolment or follow-up visit.  
The subject’s anonymity will be maintained and the confidentiality of records and documents that could identify 
subjects will be protected, respecting the privacy and confidentiality rules in accordance with applicable legal 
requirements.Patients data will be encoded: 
• 
Subjects will be identified only by their assigned study number and year of birth on all CRFs 
• 
The investigator will keep a Patient Identification List with complete identification information (name, address, 
contact number) on each subject. 
• 
The investigator will maintain all study documents in strict confidence. 
• 
CRF entries will be performed by authorized persons only, who will validate the data with an electronic 
signature after entering it into the eCRF. Copy of procedural angiogram, cardiac CCTA, TEE and ECG will be 
stored at the main site in Bern. 
 
All data will be cleared of any sensible personal information, patients will be identified by their assigned study 
number. For end-point adjudication data will be examined without any form of identification (blinded). 
13.2 Specification of source documents 
Source data must be available at the site to document the existence of the study participants. Source data must 
include the original documents or certified copies relating to the study, as well as the medical treatment and medical 
history of the participant. Source documents include demographic data, visit dates, participation in study and 
Informed Consent Forms, randomization number, SAEs, AESI and concomitant medication, and results of relevant 
examinations. The investigator assures that source documents are appropriately stored and completed. The 
patient’s file will reveal that this patient is a study participant by entering the following details: study name, protocol 
number, date of enrolment, informed consent obtained prior to any study specific procedure. Each follow up visit 
will be reported in the source data and should at least contain the information required according the protocol. The 
investigator assures that medical files and Case Record Forms are accessible for inspection by authorities and 
monitoring visits. 
All study data must be archived for a minimum of 15 years after study termination or premature termination of the 
clinical trial. 
13.3 Data management 
Clinical Trial Unit (CTU) – Bern University, will be in charge for data management and analysis. 
Every investigator has access to data of patients enrolled in the own site. CTU in Bern has access to all patient 
data and can lock patient’s data at the end of the trial. Once locked, data can no longer be modified by site 
investigator. 
13.4 Monitoring 
Monitoring, which will be carried out by experienced personel employed by CTU (Dr Enrico Frigoli, MD) and Advice 
Pharma as well as by cardiologists in training working at our institution as research or clinical/research fellows 
independent from the SWISS Apero study team, will verify that the rights and well-being of the patients are protected, 
the trial is conducted according to Good Clinical Practices (GCP) and ISO14155, and that the protocol is followed. 
The dates of the visits will be recorded by the monitor in a log kept at the site. The source data/documents should 
be accessible to monitors and questions should be answered during monitoring. The Local Investigator and their 
relevant personnel should be available during monitoring visit and possible audits and sufficient time should be 
devoted to the process. The progress of the study will be monitored by: 
- 
Informed Consent Forms for each study participant 
- 
Ensuring completed eCRFs match source documents, and resolution of any discrepancies. Direct access to 
complete source documents must be made available during monitoring visits for verification of eCRF data 
- 
Periodic on-site visits and, if necessary, remote monitoring of data. 
13.5 Audits and Inspections 
The study site may be subject to audits and inspections to verify that the rights and well-being of the patients are 
protected, the trial is conducted according to Good Clinical Practices (GCP) and ISO14155, and that the protocol 
is followed. The study documentation and the source data/documents should be accessible to auditors/inspectors 
(also EC) and questions should be answered during inspections. All involved parties must keep the participant data 
strictly confidential. 
13.6 Confidentiality, Data Protection 
Direct access to source documents will be permitted for monitoring, audits and inspections.Clinical Trial Unit – Bern 

Protocol SWISS APERO Version 5 /29.05.2020 
32/42 
has full access to protocol, dataset and statistical codes, during and after the study. 
14. PUBLICATION AND DISSEMINATION POLICY 
After the database has been closed, findings will be shared and discussed with all of the investigators for the study. 
An estimated timeline for creation of an abstract will be defined at that time. An abstract of the completed study, 
after input from all the authors, will be submitted to the most important and representative international meetings. 
A manuscript of the study, having received input from all of the authors, is tentatively scheduled for submission in 
a renowned international medical journal. Authorship will be selected according to the requirements of the New 
England Journal of Medicine (http://www.icmje.org/). These indicate that every author provided such contribution 
to the clinical trial and the subsequent publication that he can take public responsibility for the integrity of the entire 
work. Therefore the credit for authorship requires substantial contributions to: 
1. The conception and design or analysis and interpretation of the data. 
2. The drafting of the article or critical revision for important intellectual content. 
3. Final approval of the version to be published. 
Authors must have fundamentally taken part in all of the 3 aspects. 
For the main publication each of the 4 main centres will obtain at least 1 authorship, if the above-mentioned 
requirements 1-3 are met. Prior to sub-publication consultation and agreement of the coordinating investigator and 
the steering committee are mandatory. 
15. FUNDING AND SUPPORT 
This study is an Investigator Initiated Trial supported by a grant from St. Jude Medical-Abbott. 
16. INSURANCE 
Subjects who participate in this study will be insured against study related injury according to local regulatory 
requirements. A copy of the certificate is filed in each investigator site file and in the trial master file. 
 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
33/42 
17. REFERENCE 
1. 
Declaration 
of 
Helsinki, 
Version 
October 
2013,. 
(http://www.wma.net/en/30publications/10policies/b3/index.html 
). 
2. 
Dixon JR, Jr. The International Conference on Harmonization Good Clinical Practice guideline. 
Qual Assur. 1998;6(2):65-74. 
3. 
Englev E, Petersen KP. [ICH-GCP Guideline: quality assurance of clinical trials. Status and 
perspectives]. Ugeskr Laeger. 2003;165(16):1659-1662. 
4. 
ISO 14155:2011 Clinical investigation of medical 
devices for human subjects -- Good clinical practice. 
5. 
Glikson M, Wolff R, Hindricks G, et al. EHRA/EAPCI expert consensus statement on catheter-
based left atrial appendage occlusion - an update. EuroIntervention : journal of EuroPCR in 
collaboration with the Working Group on Interventional Cardiology of the European Society of 
Cardiology. 2020;15(13):1133-1180. 
6. 
Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national 
implications for rhythm management and stroke prevention: the AnTicoagulation and Risk 
Factors in Atrial Fibrillation (ATRIA) Study. Jama. 2001;285(18):2370-2375. 
7. 
Mozaffarian D, Benjamin EJ, Go AS, et al. Executive Summary: Heart Disease and Stroke 
Statistics--2016 Update: A Report From the American Heart Association. Circulation. 
2016;133(4):447-454. 
8. 
Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients 
with atrial fibrillation. Ann Thorac Surg. 1996;61(2):755-759. 
9. 
Halperin JL, Gomberg-Maitland M. Obliteration of the left atrial appendage for prevention of 
thromboembolism. J Am Coll Cardiol. Vol 42. United States2003:1259-1261. 
10. 
Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus 
warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-
inferiority trial. Lancet. 2009;374(9689):534-542. 
11. 
Holmes DR, Jr., Kar S, Price MJ, 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):1-12. 
12. 
Tzikas A, Shakir S, Gafoor S, et al. Left atrial appendage occlusion for stroke prevention in atrial 
fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention. 
2016;11(10):1170-1179. 
13. 
Kanderian AS, Gillinov AM, Pettersson GB, Blackstone E, Klein AL. Success of surgical left 
atrial appendage closure: assessment by transesophageal echocardiography. Journal of the 
American College of Cardiology. 2008;52(11):924-929. 
14. 
Freixa X, Tzikas A, Sobrino A, Chan J, Basmadjian AJ, Ibrahim R. Left atrial appendage closure 
with the Amplatzer Cardiac Plug: impact of shape and device sizing on follow-up leaks. 
International journal of cardiology. 2013;168(2):1023-1027. 
15. 
Saw J, Fahmy P, DeJong P, et al. Cardiac CT angiography for device surveillance after 
endovascular left atrial appendage closure. European heart journal cardiovascular Imaging. 
2015;16(11):1198-1206. 
16. 
Jaguszewski M, Manes C, Puippe G, et al. Cardiac CT and echocardiographic evaluation of 
peri-device flow after percutaneous left atrial appendage closure using the AMPLATZER 
cardiac plug device. Catheterization and cardiovascular interventions : official journal of the 
Society for Cardiac Angiography & Interventions. 2015;85(2):306-312. 
17. 
Angelillis M, Gargiulo G, Moschovitis A, et al. Computed tomography detection and 
quantification of left atrial appendage residual patency as collateral finding after percutaneous 
closure. International journal of cardiology. 2018;260:42-46. 
18. 
Kim JS, Lee H, Suh Y, et al. Left Atrial Appendage Occlusion in Non-Valvular Atrial Fibrillation 
in a Korean Multi-Center Registry. Circulation journal : official journal of the Japanese 
Circulation Society. 2016;80(5):1123-1130. 
19. 
Lazoura O, Ismail TF, Pavitt C, et al. A low-dose, dual-phase cardiovascular CT protocol to 
assess left atrial appendage anatomy and exclude thrombus prior to left atrial intervention. The 

Protocol SWISS APERO Version 5 /29.05.2020 
34/42 
international journal of cardiovascular imaging. 2016;32(2):347-354. 
20. 
Xu H, Xie X, Wang B, Ma S, Wang F. Efficacy and Safety of Percutaneous Left Atrial Appendage 
Occlusion for Stroke Prevention in Nonvalvular Atrial Fibrillation: A Meta-analysis of 
Contemporary Studies. Heart, lung & circulation. 2016;25(11):1107-1117. 
21. 
Saw J, Lopes JP, Reisman M, McLaughlin P, Nicolau S, Bezerra HG. Cardiac Computed 
Tomography Angiography for Left Atrial Appendage Closure. The Canadian journal of 
cardiology. 2016;32(8):1033 e1031-1039. 
22. 
Cochet H, Iriart X, Sridi S, et al. Left atrial appendage patency and device-related thrombus 
after percutaneous left atrial appendage occlusion: a computed tomography study. European 
heart journal cardiovascular Imaging. 2018;19(12):1351-1361. 
23. 
Smit JM, van Rosendael AR, El Mahdiui M, et al. Impact of Clinical Characteristics and Statins 
on Coronary Plaque Progression by Serial Computed Tomography Angiography. Circulation. 
Cardiovascular imaging. 2020;13(3):e009750. 
24. 
Tzikas A, Holmes DR, Jr., Gafoor S, et al. Percutaneous left atrial appendage occlusion: the 
Munich consensus document on definitions, endpoints, and data collection requirements for 
clinical studies. Europace : European pacing, arrhythmias, and cardiac electrophysiology : 
journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular 
electrophysiology of the European Society of Cardiology. 2017;19(1):4-15. 
25. 
Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: 
a statement for healthcare professionals from the American Heart Association/American Stroke 
Association. Stroke. 2013;44(7):2064-2089. 
 
 
 

Protocol SWISS APERO Version 5 /29.05.2020 
35/42 
APPENDIX 1: ENDPOINT AND ADVERSE CLINICAL EVENT DEFINITIONS 24 
17.1 INDICATIONS FOR LAAC THERAPY 
 
Potential indications 
 
 
 
Example 
 
A.Patient not eligible for long-termOACtherapy 
(absolute or relative contraindications to OAC) 
 
 
1. High bleeding risk (HBR) 
 
 
History of major or minor bleeding (with or 
without OAC therapy)  
 
 
 
 
 
 
 
Increased risk for bleeding due to physical 
condition and/orco-morbidities 
 
 
 
 
Intracranial bleeding  
 
GI bleeding 
 
Symptomatic bleeding in critical organ (i.e. 
ocular, pericardial, spinal cord) 
 
Recurrent 
epistaxis 
needing 
medical 
attention 
 
 
 
Recurrent falls with head trauma and 
significant musculoskeletal injury 
 
Need for additional dual antiplatelet therapy 
for CAD and stenting. 
 
Diffuse intracranial amyloid angiopathy 
 
Bowel angiodysplasia 
 
Severe renal insufficiency/haemodialysis 
 
Blood cell dyscrasia 
 
2. Inability to take OACs for reasons other than high 
risk for bleeding 
 
 
Intolerance 
 
Documented poor adherence to medication 
 
Documented 
variability 
in 
international 
normalized ratio on warfarin 
 
Higher-risk occupation with increased injury 
potential 
 
Patient’s choice 
 
B. Thromboembolic event or documented 
presence ofthrombus in the LAA despite 
adequate OAC therapy 
 
 
 
Embolic 
stroke 
or 
other 
systemic 
thromboembolism on adequate OACtherapy 
with evidence for thrombus origin from the 
LAA (‘malignant LAA’) 
 
Documented thrombus formation in the LAA 
on adequate OAC therapy 
 
 
 
 
17.2 MORTALITY DEFINITIONS 
All deaths will be categorized as cardiovascular (CV) or non-cardiovascular based on the definitions 
below. 
Cardiovascular Death 
CV Death is defined as death resulting from a proximate cardiac cause (e.g. myocardial infarction, 
worsening heart failure, etc.), vascular cerebral nervous system (CNS) causes, sudden cardiac death, 
from CV procedures, from other cardiovascular causes, and death of unknown cause. 
 
Death due to proximate cardiac causes 
Death related to proximate cardiac causes include those resulting from one or more of the following 
conditions: acute myocardial infarction (AMI), worsening heart failure, endocarditis. 
Acute Myocardial Infarction- Death by any mechanism (arrhythmia, heart failure, low output) within 
30 days after an AMI and related to its immediate consequences, such as progressive congestive heart 
failure (CHF), inadequate cardiac output, or refractory arrhythmia. If these events occur after a “break” 

Protocol SWISS APERO Version 5 /29.05.2020 
36/42 
(e.g., a CHF and arrhythmia free period of at least a week), they should be designated by the immediate 
cause, even though the AMI may have increased the risk of that event. AMI should be verified to the 
extent possible by the diagnostic criteria outlined for AMI or by autopsy findings showing recent 
myocardial infarction or recent coronary thrombus. Sudden cardiac death, if accompanied by symptoms 
suggestive of myocardial ischemia, new ST elevation, new LBBB, or evidence of fresh thrombus by 
coronary angiography and/or at autopsy should be considered death resulting from an acute myocardial 
infarction, even if death occurs before blood samples or 12-lead electrocardiogram (ECG) could be 
obtained, or at a time before the appearance of cardiac biomarkers in the blood. Death resulting from a 
procedure to treat a myocardial infarction percutaneous coronary intervention (PCI), coronary artery 
bypass graft surgery (CABG), or to treat a complication resulting from myocardial infarction, should 
also be considered death due to AMI. Death resulting from an elective coronary procedure to treat 
myocardial ischemia (i.e., chronic stable angina) or death due to a myocardial infarction that occurs as 
a direct consequence of a CV investigation/procedure/operation should be considered as a death due to 
a CV procedure.               Worsening Heart Failure- Death due to worsening heart failure refers to a 
death in association with clinically worsening symptoms and/or signs of heart failure not following an 
AMI. Deaths due to heart failure can have various etiologies, including single or recurrent myocardial 
infarctions, ischemic or non-ischemic cardiomyopathy, endocarditis, hypertension, valvular disease.  
Death due to vascular cerebral nervous system causes 
Death that occurs after a stroke that is either a direct consequence of the stroke or a complication of 
the stroke. Acute stroke should be verified to the extent possible by the diagnostic criteria outlined for 
stroke.  
 
Sudden Cardiac Death  
Death that occurs unexpectedly, not following an AMI, and including the following deaths: 
death witnessed and occurring without new or worsening symptoms; death witnessed within 60 
minutes of the onset of new or worsening cardiac symptoms, unless documented (i.e. by ECG or other 
objective) to be due to acute myocardial infarction; death witnessed and attributed to an identified 
arrhythmia (e.g., captured on an electrocardiographic (ECG) recording, witnessed on a monitor, or 
unwitnessed but found on implantable cardioverter-defibrillator review); death after unsuccessful 
resuscitation from cardiac arrest; death after successful resuscitation from cardiac arrest and without 
identification of a noncardiac etiology; unwitnessed death without other cause of death (information 
regarding the patient’s clinical status preceding death should be provided, if available). 
General Considerations- A subject seen alive and clinically stable 24 hours prior to being found dead 
without any evidence or information of a specific cause of death should be classified as “sudden 
cardiac death.” Typical scenarios include: Subject well the previous day but found dead in bed the 
next day; 
Subject found dead at home on the couch with the television on. Deaths for which there is no 
information beyond “Patient found dead at home” may be classified as “death due to other 
cardiovascular causes”. 
 
Death due to Cardiovascular procedures  
Death related to CV procedures refers to death caused by the immediate complications of a CV 
procedure and excludes death resulting from procedures to treat an AMI or the complications resulting 
from an AMI.  
 
Death due to Other Cardiovascular Causes 
CV deaths not included in the above categories will be considered “due to other CV causes”. This 
category includes deaths resulting from one of the following conditions: pulmonary embolism, 
peripheral arterial disease, non-stroke intracranial hemorrhage, non-procedural or non-traumatic 
vascular rupture (e.g., aortic aneurysm), or hemorrhage causing cardiac tamponade.  
 
Death of unknown cause 
Death of unknown cause refers to a death not attributable to CV or non CV death due to absence of 
any information (e.g., the only available information is “patient died”). The use of this category of 
death is discouraged and should apply to a minimal number of cases when no information at all on the 
circumstances of death are available (i.e. found on obituary of local newspaper). In all circumstances 

Protocol SWISS APERO Version 5 /29.05.2020 
37/42 
the reviewer will use all available information to attribute to one of the categories based on best 
clinical judgment.   
 
Non Cardiovascular Death 
Non Cardiovascular Death is defined as death of a primary cause that is clearly related to another 
condition (e.g. trauma, cancer, suicide). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17.3 DIAGNOSTIC CRITERIA FOR STROKE AND TIA 
 
Stroke is defined as brain, spinal cord, or retinal cell death attributable to ischemia or hemorrhage, 
based on at least one of the following conditions: 
 
-clinical evidence of focal ischemic injury with symptoms persisting ≥24 hours or until death 
and without any possible etiologies, OR 
 
-objective evidence of focal ischemic injury in a defined vascular distribution.25  
 
Based on this definition, stroke endpoint will be adjudicated taking into account three elements: the 
neurological dysfunction, absence of a nonvascular mechanism, and imaging evidence of ischemic 
injury. The neurologic dysfunction consists of 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. Furthermore, duration of 
neurological dysfunction longer than 24h helps to exclude transient ischemic attack (TIA). Other 
readily identifiable non-stroke cause for the clinical presentation (e.g. brain tumour, trauma, infection, 
hypoglycaemia, peripheral lesion, pharmacologic influences) will be excluded based on 
clinical/imaging assessment. The objective evidence of focal ischemic injury will be performed by 
means of neuroimaging procedure (computed tomography (CT) scan or brain magnetic resonance 
imaging (MRI)) findings. Again, imaging-documented new haemorrhage or infarction will be useful 
to exclude TIA in the event that duration of neurological dysfunction is shorter than 24 h.  
 
Classification:  
Ischemic Stroke 
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused 
by CNS infarction. Evidence of infarction is defined as pathological, imaging, or other objective 
evidence of acute cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular 
distribution. In absence of the above (i.e. imaging or autopsy unavailable), clinical evidence of 
cerebral, spinal cord, or retinal focal ischemic injury is based on symptoms persisting ≥24 hours or 
until death, after excluding other etiologies.  
Note, hemorrhagic infarction, defined as a parenchymal hemorrhage after CNS infarction, is 
considered an ischemic stroke. 
 
Haemorrhagic Stroke 
Haemorrhagic Stroke is defined as a rapidly developing clinical signs of neurological dysfunction 
(focal or global) attributable to a focal collection of blood within the brain parenchyma, ventricular 
system or subarachnoid space (the space between the arachnoid membrane and the pia mater of the 
brain or spinal cord), that is not caused by trauma. Hemorrhages in the CNS are classified as stroke if 
they are nontraumatic, caused by a vascular event, and result in injury to the CNS. In contrast, 

Protocol SWISS APERO Version 5 /29.05.2020 
38/42 
traumatic hemorrhages and subdural hematoma will not be characterized as stroke. The diagnoses 
included in this section are intracerebral hemorrhage (intraparenchymal and intraventricular) and 
subarachnoid hemorrhage (both aneurysmal and nonaneurysmal).   
 
Undetermined Stroke  
Undetermined Stroke is defined as an acute episode of focal or global neurological dysfunction 
persisting ≥24 hours (or until death) caused by presumed brain, spinal cord, or retinal vascular injury 
as a result of haemorrhage or infarction but with insufficient information to allow categorization as an 
ischaemic or haemorrhagic stroke.  
 
Stroke severity  
Disabling strokes will be adjudicated based on residual neurological dysfunction. 
Stroke is defined as “disabling” if at 90 days after the index event, a modified Rankin Scale (mRS) 
score of  ≥ 3 and a mRS score increases of at least 1 compared with pre-stroke baseline.  
Non-disabling stroke are defined as any stroke not satisfying the criteria for disabling stroke (i.e. an 
mRS score of 2 at 90 days or an increase in mRS score of 1 compared with pre-stroke baseline). 
Furthermore mortality stroke related will be assessed. Death will be considered stroke related (CV 
death) even if it results from other causes but occurs ≤ 30 days after onset of stroke. 
 
 
 
17.4  
DEFINITION OF SYSTEMIC EMBOLISM 
 
Systemic embolism is defined as an acute vascular insufficiency or occlusion of the extremities or any 
non-CNS organ associated with clinical, imaging, surgical/autopsy evidence of arterial occlusion in the 
absence of other likely mechanism (e.g. trauma, atherosclerosis, or instrumentation). When there is 
presence of prior peripheral artery disease, angiographic or surgical or autopsy evidence is required to 
show abrupt arterial occlusion. 
 
17.5  
PULMONARY EMBOLISM 
 
Pulmonary embolism (PE) is defined as an acute vascular insufficiency or occlusion in one of the 
pulmonary arteries or one of their branches. Clinical signs and symptoms suggesting PE should be 
confirmed by a recommended imaging diagnostic test as CT (or perfusion/ventilation pulmonary 
scintigraphy if CT is not available). Clinical features such as cyanosis, dyspnoea, tachycardia and 
hypotension should be documented to enable assessment of severity but are not sufficient for diagnosis 
because of lack of specificity and low sensitivity. Similarly changes in electro-cardiographs, pulse 
oximetry and chest x-ray cannot be relied upon for diagnosis but may be used as auxiliary tests. 
 
17.6 DEFINITIONS FOR SEVERITY AND TIME OF OCCURRENCE OF 
PERICARDIAL EFFUSION 
 
Clinically non-relevant 
 
Requiring no intervention 
 
Treated pharmacologically 
 
Clinically relevant 
 
Treated with therapeutic pericardiocentesis 
 
Treated with surgical intervention 
 
Requiring blood transfusion 
 
Resulting in shock and/or death 
 
 
17.7  
BLEEDING DEFINITIONS 
All potential bleeding events will be adjudicated according to Bleeding Academic 
Research Consortium (BARC) classification (see the table below) as well as 
 

Protocol SWISS APERO Version 5 /29.05.2020 
39/42 
according to TIMI and GUSTO classifications. 
Type 0 
No bleeding 
Type 1 
Bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a health 
care professional.  May include episodes leading to self-discontinuation of 
medical therapy by the patient, without consulting a health care professional. 
Type 2 
Any overt, actionable sign of hemorrhage (e.g. more bleeding than would be 
expected for a clinical circumstance; including bleeding found by imaging 
alone) that does not fit the criteria for Types 3, 4, or 5 but does meet at least 
one of the following criteria:  
-Requiring non-surgical, medical intervention by a health care professional  
-Leading to hospitalization of increased level of care  
-Prompting evaluation 
Type 
3a 
 
 
Type 
3b 
 
 
 
 
 
Type 
3c 
Overt bleeding plus hemoglobin drop of 3 to <5* g/dL (provided hemoglobin 
drop is related to bleed)  
Any transfusion with overt bleeding 
 
Overt bleeding plus hemoglobin drop ≥5* g/dL (provided hemoglobin drop is 
related to bleed)  
Cardiac tamponade  
Bleeding requiring surgical intervention for control (excluding dental / nasal / 
skin / hemorrhoid)  
Bleeding requiring intravenous vasoactive agents 
 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation; does include intraspinal)  
Subcategories: confirmed by autopsy or imaging or lumbar puncture  
Intra-ocular bleed compromising vision 
Type 4 
CABG-related bleeding  
Perioperative intracranial bleeding within 48 hours  
Reoperation following closure of sternotomy for the purpose of controlling 
bleeding Transfusion of ≥ 5 units of whole blood or packed red blood cells 
within 48 hour period†  
Chest tube output ≥ 2 L within a 24 hour period 
Type 
5a 
 
Type 
5b 
Probable fatal bleeding; no autopsy or imaging confirmation, but clinically 
suspicious 
 
Definite fatal bleeding: overt bleeding or autopsy or imaging confirmation 
* Corrected for transfusion (1 U packed red blood cells or 1 U whole blood_1g/dL 
hemoglobin). † Cell saver products will not be counted 
 
17.8  
DEFINITION OF VASCULAR ACCESS-RELATED COMPLICATIONS 
Any of the following events: 
 
Haematoma at access site >6 cm 
 
Retroperitoneal haematoma, 
 
Arteriovenous fistula 
 
Arterial complications (thrombosis and/or stenosis and/or distal embolization with clinical ischaemia, 
perforation, dissection, aneurysm, 
 
pseudoaneurysm) 
 
Venous complications (venous dissection, laceration, perforation) 
 
Symptomatic peripheral ischaemia/nerve injury with clinical symptoms lasting >24 h 
 
Vascular surgical repair at catheter access sites 
 
Pulmonary embolism 
 
Ipsilateral deep vein thrombosis 
 
Access site-related infection requiring intravenous antibiotics or extended hospitalizationand at the follow 
up visits. 

Protocol SWISS APERO Version 5 /29.05.2020 
40/42 
 
17.9  
DEFINITION OF EPICARDIAL OR MINIMAL INVASIVE SURGICAL 
ACCESS-RELATED COMPLICATIONS 
Any of the following events: 
 
Perforation of cardiac vessel or cardiac wall requiring blood transfusion or surgical or percutaneous 
intervention, 
 
Puncture of pulmonary tissue requiring blood transfusion, chest tube, or surgical or percutaneous 
intervention, 
 
Puncture of abdominal organs requiring blood transfusion or surgical intervention, 
 
Perforation or laceration of superficial epigastric artery or LIMA requiring surgical or percutaneous 
intervention. 
 
 
17.10 
DEVICE-RELATED COMPLICATIONS 
 
Device embolization 
 
Major: Device embolization that requires repeated catheterization or surgery or results in 
damage to surrounding cardiovascular structures. 
 
Minor: Device embolization resolved by percutaneous retrieval during the procedure without 
surgical intervention or damage to surrounding cardiovascular structures. 
 
Device erosion 
 
Clinically significant device interference with surrounding structure (circumflex coronary artery, mitral 
valve, pulmonary artery, pulmonary vein) 
 
Device thrombus 
 
Device fracture 
 
Device infection/endocarditis/pericarditis 
 
Device perforation/laceration 
 
Device allergy. 
 
17.11 
DEVICE RELATED THROMBOSIS  
DRT is a clot that forms on the atrial surface of the device during or after its implantation. However, 
there is currently no uniform definition or classification of DRT for LAA closure devices. The shape could 
be pedunculated or laminar. It can develop on many different parts of the device’s surface, mostly on 
the central part of the lobe/disc (at the level of the pin) or in the recess adjacent to the Coumadin ridge.  
This endpoint will be separately adjudicated by means of two imaging methods: TEE and CCTA.  
TEE – DRT is defined at TEE evaluation as a homogenous mass with an echogenicity 
comparable to the myocardium on the atrial surface of the device, inconsistent with normal 
healing/device incorporation process and not explained by imaging artefact. DRT can have a 
pedunculated shape with an independent motion or be sessile without any motion and is visible 
in multiple planes. The occurrence of DRT will be locally ascertained  at the very time of the 
TEE by an expert echocardiographer with extensive previous and ongoing work imaging on 
LAAC devices. 
 
CCTA – DRT is defined at CCTA evaluation as homogenous hypoattenuated thickening (HAT) 
on the atrial surface of the device. Currently there is no uniform definition of DRT and 
differentiating it from prominent endothelialization by CCTA is not always easy. The occurrence 
of DRT will be centrally evaluated and adjudicated by the ICL, composed of three imaging 
experts who will independently score each of the studies as positive, possible or negative for 
DRT. In the event of inconsistent adjudication between the three readers, a consensus between 
all of them will be required. As previously suggested, assessment and scoring of HAT will be 
based on the following parameters: shape, maximum tickening, continuation onto the LA wall, 
HU HAT/HU LA ratio, cross sectional area at the base. 
 
17.12 
SUCCESS DEFINITIONS 
Device success 
 
Device deployed and implanted in correct position 
 

Protocol SWISS APERO Version 5 /29.05.2020 
41/42 
Technical success 
 
Exclusion of the LAA 
 
No device-related complications 
 
No leak ≥ 3 mm on colour Doppler TEE 
 
Procedural success 
 
Technical success 
 
No procedure-related complications, except for 
uncomplicated (minor) device embolization. 
 
 
17.13 
 LAA PATENCY ASSESSED BY TEE 
At 45 days after LAAC, patients will undergo a TEE assessment (and a CCTA as well). Device 
deployment will be assessed from 0° to 135° (0° - 45° - 90° - 135°) with and without color Doppler (using 
a scale 50-60 cm/sec). Presence of leak will be locally ascertained by expert echocardiographers with 
extensive previous and ongoing work imaging on LAAC devices. Leak on TEE is defined as any jet 
between LAA and LA or conversely detectable by means of color-Doppler (high velocity 50-60 cm/sec). 
The size is measured taking the narrowest flow region of the jet that occurs at, or just close to, the 
device.  
Of note, rate of LAA patency at 45 day CCTA will be compared with rate of leak at 45 day TEE. 
 
17.14 
 FEASIBILITY OUTCOMES  
During the index procedure, data related to number of device implantation attempts, total time procedure, 
x-ray dose and total contrast dose used in the procedure will be recorded (secondary endpoints). 
 
Number of device implantation attempts 
Device implantation attempt is defined as any delivery sheath retracting (or any advancement of device 
outside of delivery sheath in the event of “advancement technique” with Watchman FLX) aimed at 
exposing and implanting the device lobe. The number of partial and complete device recaptures will be 
recorder. Partial recapture is defined as the partial re-entry of the device into the delivery sheath keeping 
the hooks/anchors outside. Complete recapture is defined as the complete re-entry of the device into 
the delivery sheath (including the hooks/anchors). 
 
Total time procedure 
It refers to the time between the venous access puncture and its closure. In the event of a concomitant 
procedure performed right after LAAC, the ending time will be considered the time of device release. 
 
X-ray dose procedure and total contrast dose procedure 
Data related to X-ray and medium contrast doses used during LAAC will be recorded. In the event of a 
concomitant procedure, a careful differentiation between LAAC data and concomitant procedure data 
will be performed. 
 
17.15 
STAGING SYSTEM FOR ACUTE RENAL INJURY 
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function, resulting in the retention of 
urea and other nitrogenous waste products and in the dysregulation of extracellular volume and 
electrolytes. AKI will be adjudicated, according the latest Guidelines for AKI management,8 if one of the 
following criteria is met: 
• 
Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 micromol/L) within 48 hours; 
• 
Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have 

Protocol SWISS APERO Version 5 /29.05.2020 
42/42 
occurred within the prior seven days; 
• 
Urine volume <0.5 mL/kg/hour for six hours. 
AKI will be subsequently staged for severity according to the criteria mentioned below. 
 
 
Stage 
Serum creatinine criteria 
Urine output criteria 
 
1 
Increase in serum creatinine to 150–
200% (1.5–1.99× increase compared 
with baseline) 
OR increase of ≥0.3 mg/dL (≥26.4 
mmol/L) 
 
Less than 0.5 mL/kg/h for more than 
6 but<12 h 
 
2 
Increase in serum creatinine to 200–
300% (2.0–2.99× increase compared 
with baseline) 
Less than 0.5 ml/kg/h for more than 
12 but <24 h 
 
3 
 
 
 
 
 
 
 
 
Increase in renal creatinine to ≥300% 
(.3× 
increase 
compared 
with 
baseline) OR serum 
creatinine of ≥4.0 mg/dL (≥354 
mmol/L) with an acute increase of at 
least 0.5 mg/dL 
(44 mmol/L) 
 
 
 
 
 
 
Less than 0.3 mL/kg/h for 24 h OR 
anuria for 12 h 
 
18. APPENDIX 2: ISTRUCTIONS FOR USE 
See Instructions for Use - AMPLATZER™ AMULET™Left Atrial Appendage Occluder, 2017-02St Jude 
Medical 
 
See Instructions for Use - WATCHMAN™Left Atrial Appendage Closure Device withDelivery System 
2017-08Boston Scientific Corporation 
 
See Instructions for Use – WATCHMAN FLX™Left Atrial Appendage Closure Device withDelivery 
System 2017-08Boston Scientific Corporation 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
 
Statistical Analysis Plan (SAP) 
 
SWISS-APERO 
Comparison of Amplatzer Amulet vs Watchman device in pa-
tients undergoing left atrial appendage closure: the SWISS-AP-
ERO randomized clinical trial 
Administrative Information 
Project number: 
657 
Trial registration number: 
NCT03399851 
SAP version: 
v2.0 of 17.08.2021 
Protocol version: 
Version 5 /29.05.2020 
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Contributors 
Name 
Affiliation 
Role in SAP writing 
Dik Heg 
CTU Bern 
Author 
Flora Babongo 
CTU Bern 
Reviewer 
 
 
 
 
 
Revision history 
Revision 
Justification  
Timing  
Added subgroups section 6.2.4 
Not mentioned in v1.0 
v2.0 
Revised all Tables section 5.4 
and further 
To conform with publication 
style 
v2.0 
 
 
 
 
 
Approved by  
Name 
Affiliation 
Study Role  
Date and Signature (wet ink) 
Flora Babongo 
CTU Bern 
Trial Statistician 
 
Dik Heg 
CTU Bern 
Senior Statistician 
 
Marco Valgimigli 
Cardiocentro Ti-
cino 
Coordinating Investi-
gator 
 
Lorenz Räber 
Inselspital Bern 
Sponsor Investigator 
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Contents 
1. 
Introduction ........................................................................................................................ 5 
1.1 
Background and rationale .................................................................................................... 5 
1.2 
Objectives ............................................................................................................................ 5 
2. 
Study methods ................................................................................................................... 7 
2.1 
Trial design .......................................................................................................................... 7 
2.2 
Randomization ..................................................................................................................... 7 
2.3 
Sample size ......................................................................................................................... 8 
2.4 
Framework ........................................................................................................................... 8 
2.5 
Statistical interim analyses and stopping guidance .............................................................. 8 
2.6 
Timing of final analysis ......................................................................................................... 8 
2.7 
Timing of outcome assessments .......................................................................................... 8 
2.8 
Blinding .............................................................................................................................. 11 
3. 
Data management ............................................................................................................ 12 
3.1 
Data export ........................................................................................................................ 12 
3.2 
Data validation ................................................................................................................... 12 
3.3 
Data preparation ................................................................................................................ 12 
3.4 
Data sharing (if applicable) ................................................................................................ 13 
4. 
Statistical principles ........................................................................................................ 14 
4.1 
Confidence intervals and P values ..................................................................................... 14 
4.2 
Analysis populations .......................................................................................................... 14 
4.2.1 
Full analysis set (FAS) ....................................................................................................... 14 
4.2.2 
Per-protocol (PP) ............................................................................................................... 14 
4.2.3 
Safety population ............................................................................................................... 15 
4.3 
Estimands .......................................................................................................................... 15 
5. 
Trial Population ................................................................................................................ 17 
5.1 
Screening data ................................................................................................................... 17 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5.2 
Eligibility ............................................................................................................................. 17 
5.3 
Recruitment ........................................................................................................................ 18 
5.4 
Baseline patient characteristics ......................................................................................... 19 
5.5 
LAAC procedural characteristics ........................................................................................ 21 
5.6 
Medication .......................................................................................................................... 24 
5.7 
Primary and secondary outcomes at 45 days of Follow-up ................................................ 27 
5.8 
LAA assessments at 45 days of Follow-up ........................................................................ 28 
5.9 
Evaluation of Amulet and Watchman implantations ........................................................... 29 
5.10 
Withdrawal/follow-up .......................................................................................................... 32 
6. 
Analysis ............................................................................................................................ 33 
6.1 
Outcome definitions ........................................................................................................... 33 
6.1.1 
Primary outcome ................................................................................................................ 33 
6.1.2 
Secondary outcome ........................................................................................................... 33 
6.1.3 
Safety outcome .................................................................................................................. 33 
6.1.4 
Feasibility outcome ............................................................................................................ 34 
6.2 
Analysis methods ............................................................................................................... 34 
6.2.1 
Primary analysis ................................................................................................................. 34 
6.2.2 
Secondary analyses ........................................................................................................... 34 
6.2.3 
Sensitivity analyses ............................................................................................................ 34 
6.2.4 
Additional analyses ............................................................................................................ 35 
6.2.5 
Assessment of statistical assumptions ............................................................................... 35 
6.3 
Interim analyses ................................................................................................................. 35 
6.4 
Missing data ....................................................................................................................... 35 
6.5 
Safety evaluation ............................................................................................................... 35 
6.6 
Statistical software ............................................................................................................. 36 
6.7 
Quality control .................................................................................................................... 36 
7. 
References ........................................................................................................................ 37 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
 
1. 
Introduction  
1.1 
Background and rationale  
Non-valvular Atrial fibrillation (NVAF) is the most common cardiac arrhythmia and a major cause of morbidity 
and mortality because of cardioembolic stroke. Cardiac embolism due to AF causes up to 25% of all ischemic 
strokes, which makes it socioeconomically highly relevant. Oral anticoagulation (OAC) with vitamin K antag-
onists (VKA) or Non-vitamin K antagonist anticoagulant (NOAC) is the most effective prophylaxis for stroke 
in AF. Yet, (N)OAC therapy is associated with a significant bleeding liability and long-term (N)OAC therapy 
in patients with NVAF and concomitant high bleeding risk poses safety issues in a sizable and growing 
population in clinical practice. Post-mortem and echocardiographic studies have shown that the vast majority 
of all cardiac thrombi in patients with NVAF form in the left atrial appendage (LAA). Thus, a new and emerg-
ing therapeutic option in this high-risk patient population is the exclusion of the LAA cavity from the circula-
tion via percutaneous intervention. 
Currently, the Amplatzer ACP/Amulet ™ (St. Jude Medical-Abbott), and the Watchman™ (Boston Scientific, 
Natick, MA, USA) are the devices with most clinical experience reported to date for percutaneous closure of 
LAA. The Watchman was tested in the setting of two randomized control trials, which demonstrated the 
safety of the procedure and the non-inferiority in terms of stroke reduction compared to OAC. A second-
generation device, the Watchman FLX was developed and released for simplified implantation to fit a wider 
range of patients and to enhance sealing within the left atrial appendage. It gained the CE mark in the 
beginning of 2019. 
Until a few years ago in Europe the device most frequently utilized for LAA closure was the Amplatzer 
Cardiac Plug™ (ACP, St. Jude Medical-Abbott), which gained CE approval in late 2008. There is no RCT 
comparing ACP with OAC, but many prospective and retrospective studies had shown the same safety 
profile and the non-inferiority with the OAC. A second-generation device, the Amulet™, was developed and 
released in 2013 for easier delivery, better coverage, and reduction of complications. 
A critical step for each LAA closure procedure is the appraisal of LAA residual or new patency/leaks after 
device implantation. In the setting of available randomized trials (currently only limited to the Watchman 
device), successful closure was defined by the presence of a peridevice flow ≤ 5 mm assessed with TEE 45 
days after the procedure. In these trials, as well as according to the current instruction for use of Watchman, 
the appraisal of residual leaks 45 days after LAAC was/is considered mandatory for a correct post procedural 
management of pharmacotherapy (in terms of continuation or reinstitution of OAC therapy). Furthermore, 
there is a growing attention to the natural history of peridevice leaks given their unpredictable evolution. 
Currently the gold standard for the assessment of LAA patency after closure is the TEE. However it is an 
invasive and operator dependent examination, and replacing it with an alternative non-invasive exam is also 
desirable for patient’s comfort 
In the last years, several groups (including ours) assessed the value of CCTA as non-invasive post-proce-
dural surveillance imaging modality after endovascular LAA closure to evaluate residual leak and reported 
higher sensitivity for CCTA as compared to TEE in the identification of LAA residual patency. 
There are currently no randomized controlled trials assessing the degree of LAA closure between Amulet 
and Watchman/FLX. 
 
1.2 
Objectives 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
The purpose of this study is to compare the efficacy and safety of the two devices for the LAAC, to assess 
whether Amplatzer Amulet is superior to Watchman/FLX in terms of degree of LAA occlusion as evaluated 
by CCTA 45 days after implantation. 
The primary outcome is the composite of LAA patency at 45 day CCTA and the adjudicated crossover from 
one device to the other device based on morphological/anatomical considerations during device implanta-
tion, including failed implantation adjudicated cross-overs. Post-intervention LAA patency will also assessed 
via TEE based on the more conservative criterion of residual flow ≥3mm. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
2. 
Study methods 
2.1 
Trial design 
 
This will be a multicentre, open-label, prospective, randomized study in patients with AF and an indication for 
anticoagulant therapy with high bleeding risk, that agree to the LAAC procedure. Patients will be submitted to a 
screening protocol in a period not greater than 90 days before procedure, including medical and drug history, 
physical examination, 12-lead ECG, CCTA(as per standard of care) and TEE if clinically indicated. 
Once the patient is judged eligible and the informed consent has been signed, the patient will be randomly 
assigned in a 1:1 to receive a LAAC with Amplatzer Amulet or Watchman/FLX device. In the event that the 
patient is randomized to the Watchman/FLX arm, the operator will be able to choose, on the basis of clinical 
reasons, if to implant Watchman or the new generation Watchman FLX (if available in the center). 
Implantation will be performed according to common practice guidelines (and so with TEE/ICE guidance of 
procedure). Angiography at the end of the procedure is recommended to assess PDL. In case of concomitant 
procedure during LAAC, it will be reported separately in term of duration time, contrast dose and x-ray dose. 
At the end of procedure, a measure of PDL must be provided. 
A transthoracic echocardiogramis encouraged (but not mandatory) before the hospital discharge in order to 
detect pericardial effusion. 
All patients randomly allocated to the Watchman/FLX or Amulet arm will receive ASA and clopidogrel or (N)OAC 
(at discretion of the treating physician and according to the bleeding risk, stroke risk as well as based on post-
procedural TEE evaluation) for 45 days and then will undergo TEE assessment(as well as CCTA): 
• 
If a residual peri-device leak flow at 45 days > 5 mm or a intra-cardiac thrombus is detected, a 
therapy with ASA and (N)OAC could be considered up a sequential TEE evaluation at 6 months. 
• 
If a residual peri-device leak flow at 45 days ≤ 5 mm is detected, patients will continue to receive 
ASA and clopidogrelor (N)OAC (at discretion of the treating physician according to the bleeding 
and stroke risk) up until 3 months after procedure. Thereafter, monotherapy with ASA will be 
continued until 12 months after procedure. 
These drug regimens are strongly recommended according the actually evidence and the instruction for use of 
the two devices. Nevertheless, if a clinical condition lead to prescribe other drugs regimen, it will be permitted 
given an exhaustive explanation by physician. 
Further procedures, such as physical examination or blood sampling will be done according the study schedule, 
in particular visits or phone calls will take place after 6 and 13 month as well as 2/ 3/ 4/ 5 years. 
 
2.2 
Randomization 
 
Balanced (1:1) randomization will be performed via a web-based interactive randomization system (ICE-Advice 
Pharma), based on a computer-generated random sequence with a random block size stratified according to 
site and an allocation to either Amulet Amplatzer device or Watchman/FLX. In the event that the patient is 
randomized to the Watchman/FLX arm, the operator will be able to choose, on the basis of clinical reasons, if 
to implant Watchman or the new generation Watchman FLX (if available in the center). Randomization will occur 
as close as possible to but always before the procedure and once the patient is judged eligible and the informed 
consent has been signed. 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
2.3 
Sample size  
 
Considering an incidence of the primary composite end-point in the range of 50% in the Watchman/FLX group, 
which is a conservative estimate based on previous reports, we estimate that 200 patients will provide greater 
than 80% power to prove superiority of Amulet as compared to Watchman/FLX assuming a 40% risk reduction 
(i.e. corresponding to an event rate in the range of 30%) and a significance level of 5% (alpha). 
2.4 
Framework 
 
We formulate the following hypotheses: 
• 
Null hypothesis A (H0A): Amulet is superior to WATCHMAN/FLX device in terms of complete LAA 
occlusion degree and feasibility. 
• 
Null hypothesis B (H0B): there is no difference between Amulet and WATCHMAN/FLX in terms of 
LAA occlusion degree and feasibility. 
2.5 
Statistical interim analyses and stopping guidance 
 
No statistical interim analyses are planned. 
2.6 
Timing of final analysis 
 
The primary endpoint analyses will be performed after all 45 days follow-up visits are conducted and completely 
entered into the data capture system; and after all data are cleaned and events have been adjudicated. Longer 
follow-up analyses at e.g. 13 months, 2 years, 3 years, 4 years and 5 years will be conducted as requested, 
after all data have completely entered into the data capture system; and after all data are cleaned and events 
have been adjudicated. 
2.7 
Timing of outcome assessments 
 
Assessment of primary outcome 
The primary outcome is the composite of LAA patency at 45 day evaluated with CCTA; or the crossover from 
one device to the other device based on morphological/anatomical considerations during device implantation, 
including failed implantation attempts. 
Patency LAA will be estimated at CCTA by measurement of the linear attenuation coefficient (Hounsfield unit, 
HU) in the LAA distal to the device and comparison of contrast density to atrial chamber. LAA patency was 
defined with LAA HU ≥ 100 or LAA HU ≥ 25% of LA HU, as reported in a previous publication Saw et al. 2015. 
Adjunctive CCTA criteria of complete occlusion will be collected in order to validate them. 
A TEE evaluation of PDL presence will be performed at 45-days in order to compare the two imaging technique. 
Assessment of secondary outcomes 
Secondary outcomes will be collected at 45 days, 6 months, 13 months, 2 years, 3 years, 4 years and 5 years 
follow up. Data about event will be collected both in electronic form that with related document (medical reports, 
CT and other imaging report). LAA patency on arterial phase has been already defined in the previous section 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
(“Assessment of primary outcome”). LAA patency on venous phase is defined, as reported in a previous publi-
cation22, as a LAA density ≥ 100 HU or ≥ 150% of that measured at the same site on arterial phase. 
Assessment of safety outcomes 
Safety outcomes will be assessed 45 days, 6 months, 13 months, 2 years, 3 years, 4 years and 5 years follow 
up. Data about adverse clinical events will be collected both in electronic form (ICE-Advice Pharma) that with 
related document (medical reports, CT and other imaging report). 
Assessments in participants who prematurely stop the study 
Data of withdrawn participants will be collected up to the time of withdrawn. However, withdrawn participants 
will be asked the permission to continue collecting and evaluate data about them from routine data or other 
sources (general practitioners, Health System Softwares available) in order to respect the patient choice without 
affecting the scientific quality of the study. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
  

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
2.8 
Blinding 
 
 
Allocation to the two randomized devices Amulet vs Watchman/FLX is concealed. After the randomization result 
is available, the study personnel, monitors, the trial statistician receiving the raw data download are not blinded 
to the randomized device.  
However, independent blinded analyses will be conducted by a second statistician who does not know the 
allocation result of the randomization (e.g. coded X vs Y). Moreover, also the clinical event adjudication com-
mittee adjudicating the events is blinded to the randomized device. 
The Sponsor will be provided with blinded tables of the primary outcome analyses (e.g. coded X vs Y with no 
denominators), which the Sponsor can use for final plausibility checks and queries for e.g. outliers to be send 
to the centres. If this final cleaning process is performed, the Sponsor will receive the unblinded results. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
3. 
Data management 
3.1 
Data export 
 
Data are stored in the web-based electronic data capturing portal of ICE-Advice Pharma. Data are exported 
from the ICE-Advice Pharma data capture portal in comma delimited text files with a codebook also in 
comma delimited text files, by the statisticians. 
3.2 
Data validation 
 
Before locking, the data will be checked for completeness using e.g. missing tables functions. The plausibility 
of the primary and secondary outcomes will be checked using outlier analyses and histograms, and will be 
queried if they are outside the expected range, including dates of events. Only events occurring after the im-
plantation (attempt) of the LAAC device will be analysed, in case no LAAC procedure was started the random-
ization date will be used instead. 
3.3 
Data preparation 
 
LAA patency is derived from the average Linear attenuation coefficient within the LAA distal to the device’s lobe 
(artphase_mean2) ≥100 HU OR average Linear attenuation coefficient within the LAA distal to the device’s lobe 
≥25% of the average Linear attenuation coefficient within the LAA  (artphase_mean2/artphase_mean1≥0.25), 
as recorded inside the follow-up 45 days visit of the Consensus estimate (this is the consensus of the three 
Core laboratory assessments by three different assessors). LAA patency is a marker of leaks in/out of the LA 
and therefore a marker of potential thrombus material migration from the LAA to blood circulation system. 
Cross-overs are captured in the procedure eCRF and Adjudicated by the clinical event adjudication committee, 
both successful and failed attempts to cross-over.  
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
The primary endpoint is defined as LA patent or adjudicated cross-overs including failed cross-overs. 
 
Table 1: Derivation of LA patency used in the primary outcome. 
Outcome 
eCRF 
sheet 
Variable 
Variable 
type 
Remarks 
LAA patency 
  patent = 1 
CCTA 
fu_reader = 6 = Consensus 
Categori-
cal 
Consensus assessment of three as-
sessors 
 
 
AND (artphase_mean2≥100 OR 
artphase_mean2/artphase_mean1≥0.25 
Continu-
ous 
LAA HU mean distal from device’s 
lobe in arterial phase = 
artphase_mean2 
LA HU mean in arterial phase = 
artphase_mean1 
  not patent = 0 
 
 
 
artphase_mean2 not missing and 
not patent as reverse of the above 
 
Clinical events are also adjudicated and these adjudicated events up to 45 days after the LAAC procedure (or 
randomization date if no procedure was initiated) will be analysed, excluding events occurring before the LAAC 
procedure (or randomization date if no procedure was initiated) and excluding events occurring on day 46 and 
later. Adjudicated events beyond 45 days are used for the longer-term follow-up analyses and censored ac-
cordingly (e.g. at 1 year, at 5 years). 
 
3.4 
Data sharing (if applicable) 
 
Data sharing will be prepared using the CTU Bern Anonymization SOP. Data will be shared on the portal BORIS 
of the University Bern or equivalent portal. Data can be shared after formal requests with a study proposal are 
evaluated by the Sponsor. 
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
4. 
Statistical principles 
4.1 
Confidence intervals and P values 
 
Primary and secondary end points will be analysed on an intention-to-treat basis. Additional analyses will be 
also carried out in the per-protocol and as-treated populations.  Categorical outcome measures will compared 
using a χ2 test or Fisher exact test as required. Continuous variables will compared using a 2-sided unpaired t 
test or a Mann-Whitney test, as appropriate. Estimation of the cumulative incidence of safety and efficacy end-
points will be performed using the Kaplan-Meier method in case of time-to-event endpoints, and event rates will 
be compared by the log rank test. The estimated relative risk (RR) is the ratio of the risk probabilities, and a 
confidence interval will constructed based on a logarithmic transformation. 
The primary endpoint LAA patency or adjudicated cross-over including failed cross-over to other device at 45 
days will be analyzed using risk ratios and risk differences. 
 All statistical tests will be performed using a 5% significance level. 
4.2 
Analysis populations 
 
The primary endpoint analysis will be performed using the intention to treat principle on the intention-to-treat, 
full-analysis set population. Sensitivity analyses will be performed on the per-protocol population. Crossover 
patients will be considered as a primary end-point event in all analyses. 
4.2.1 
Full analysis set (FAS) 
 
The full analysis set (FAS) will include all randomized subjects. Following the intent-to-treat principle, subjects 
will be analyzed according to the treatment they are assigned to at randomization. 
4.2.2 
Per-protocol (PP) 
 
Per-protocol population PP consists of all subjects in the FAS who do not have any major protocol violation. 
The following items will be considered such a major protocol deviations, which will exclude the patient from the 
PP (Table 2): 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Table 2: Derivation of major protocol violations used for PP definition. 
Protocol deviation 
eCRF 
sheet 
Variable 
Variable 
type 
Derivation of violation 
Violation of inclusion or exclusion criteria 
Age ≥18 years (ic1) 
Baseline 
age 
Continuous 
age<18 
Written informed consent 
(ic2) 
Baseline 
ic2 
Binary: 
yes/no 
no 
CHADS2VASC score ≥2 
(ic5) 
Baseline 
{score based on 
baseline varia-
bles, add points 
into score} 
Add points 
hf=yes (1 point), hypertension=yes (1 point), age≥75 (2 points) 
OR age 65-74 years (1 point), diabetes=yes (1 point), 
prior_cerebr=yes OR arterial_embolism=yes OR conc_th=yes 
(2 points), vasculopathy=yes OR prior_mi=yes OR aor-
tic_plaque=yes (1 point), gender=female (1 point). 
Violation if score<2 
HASBLED ≥3 or High bleed-
ing risk HBR as defined by 
Munich consensus docu-
ment (ic6) 
Baseline 
{score based on 
baseline varia-
bles, add points 
into score} 
Add points 
HASBLED: uncontroll=yes (1 point), kidney_disease=yes (1 
point), liverdisease=yes (1 point), type_cerebr=stroke (1 point), 
priorbleeding=yes OR anemia=yes OR ind_primary={any of: 
history of major or minor bleeding, wish to avoid triple therapy, 
risk of fall, concomitant disease improving bleeding risk 
,HASBLED≥3} (1 point) OR hb≤130g/L in male/hb<120g/L in 
female, inab_oac_variability=3 (1 point), age>65 (1 point), 
bl_drugs _{oac, noac, aspirin, thienopyridine,fans }=any yes (1 
point), alcohol=yes (1 point) 
HBR: priorbleeding=yes OR anemia=yes OR hb≤130g/L in 
male/hb<120g/L in female 
Violation if score≤2 AND HBR=no 
Exclusion criteria not met 
Randomi-
zation 
exclusion_cit-
eria_exclu-
sion_crit 
Binary: 
yes/no 
no 
First LAAC device used not 
according to randomization 
Procedure 
first_device, 
first_imp_att  
Categorical, 
Number 
Equal to randomized but implantation attempts 
= 0 OR 
Procedure 
first_device 
Categorical 
Unequal to randomized 
CHADS2VASC: see https://www.mdcalc.com/cha2ds2-vasc-score-atrial-fibrillation-stroke-risk 
HASBLED: see https://www.mdcalc.com/has-bled-score-major-bleeding-risk 
 
4.2.3 
Safety population 
 
The safety population is the population with at least one LAAC device implanted, and is analysed according to 
the LAAC device actually implanted. 
 
4.3 
Estimands 
 
The primary outcome which is the composite of LAA patency at 45 day evaluated with CCTA; or the crossover 
from one device to the other device based on morphological/anatomical considerations during device implanta-
tion, will be reported as the number of occurrences and the proportion of these occurrences given the number 
of patients. 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
 
 
 
 
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5. 
Trial Population 
5.1 
Screening data 
 
Screening will be performed up to 90 days prior LAAC. Potential patients will be informed about the study and 
asked for participation. Subjects are considered provisionally enrolled with the signature on the written informed 
consent form (screening phase). Formal inclusion into the study will occur after baseline eligibility is confirmed 
and only once randomization takes place as close as possible to but always before LAAC. A copy of the informed 
consent form with the patient’s information document will be given to the patient. 
The following evaluations will be performed at baseline/enrolment: 
• 
Demographics; 
• 
Relevant medical history that includes: general medical, cardiovascular, neurologic and renal his-
tory; cardiovascular risk factors (e.g. dyslipidaemia, hypertension, diabetes mellitus, tobacco 
use); history of peripheral vascular disease, stroke, transient ischemic attack;documentation of 
current cardiovascular and diabetic medications;Stroke and bleeding risk evaluation with 
CHADS2, CHA2DS2VASc, HAS-BLEED and ABC score; 
• 
Evaluation of In-/Exclusion criteria; 
• 
12-lead ECG; 
• 
Routine laboratory tests within 48 hours prior to the index procedure as defined in 9.1.7; 
• 
CCTA according to current standard of care; 
• 
TEE if clinically indicated. 
 
5.2 
Eligibility 
 
Participants fulfilling all the following inclusion criteria are eligible for the study: 
• 
Written informed consent 
• 
Male or female subject aged 18 years or more with no upper age limit and willing to comply with 
the protocol 
• 
Indication to a LAA closure as indicated in study population (HAS BLEED ≥3 or High bleeding risk 
as defined by Munich consensus document and CHA2DS2-VASc≥2). 
The presence of anyone of the following exclusion criteria will lead to exclusion of the participant: 
• 
New York Heart Association class IV congestive heart failure 
• 
ASD or atrial septal repair or closure device 
• 
Single occurrence of AF 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
• 
Cardioversion or ablation procedure planned within 30 days 
• 
Implanted mechanical valve prosthesis 
• 
Heart transplantation 
• 
Enrolled in another IDE or IND investigation of a cardiovascular device or an investigational drug 
• 
Female of childbearing potential (age < 50 years and last menstruation within the last 12 
months), who did not undergo tubal ligation, ovariectomy or hysterectomy. 
• 
Active infection of any kind 
• 
Severe chronic kidney insufficiency (CrCl< 30 ml/min) 
• 
Terminal illness with life expectancy < 1 year 
• 
Echocardiographic exclusion criteria 
• 
LVEF < 20% 
• 
Intracardiac thrombus or dense spontaneous echo contrast as visualized by TEE within 2 days be-
fore implant 
• 
Significant mitral valve stenosis (ie, MV <1.5 cm2) 
• 
Complex aortic atheroma with mobile plaque of the descending aorta and/or aortic arch 
• 
Cardiac tumor. 
5.3 
Recruitment 
 
Patients will be screened previous the admission index. After complete screening pre-evaluation resulting in 
eligibility for LAAC, patients will be adequate informed and those accepting to participate will sign the informed 
consent form and will be enrolled in the study by dedicated staff previously identified at each center. 
Study participants will not receive any payment or compensation for participation in the study. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5.4 
Baseline patient characteristics 
 
A Table of baseline clinical and risk factors will be produced, no comparison randomized to Amulet vs ran-
domized to Watchman will be made. 
Table 1. Baseline Clinical Characteristics 
  
Watchman/FLX 
Amulet 
  
N = xx 
N = xx 
  
  
  
Demographics 
  
  
Age — years mean(SD) 
mean +- sd 
mean +- sd 
Male gender — no. (%) 
count (%) 
count (%) 
Body mass index — kg/m² mean(SD) 
mean +- sd 
mean +- sd 
Behavioural risk factors 
  
  
Smoker — no. (%) 
count (%) 
count (%) 
Alcohol abuse — no. (%) 
count (%) 
count (%) 
Medical history 
  
  
Arterial hypertension — no. (%) 
count (%) 
count (%) 
Dyslipidemia — no. (%) 
count (%) 
count (%) 
Family history of CAD — no. (%) 
count (%) 
count (%) 
Diabetes mellitus — no. (%) 
count (%) 
count (%) 
Chronic renal failure — no. (%) 
count (%) 
count (%) 
Uncontrolled hypertension — no. (%) 
count (%) 
count (%) 
Abnormal liver function — no. (%) 
count (%) 
count (%) 
Coronary artery disease — no. (%) 
count (%) 
count (%) 
Documented anaemia — no. (%) 
count (%) 
count (%) 
Long-term oral NSAIDs use — no. (%) 
count (%) 
count (%) 
Long-term steroids use — no. (%) 
count (%) 
count (%) 
Active malignancy — no. (%) 
count (%) 
count (%) 
Prior Cerebrovascular event — no. (%) 
count (%) 
count (%) 
Known carotid artery disease — no. (%) 
count (%) 
count (%) 
History of extracranial systemic embolic events — no. (%) 
count (%) 
count (%) 
History of clinically-overt pulmonary embolism — no. (%) 
count (%) 
count (%) 
Primary reason for an alternative to OAC 
  
  
History of Major bleedings 
count (%) 
count (%) 
Wish to avoid triple therapy 
count (%) 
count (%) 
Risk of fall or prior falls 
count (%) 
count (%) 
Concomitant disease increasing bleeding risk 
count (%) 
count (%) 
HASBLED score >=3 
count (%) 
count (%) 
Rejection of OAC 
count (%) 
count (%) 
Embolic event under OAC 
count (%) 
count (%) 
Others 
count (%) 
count (%) 
Prior myocardial infarction — no. (%) 
count (%) 
count (%) 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Valvular heart disease — no. (%) 
count (%) 
count (%) 
History of heart failure — no. (%) 
count (%) 
count (%) 
Decompensated heart failure at randomisation — no. (%) 
count (%) 
count (%) 
EHRA III — no. (%) 
count (%) 
count (%) 
Ejection fraction — mean (SD) 
mean +- sd 
mean +- sd 
Pacemaker or ICD — no. (%) 
count (%) 
count (%) 
CHA2DS2VASC Score — mean(SD) 
mean +- sd 
mean +- sd 
 — no. (%) 
  
  
0 
count (%) 
count (%) 
1 
count (%) 
count (%) 
2 
count (%) 
count (%) 
3 
count (%) 
count (%) 
4 
count (%) 
count (%) 
5 
count (%) 
count (%) 
6 
count (%) 
count (%) 
7 
count (%) 
count (%) 
8 
count (%) 
count (%) 
HASBLED Score — mean(SD) 
mean +- sd 
mean +- sd 
— no. (%) 
  
  
0 
count (%) 
count (%) 
1 
count (%) 
count (%) 
2 
count (%) 
count (%) 
3 
count (%) 
count (%) 
4 
count (%) 
count (%) 
5 
count (%) 
count (%) 
6 
count (%) 
count (%) 
Atrial fibrillation or flutter — no. (%) 
  
  
paroxysmal — no. (%) 
count (%) 
count (%) 
persistent or chronic — no. (%) 
count (%) 
count (%) 
undetermined — no. (%) 
count (%) 
count (%) 
atrial flutter — no. (%) 
count (%) 
count (%) 
History of relevant bleeding — no. (%) 
count (%) 
count (%) 
Intracranial bleeding  — no. (%) 
count (%) 
count (%) 
Gastrointestinal bleeding  — no. (%) 
count (%) 
count (%) 
Urinary  — no. (%) 
count (%) 
count (%) 
Epistaxis  — no. (%) 
count (%) 
count (%) 
Other bleeding  — no. (%) 
count (%) 
count (%) 
unknown  — no. (%) 
count (%) 
count (%) 
  
  
  
  
  
  
Data expressed as n (%) or means±standard deviations. 
  
  
MI: myocardial infarction; LAA: left-atrial appendage; EHRA: European Heart Rhythm score. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5.5 
LAAC procedural characteristics  
 
A Table of LAAC details will be produced comparing randomized to Amulet vs randomized to Watchman. In 
case none or very few second, third or fourth devices are used or implanted, this table will be simplified 
accordingly. 
Table 2. LAAC Procedural Characteristics 
  
  
Watchman/FLX 
Amulet 
p-value 
  
N = xx 
N = xx 
  
  
  
  
  
Starting cardiac rhythm— no. (%) 
  
  
x.xxx 
Sinus 
count (%) 
count (%) 
x.xxx 
Atrial fibrillation or flutter 
count (%) 
count (%) 
x.xxx 
Other (e.g.pacemaker) 
count (%) 
count (%) 
x.xxx 
General anaesthesia — no. (%) 
count (%) 
count (%) 
x.xxx 
Left atrium reached by — no. (%) 
  
  
x.xxx 
atrial septum 
count (%) 
count (%) 
x.xxx 
fossa ovalis 
count (%) 
count (%) 
x.xxx 
PFO or ASD 
count (%) 
count (%) 
x.xxx 
Nr of transeptal punctures — no. (%) 
  
  
x.xxx 
zero 
count (%) 
count (%) 
x.xxx 
one 
count (%) 
count (%) 
x.xxx 
two or more 
count (%) 
count (%) 
x.xxx 
Distance between puncture and mitral plane — mm (SD) 
mean +- sd 
mean +- sd 
x.xxx 
Mean left atrial pressure before implantation — mmHg 
mean +- sd 
mean +- sd 
x.xxx 
Intracardiac echocardiography — no. (%) 
count (%) 
count (%) 
x.xxx 
Procedure time — minutes 
mean +- sd 
mean +- sd 
x.xxx 
Fluoroscopy time — minutes 
mean +- sd 
mean +- sd 
x.xxx 
Contrast medium — ml med(IQR) 
mean +- sd 
mean +- sd 
x.xxx 
Contrast medium/body mass — ml/kg 
mean +- sd 
mean +- sd 
x.xxx 
X-ray dose — cGy.cm2 med(IQR) 
median (IQR) 
median (IQR) 
x.xxx 
Concomitant procedure* — no. (%) 
count (%) 
count (%) 
x.xxx 
Final device 
  
  
  
LAAC device — no. (%) 
  
  
x.xxx 
Amulet  
count (%) 
count (%) 
x.xxx 
Watchman  
count (%) 
count (%) 
x.xxx 
Watchman FLX  
count (%) 
count (%) 
x.xxx 
Implanted device size  — mm (SD) 
mean +- sd 
mean +- sd 
x.xxx 
Procedure aborted 
count (%) 
count (%) 
x.xxx 
All LAAC devices 
  
  
  
Total Nr of implantation attempts  — no. (%) 
  
  
x.xxx 
1 
count (%) 
count (%) 
x.xxx 
2 
count (%) 
count (%) 
x.xxx 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
3 
count (%) 
count (%) 
x.xxx 
4 or more 
count (%) 
count (%) 
x.xxx 
Total Nr of partial recaptures  — no. (%) 
  
  
x.xxx 
0 
count (%) 
count (%) 
x.xxx 
1 
count (%) 
count (%) 
x.xxx 
2 
count (%) 
count (%) 
x.xxx 
3 
count (%) 
count (%) 
x.xxx 
4 or more 
count (%) 
count (%) 
x.xxx 
Total Nr of complete recaptures  — no. (%) 
  
  
x.xxx 
0 
count (%) 
count (%) 
x.xxx 
1 
count (%) 
count (%) 
x.xxx 
2 
count (%) 
count (%) 
x.xxx 
3 
count (%) 
count (%) 
x.xxx 
4 or more 
count (%) 
count (%) 
x.xxx 
Total nr of LAAC devices implanted 
  
  
x.xxx 
none 
count (%) 
count (%) 
x.xxx 
one 
count (%) 
count (%) 
x.xxx 
two 
count (%) 
count (%) 
x.xxx 
Total nr of LAAC devices used 
  
  
x.xxx 
1 
count (%) 
count (%) 
x.xxx 
2 
count (%) 
count (%) 
x.xxx 
3 
count (%) 
count (%) 
x.xxx 
End of procedure cardiac rhyth  no. (%) 
  
  
x.xxx 
Sinus 
count (%) 
count (%) 
x.xxx 
Atrial fibrillation or flutter 
count (%) 
count (%) 
x.xxx 
Pacemaker (incl.temporary pacer) 
count (%) 
count (%) 
x.xxx 
Post-procedure peri-LAAC device leaks PDL — no. (%) 
  
  
  
Any PDL detected by TEE or Angiography? 
count (%) 
count (%) 
x.xxx 
detected by TEE only 
count (%) 
count (%) 
x.xxx 
detected by Angiography only 
count (%) 
count (%) 
x.xxx 
detected by TEE and Angiography 
count (%) 
count (%) 
x.xxx 
Periprocedural complications — no . (%) 
  
Death 
count (%) 
count (%) 
x.xxx 
Stroke or TIA 
count (%) 
count (%) 
x.xxx 
Bleeding       
count (%) 
count (%) 
x.xxx 
BARC 1 
count (%) 
count (%) 
x.xxx 
BARC 2 
count (%) 
count (%) 
x.xxx 
BARC 3abc 
count (%) 
count (%) 
x.xxx 
BARC 4 
count (%) 
count (%) 
x.xxx 
BARC 5ab 
count (%) 
count (%) 
x.xxx 
BARC 3-5 
count (%) 
count (%) 
x.xxx 
Peripheral or pulmonary embolization     
count (%) 
count (%) 
x.xxx 
Pericardial effusion (new onset)  
count (%) 
count (%) 
x.xxx 
Pericardial effusion clinically relevant 
count (%) 
count (%) 
x.xxx 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Vascular access site complication   
count (%) 
count (%) 
x.xxx 
Device embolization 
count (%) 
count (%) 
x.xxx 
Acute kidney injury 
count (%) 
count (%) 
x.xxx 
Electrical or mechanical resuscitation 
count (%) 
count (%) 
x.xxx 
  
  
  
  
  
  
Data expressed as n (%, p-value from Fisher's tests) or means±standard deviations (p-value from unpaired t-tests) or me-
dian[IQR] (p-value from Mann-Whitney U-test). 
LAAC: left-atrial appendage closure; PFO: patent foramen ovale; ASD: atrial septal defect; ICU: intensive care unit; TIA: transi-
ent ischemic attack; TEE: transoesophagal echocardiography. 
* Coronary angiography included 
  
  
  
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5.6 
Medication 
 
A Table of medications at each visit will be produced, comparing randomized to Amulet vs randomized to 
Watchman. 
Table 3. Medication use 
  
  
Watchman/FLX 
Amulet 
p-value 
  
N = xx 
N = xx 
  
within 7 days before LAAC — no. (%) 
  
  
  
Aspirin 
count (%) 
count (%) 
  
Clopidogrel 
count (%) 
count (%) 
  
Prasugrel 
count (%) 
count (%) 
  
Ticagrelor 
count (%) 
count (%) 
  
Vitamin K-antagonist 
count (%) 
count (%) 
  
NOAC 
count (%) 
count (%) 
  
Dabigatran 
count (%) 
count (%) 
  
Rivaroxaban 
count (%) 
count (%) 
  
Apixaban 
count (%) 
count (%) 
  
Edoxaban 
count (%) 
count (%) 
  
   Others 
count (%) 
count (%) 
  
Low-molecular weight heparin 
count (%) 
count (%) 
  
Therapy 
  
  
  
None 
count (%) 
count (%) 
  
SAPT * 
count (%) 
count (%) 
  
DAPT ** 
count (%) 
count (%) 
  
OAC *** 
count (%) 
count (%) 
  
SAPT+OAC  
count (%) 
count (%) 
  
Triple therapy *** 
count (%) 
count (%) 
  
During/after LAAC procedure  §  — no. (%) 
  
  
  
Aspirin 
  
  
x.xxx 
 maintenance dose 
count (%) 
count (%) 
x.xxx 
 loading dose 
count (%) 
count (%) 
x.xxx 
 No 
count (%) 
count (%) 
x.xxx 
Clopidogrel 
  
  
x.xxx 
maintenance dose 
count (%) 
count (%) 
x.xxx 
loading dose 300mg 
count (%) 
count (%) 
x.xxx 
loading dose 600mg 
count (%) 
count (%) 
x.xxx 
No 
count (%) 
count (%) 
x.xxx 
Prasugrel 
  
  
x.xxx 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
maintenance dose 
count (%) 
count (%) 
x.xxx 
loading dose 60mg 
count (%) 
count (%) 
x.xxx 
No 
count (%) 
count (%) 
x.xxx 
Ticagrelor 
  
  
x.xxx 
maintenance dose 
count (%) 
count (%) 
x.xxx 
loading dose 180mg 
count (%) 
count (%) 
x.xxx 
No 
count (%) 
count (%) 
x.xxx 
Vitamin K-antagonist 
count (%) 
count (%) 
x.xxx 
NOAC 
count (%) 
count (%) 
x.xxx 
NOAC Type 
  
  
x.xxx 
 Dabigatran 
count (%) 
count (%) 
x.xxx 
 Rivaroxaban 
count (%) 
count (%) 
x.xxx 
 Apixaban 
count (%) 
count (%) 
x.xxx 
 Edoxaban 
count (%) 
count (%) 
x.xxx 
 Others 
count (%) 
count (%) 
x.xxx 
Low-molecular weight heparin 
count (%) 
count (%) 
x.xxx 
Discharge — no. (%) ¥ 
n=xx 
n=xx 
  
Aspirin 
count (%) 
count (%) 
x.xxx 
Clopidogrel 
count (%) 
count (%) 
x.xxx 
Prasugrel 
count (%) 
count (%) 
x.xxx 
Ticagrelor 
count (%) 
count (%) 
x.xxx 
Vitamin K-antagonist 
count (%) 
count (%) 
x.xxx 
NOAC 
count (%) 
count (%) 
x.xxx 
NOAC Type 
  
  
x.xxx 
 Dabigatran 
count (%) 
count (%) 
x.xxx 
 Rivaroxaban 
count (%) 
count (%) 
x.xxx 
 Apixaban 
count (%) 
count (%) 
x.xxx 
 Edoxaban 
count (%) 
count (%) 
x.xxx 
 Others 
count (%) 
count (%) 
x.xxx 
Low-molecular weight heparin 
count (%) 
count (%) 
x.xxx 
Therapy 
  
  
x.xxx 
None 
count (%) 
count (%) 
x.xxx 
SAPT * 
count (%) 
count (%) 
x.xxx 
DAPT ** 
count (%) 
count (%) 
x.xxx 
OAC *** 
count (%) 
count (%) 
x.xxx 
SAPT+OAC  
count (%) 
count (%) 
x.xxx 
Triple therapy *** 
count (%) 
count (%) 
x.xxx 
Follow-up 45 days — no. (%) ¶ 
n=xx 
n=xx 
  
Aspirin 
count (%) 
count (%) 
x.xxx 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Clopidogrel 
count (%) 
count (%) 
x.xxx 
Prasugrel 
count (%) 
count (%) 
x.xxx 
Ticagrelor 
count (%) 
count (%) 
x.xxx 
Vitamin K-antagonist 
count (%) 
count (%) 
x.xxx 
NOAC 
count (%) 
count (%) 
x.xxx 
NOAC Type 
count (%) 
count (%) 
x.xxx 
Dabigatran 
count (%) 
count (%) 
x.xxx 
Rivaroxaban 
count (%) 
count (%) 
x.xxx 
Apixaban 
count (%) 
count (%) 
x.xxx 
Edoxaban 
count (%) 
count (%) 
x.xxx 
Others 
count (%) 
count (%) 
x.xxx 
Low-molecular weight heparin 
count (%) 
count (%) 
x.xxx 
Therapy 
count (%) 
count (%) 
x.xxx 
None 
count (%) 
count (%) 
x.xxx 
SAPT * 
count (%) 
count (%) 
x.xxx 
DAPT ** 
count (%) 
count (%) 
x.xxx 
OAC *** 
count (%) 
count (%) 
x.xxx 
SAPT+OAC  
count (%) 
count (%) 
x.xxx 
Triple therapy *** 
count (%) 
count (%) 
x.xxx 
  
  
  
  
  
  
  
  
  
  
  
  
Data expressed as n (%) and p-values are from Fisher's tests. 
* SAPT (Only Aspirin, Only Clopidogrel, Only Prasugrel, Only Ticagrelor) 
** DAPT (Aspirin+Clopidogrel, Aspirin+Prasugrel, Aspirin+Ticagrelor) 
*** OAC (NOAC, Vitamin K-Antagonist, Low molecular weight heparin) 
**** Triple therapy (any combination between DAPT groups AND OAC groups) 
§  within 6 hours of the device implantation 
¥  xx patients died before discharge 
¶ xx patients did not perform 45 day followup 
  
  
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
 
5.7 
Primary and secondary outcomes at 45 days of Follow-up 
 
A Table of the primary and secondary outcomes at 45-day visit will be produced, randomized to Amulet vs 
randomized to Watchman 
 
 
 
Table 4. Primary and secondary outcomes at 45 days
Watchman/FLX
Amulet
Amulet vs Watchman 
Mean difference (95% CI)
p-value
N = xx
N = xx
 
 
 
 
 
 
 
Patent Appendage or justified cross-over to non-randomized device
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Patent Appendage*
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
 Justified cross-over to non-randomized device¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Death
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Cardiovascular death
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Cerebrovascular event
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Stroke 
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
 ischaemic stroke
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
 haemorrhagic stroke
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
 TIA
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Systemic or pulmonary embolism
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Systemic embolism
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Pulmonary embolism
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Myocardial infarction
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Device embolization
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Bleeding
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
BARC 2
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
BARC 3abc
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
BARC 4
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
BARC 5ab
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
BARC 3-5
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
TIMI major or minor
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
TIMI major
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
TIMI minor
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
TIMI minimal
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
GUSTO moderate or severe
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
GUSTO severe
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
GUSTO moderate
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
GUSTO mild
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Patient on (N)OAC at 45 days visit
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
¶ Justified crossover is defined as the switch from the randomized device to the other device based on morphological/anatomical considerations during 
device implantation as centrally assessed by an independent and multidisciplinary clinical event committee (CEC). This parameter was included in the 
composite primary outcome together with *LAA Patency.
CCTA: cardiac computer tomography angiography. TTE: Transthoracic Echocardiography.
Data expressed as n (%, p-value from Fisher's tests)

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5.8 
LAA assessments at 45 days of Follow-up 
 
A Table of the LAA assessments (CCTA by the Core laboratory, TEE by the local teams) at 45-day visit will 
be produced, randomized to Amulet vs randomized to Watchman. 
 
 
 
Table 5. Imaging assessment at 45 days visit
Watchman/FLX
Amulet
Amulet vs Watchman 
Mean difference (95% 
p-value
N = xx
N = xx
 
 
 
 
 
 
CCTA assessment
45day CCTA performed
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Linear attenuation HU— mean (SD)  ¶
n = xx, mean +- sd
n = xx, mean +- sd
n = xx, mean +- sd
x.xxx
Patent LAA  — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
LAA HU ≥100 arterial phase — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
LAA HU ≥25% arterial phase — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Peridevice leak (PDL) — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Mixed leak (MIL) — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Intradevice leak  (IDL) — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Patent LAA with no visible leak  — no. (%)  ¶
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Linear attenuation HU — mean venous phase (SD)   ¥
n = xx, mean +- sd
n = xx, mean +- sd
n = xx, mean +- sd
x.xxx
LAA patency venous phase  — no. (%)    ¥
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
LAA HU ≥100 venous phase — no. (%)   ¥
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
LAA HU on venous phase  ≥150% of LAA HU on arterial phase images  — no. (%)   ¥
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Potential thrombus — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Device related thrombus  — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
TEE assessment
45day TEE performed
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Peridevice leak PDL — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
first PDL — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
PDL leak width — mm mean(SD)
n = xx, mean +- sd
n = xx, mean +- sd
n = xx, mean +- sd
x.xxx
second PDL — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
PDL leak width — mm mean(SD)
n = xx, mean +- sd
n = xx, mean +- sd
n = xx, mean +- sd
x.xxx
Any PDL width ≥3mm  — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Device related thrombus — no. (%)
n = xx, xx (%)
n = xx, xx (%)
  x.x% (x.x%; x.x%)
x.xxx
Mixed PDL: PDL transferring into intradevice leak, or intradevice leak transferring into 
¶: In x of xx CCTAs performed, LAA patency was not assessable (n=xx)
¥: in x of xx CCTAs the venous phase scan was not performed (n=xx)
CCTA: cardiac computer tomography angiography assessed by Core Laboratory. TEE: Transoesophagus Echocardiography assessed by local team.
Data expressed as n (%, p-value from Fisher's tests) or means±standard deviations (p-value from unpaired t-tests) or median[IQR] (p-value from Mann-Whitney U-test).

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
5.9 
Evaluation of Amulet and Watchman implantations 
 
A Table of the Amulet implantation assessment post-procedure and at 45 days will be produced (according 
to actual device implanted). Similarly, a separate Table with the Watchman implantation assessment post-
procedure and at 45 days will be produced (according to actual device implanted). Note that these assess-
ments are not directly comparable across the devices, as these assessments depend on the shape and the 
structure of the device, e.g. Amulet has lobes with a separate disk, whereas the Watchman only has lobes. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
Supplemental Table 1. Evaluation of Amulet / ACP implantation post-procedure and at 45 days 
visit 
  
Amulet ACP implanted 
  
(N=xx) 
  
  
Post-procedural TEE assessment 
  
Is the disc over the left lateral ridge LLR?  — no. (%) 
x (x.x%) 
Distance disc from LLR  — mm (SD) 
n = xx, xx.x ± x.x 
Complete occlusion of the ostium by the disc 
x (x.x%) 
Concavity of the disc — no. (%) 
n = xx, xx.x ± x.x 
Separation lobe from the disc >2mm  — no. (%) 
x (x.x%) 
Lobe's shape 
  
tire — no. (%) 
x (x.x%) 
strawberry/bell — no. (%) 
x (x.x%) 
square — no. (%) 
x (x.x%) 
Angle between lobe-axis and disc-axis of the device  — de-
grees angulation (SD) 
n = xx, xx° ± x° 
Minimum device diameter — mm (SD) 
n = xx, xx.x ± x.x 
Partial prolapse of the lobe into left appendage* — no. (%) 
x (x.x%) 
Peridisk leak PDiL¶  — no. (%) 
x (x.x%) 
one PDiL — no. (%) 
x (x.x%) 
two PDiL— no. (%) 
x (x.x%) 
  
  
45 days visit CCTA assessment 
  
Is the disc over the left lateral ridge LLR?  — no. (%) 
x (x.x%) 
Distance disc from LLR  — mm (SD) 
n = xx, xx.x ± x.x 
Concavity of the disc — mm (SD) 
n = xx, xx.x ± x.x 
Lobe's shape 
  
tire — no. (%) 
x (x.x%) 
strawberry/bell — no. (%) 
x (x.x%) 
square — no. (%) 
x (x.x%) 
Separation lobe-disc maximum — mm (SD) 
n = xx, xx.x ± x.x 
Separation lobe-disc minimum — mm (SD) 
n = xx, xx.x ± x.x 
Angle between lobe-axis and disc-axis of the device  — de-
grees angulation (SD) 
n = xx, xx° ± x° 
Lobe diameter minimum — mm (SD) 
n = xx, xx.x ± x.x 
Lobe diameter maximum — mm (SD) 
n = xx, xx.x ± x.x 
Partial prolapse of the lobe into left appendage* — no. (%) 
x (x.x%) 
Peridisk leak PDiL¶  — no. (%) 
x (x.x%) 
one PDiL — no. (%) 
x (x.x%) 
two PDiL— no. (%) 
x (x.x%) 
  
  
  
Only successfully implanted LAAC devices evaluated. 
*width of the lobe is <2/3 within the circumflex artery. 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
¶leak visible between the disc and the lobe, but only measured if distance between disc and lobe large 
enough to allow assessment of hue. 
CCTA: cardiac computer tomography angiography assessed by Core Laboratory. TEE: Transoeso-
phagus Echocardiography assessed by local team. 
includes n=x patient randomized to Watchman / FLX, but were implanted a cross-over Amulet device instead. 
 
Supplemental Table 2. Evaluation of Watchman / FLX implantation post-procedure and at 45 days 
visit 
  
Watchman / FLX implanted 
  
(N=xx) 
  
  
Post-procedural TEE assessment 
  
Maximum device diameter TEE — mm (SD) 
n = xx, xx.x ± x.x 
Maximum device compression* — % (SD) 
n = xx, xx.x ± x.x 
Minimum device diameter TEE — mm (SD) 
n = xx, xx.x ± x.x 
Minimum device compression¶ — % (SD) 
n = xx, xx.x ± x.x 
Lobe's shape 
  
inverted— no. (%) 
x (x.x%) 
marshmallow — no. (%) 
x (x.x%) 
bell — no. (%) 
x (x.x%) 
hotdog — no. (%) 
x (x.x%) 
Position of device from LAA ostium 
  
at the same level — no. (%) 
x (x.x%) 
distally — no. (%) 
x (x.x%) 
proximally — no. (%) 
x (x.x%) 
Position of the device in respect to the left lateral ridge LLR? 
  
at the same level — no. (%) 
x (x.x%) 
distally — no. (%) 
x (x.x%) 
proximally — no. (%) 
x (x.x%) 
How far is the Watchman device off-axis to the LAA axis  — de-
grees angulation (SD) 
n = xx, xx° ± x° 
  
  
45 days visit CCTA assessment 
  
Minimum device diameter — mm (SD) 
n = xx, xx.x ± x.x 
Minimum device compression¶ — % (SD) 
n = xx, xx.x ± x.x 
Maximum device diameter — mm (SD) 
n = xx, xx.x ± x.x 
Maximum device compression* — % (SD) 
n = xx, xx.x ± x.x 
Lobe's shape 
  
inverted— no. (%) 
x (x.x%) 
marshmallow — no. (%) 
x (x.x%) 
bell — no. (%) 
x (x.x%) 
hotdog— no. (%) 
x (x.x%) 
Position of device from LAA ostium 
  
at the same level — no. (%) 
x (x.x%) 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
distally — no. (%) 
x (x.x%) 
proximally — no. (%) 
x (x.x%) 
Position of the device in respect to the left lateral ridge LLR? 
  
at the same level — no. (%) 
x (x.x%) 
distally — no. (%) 
x (x.x%) 
proximally — no. (%) 
x (x.x%) 
How far is the device from the left lateral ridge LLR? — mm (SD) 
n = xx, xx.x ± x.x 
How far is the Watchman device off-axis to the LAA axis  — de-
grees angulation (SD) 
n = xx, xx° ± x° 
  
  
  
Only successfully implanted LAAC devices evaluated. 
*(Manufacturer device diameter - maximum implanted device diameter)*100% 
¶(Manufacturer device diameter - minimum implanted device diameter)*100% 
CCTA: cardiac computer tomography angiography assessed by Core Laboratory. TEE: Transoesopha-
gus Echocardiography assessed by local team. 
includes n=x patient randomized to Amulet / ACP, but were implanted a cross-over Watchman device instead. 
 
 
5.10 
Withdrawal/follow-up 
 
Withdrawal, lost-to-follow-up and missed assessments of the primary outcome will be reported in the flowchart, 
separately for randomized to Amulet and randomized to Watchman. 
 
 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
6. 
Analysis 
6.1 
Outcome definitions 
Outcomes will be compared randomized to Amulet vs randomized to Watchman. 
6.1.1 
Primary outcome 
 
The primary outcome is the composite of LAA patency at 45 day CCTA or the crossover from one device to the 
other device based on morphological/anatomical considerations during device implantation. 
6.1.2 
Secondary outcome 
 
Secondary outcomes are: 
• 
LAA patency (arterial and/or venous phase) at 45 day CCTA and 13-month CCTA in the per proto-
col and as treated populations 
• 
All cause of death, stroke, systemic or pulmonary embolism and spontaneous MI 
• 
Cardiovascular death 
• 
Ischemic stroke 
• 
Hemorrhagic stroke 
• 
Bleeding events according to the BARC classification at each follow-up. 
• 
Procedure-related complications 
• 
Rate of patients on (N)OAC at 45 days and 6 months 
• 
Device related thrombosis at 45 day TEE/CCTA and 13-month CCTA in the per protocol and as 
treated populations 
• 
Feasibility outcome (number of device implantation attempts, total time procedure, x-ray dose 
and total contrast dose used in the procedure) 
• 
LAA patency at 45 day TEE in the per protocol and as treated populations 
6.1.3 
Safety outcome 
 
The main safety outcomes are: 
• 
Bleeding Academic Research Consortium (BARC) bleeding grade 2, 3 and 5 up to 48 hours or dis-
charge whichever comes first and 45 days 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
• 
Net adverse clinical events (NACE) defined as the composite of death, fatal and non-fatal stroke, 
peripheral embolization and BARC 2, 3, or 5 up to 48 hours or discharge whichever comes first 
and 45 days 
• 
Device related thrombosis at 45 day TEE/CCTA and 13-month CCTA in the per protocol and as 
treated populations 
6.1.4 
Feasibility outcome 
 
A composite of following outcomes will be analysed in order to assess the feasibility of two devices: 
• 
Number of attempts of LAA closure with a single device. 
• 
Number of same type device used in a procedure. 
• 
Total time procedure, x-ray dose and total contrast dose used in the procedure. 
 
6.2 
Analysis methods 
6.2.1 
Primary analysis 
 
The primary outcome analysis will be conducted by measuring the LAA patency at 45 days using the CCTA, 
combined with adjudicated cross-over including failed cross-over to another non-randomized LAAC device dur-
ing the index LAAC procedure. 
6.2.2 
Secondary analyses 
 
Secondary analyses of events at longer follow-ups (e.g. 1 to 5 years of follow-up) will be conducted using Cox’s 
regressions comparing the randomized arms (hazard ratios with 95% confidence intervals) and reporting event 
rates (from Kaplan-Meier estimates accounting for lost-to-follow-up and withdrawal of consent). In most cases 
only the first event of each event (sub)type will be reported, except if requested otherwise and the statistical 
analyses will be adapted to a multi-event analyses design. 
 
6.2.3 
Sensitivity analyses 
 
The primary and secondary outcomes will be analyses in multiple imputed data-sets using chained equations 
and combining estimates and p-values using Rubin’s rule, if requested. It will also be explored whether delayed 
45 days visit CCTA assessments (scheduled was 45 days ± 7 days, but e.g. delays can be due to e.g. the 
SARS-CoV-2 pandemic forcing postponement of some clinical visits) impacted the primary outcome comparison 
Amplatzer vs Watchman, by adding the delay in days of the follow-up CCTA as a covariate in the analyses. 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
6.2.4 
Additional analyses 
 
The following subgroups are defined for additional analyses (e.g. primary endpoint): 
- 
Age > vs.<= 75 years old 
- 
Gender male vs female 
- 
Left ventricular ejection fraction >40% vs.<= 40% (EF) 
- 
Diabetes yes vs no 
- 
Prior bleeding yes vs no 
- 
Prior cerebrovascular event yes vs no 
- 
Device (Watchman 2.5 vs. Amulet), Watchman FLX  vs Amulet 
- 
Pre-procedural therapy with all combinations (none vs. SAPT vs DAPT vs. OAC vs. OAC+APT) 
 
6.2.5 
Assessment of statistical assumptions 
 
Time-to-event curves will be compared and checked for the proportional hazards assumption using Schoen-
feld’s residuals. 
 
6.3 
Interim analyses 
 
No statistical interim analyses are planned. 
 
6.4 
Missing data 
 
The primary and secondary outcomes will be analyses in multiple imputed data-sets using chained equations 
and combining estimates and p-values using Rubin’s rule, if requested. 
 
6.5 
Safety evaluation 
 
The safety outcomes, AE and SAEs will be summarized in tables at all study periods, namely: 
• 
Enrolment 
• 
Procedure 
• 
Post procedural hospital discharge 
• 
7 days 
• 
45-day follow-up 
• 
6-month follow-up 
• 
13-month follow-up 
• 
2-year follow-up 
• 
3-year follow-up 
• 
4-year follow-up 
• 
5-year follow-up 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
6.6 
Statistical software 
Stata version 16.1 or higher and R version 4.03 or higher will be used. 
 
6.7 
Quality control 
The primary and secondary outcomes will be double-programmed. 
 
 

 
 
CTU Bern 
Swiss APERO SAP 
Version: 2.0 
Template: CS_STA_TEM-11 
Valid from: 17.08.2021 
 
7. 
References 
 
Saw J, Fahmy P, DeJong P, et al. Cardiac CT angiography for device surveillance after endovascular left atrial 
appendage closure. Eur Heart J Cardiovasc Imaging. 2015;16(11):1198-1206