Diagnostic Accuracy of the ATE Score for the Exclusion of Intra-atrial Thrombi Before Catheter Ablation of Atrial Fibrillation: a Confirmatory Study
Conditions: Atrial Fibrillation, Thrombi
Sponsor: Groupe Hospitalier de la Rochelle Ré Aunis

 
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Diagnostic accuracy of the ATE score for the exclusion of intra-
atrial thrombi before catheter ablation of atrial fibrillation: a 
confirmatory study 
EXTRALUCID-d CS 
2017/P02/211 
 
INTERVENTIONAL STUDIES WITH MINIMAL RISK OR BURDEN  
Version n°5.0, 27/01/2020 
 
ID-RCB number: 2017-A01726-47 
NCT number: NCT03455673 
 
 
Sponsor: 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle 
 
Study director: 
Dr Antoine MILHEM 
Cardiology department 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle 
: +33 546 456 683  
Antoine.MILHEM@ch-larochelle.fr 
 
Methodology:  
Pr Pierre INGRAND 
Unité de biostatistique 
Université de Poitiers  
6, rue de la milétrie 
86073 POITIERS Cedex 9 
: +33 549 454 645 
pierre.ingrand@univ-poitiers.fr 
 
 
 

 
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Protocol revision history 
 
Version
Date
Description 
1 
27/11/2017 Original document 
2 
26/01/2018 Revised document according to ethical committee 
comments 
3 
09/03/2018 Additional information and amendments 
4 
26/10/2018 Revised document according common practices in care 
services and amendments 
5 
27/01/2020 Revised document to increase the duration of the inclusion 
period 
 
 

 
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PROTOCOL SIGNATURE PAGE 
Diagnostic accuracy of the ATE score for the exclusion of intra-
atrial thrombi before catheter ablation of atrial fibrillation: a 
confirmatory study 
EXTRALUCID-d CS 
 
2017/P02/211 
 
 
Sponsor 
 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du docteur Schweitzer 
17019 La Rochelle Cedex  
Tel : 05 46 45 50 50 
Fax : 05 46 45 50 00 
Courriel : direction@ch-larochelle.fr 
 
 
à La Rochelle, le : ………………….. 
 
 
 
 
 
Monsieur Pierre THEPOT, directeur général 
 
Signature 
 
 
 
 
 
 
 
Study director 
 
Dr Antoine MILHEM 
Cardiology department 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle 
: +33 546 456 683  
Antoine.MILHEM@ch-larochelle.fr 
 
 
à La Rochelle, le : ………………….. 
 
 
 
 
Docteur Antoine MILHEM 
 
Signature 
 
 

 
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PROTOCOL SUMMARY 
 
SPONSOR 
Groupe Hospitalier de la Rochelle Ré Aunis 
STUDY DIRECTOR 
Dr Antoine MILHEM 
Cardiology department 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle 
: +33 546 456 683  
Antoine.MILHEM@ch-larochelle.fr 
TITLE 
EXTRALUCID-d CS 
Diagnostic accuracy of the ATE score for the exclusion of 
intra-atrial thrombi before catheter ablation of atrial 
fibrillation: a confirmatory study 
STUDY PRODUCT 
STA – Liatest D-Di Plus 
BACKGROUND 
Atrial fibrillation is the most frequent heart rhythm disorder. Its 
symptomatic forms, resistant to drug therapy, require invasive 
management (catheter ablation), which exposes to potentially 
serious complications including thromboembolic complications. 
Despite anticoagulant treatment, intra-atrial thrombus, which is a 
contraindication to catheter ablation, is detected in nearly 2 % of 
cases. 
Its 
diagnosis 
requires 
prior 
transoesophageal 
echocardiography, an unpleasant examination. 
The previous EXTRALUCID-d study showed that a zero ATE 
score, defined by no heart failure, no hypertension, no history of 
stroke, d-dimer < 270 ng/mL, has a negative predictive value of 
100 % for the exclusion of intra-atrial thrombus. 
PRIMARY OBJECTIVE 
The objective of the study is to confirm the negative predictive 
value, sensitivity and specificity of the ATE score for the exclusion 
of intra-atrial thrombus. 
SECONDARY OBJECTIVE(S) 
• 
 To determine the prevalence of atrial thrombi in the study 
population, 
• 
 To determine the negative predictive value of the 
CHADS2VASC score of cardiac thrombus risk in the study 
population, 
• 
 To determine the negative predictive value of the CHADS2 
score of cardiac thrombus risk in the study population, 
• 
 To collect a biobank of plasma samples to further confirm 
the study performances with other D-dimer assays. 
OUTCOME(S) 
The primary outcome is the number of patients with intra-atrial 
thrombus 
diagnosed 
by 
pre-procedural 
transoesophageal 
echocardiography. 

 
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STUDY TYPE 
Prospective, multicentre diagnostic accuracy study in a standard 
of care setting. 
MAIN INCLUSION CRITERIA 
• 
Adult patients  
• 
Patients hospitalized for ablation of atrial fibrillation or 
symptomatic left atrial tachycardia  
• 
Affiliated person or beneficiary of a social security system 
• 
who have signed or orally given an informed consent 
MAIN EXCLUSION CRITERIA 
• 
Contraindication to transoesophageal echocardiography 
• 
Transoesophageal echocardiography made in another 
centre than the centre of ablation 
• 
Vulnerable persons 
• 
Refusal to participate in the study 
INTERVENTION 
Patient management (preoperative assessment, intervention, 
surveillance, and follow-up) is carried out according to centre 
standard procedures. 
An additional blood sample (7.2 ml) is collected for the d-dimer 
assay and the constitution of a biocollection. 
TOTAL NUMBER OF 
SUBJECTS 
3,000 patients 
DURATION OF THE STUDY 
Duration of inclusion: 30 months 
Duration by subject: at most 48 hours (from enrolment to 
transoesophageal echocardiography result) 
Total expected duration of the study: 30 months 
STATISTICAL ANALYSIS 
Sensitivity, 
specificity, 
positive 
predictive 
value, 
negative 
predictive value, and 95 % confidence intervals will be calculated. 
The ATE score will be considered clinically relevant if a negative 
predictive value of 100 % is obtained for a zero score. 
EXPECTED RESULTS 
This study is expected to confirm the negative predictive value of 
the ATE score. 
This score could be proposed for the diagnosis of exclusion of 
intra-atrial thrombus in patients hospitalized for atrial fibrillation 
ablation or left atrial tachycardia. A zero score would avoid the 
systematic transoesophageal echocardiography. 
 

 
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CONTENT 
 
Protocol revision history .......................................................................................... 2 
1. 
Definitions and abbreviations ................................................................................... 8 
2. 
Contacts ...................................................................................................................... 9 
3. 
Scientific justification and general description ..................................................... 10 
3.1. Background ................................................................................................. 10 
3.1.1. 
Pathology ................................................................................................. 10 
3.1.2. 
Description of the ATE score to be validated ........................................... 11 
3.1.3. 
Description of the reference method ........................................................ 11 
3.2. Study hypothesis and expected results ....................................................... 12 
3.3. Overall risk/benefit assessment ................................................................... 12 
3.4. Justification of low interventional level ......................................................... 12 
4. 
Validation study objectives ..................................................................................... 13 
4.1. Primary objective ......................................................................................... 13 
4.2. Secondary objectives .................................................................................. 13 
5. 
Outcomes .................................................................................................................. 14 
5.1. Primary outcome ......................................................................................... 14 
5.2. Secondary outcome ..................................................................................... 14 
6. 
Study design ............................................................................................................. 15 
7. 
Study population ...................................................................................................... 16 
7.1. Inclusion / Exclusion criteria for intended population ................................... 16 
7.2. Feasibility and recruitment modalities .......................................................... 16 
8. 
Material and Methods ............................................................................................... 18 
8.1. Transoesophageal echocardiography ......................................................... 18 
8.2. D-dimer assay ............................................................................................. 18 
8.2.1. 
Material .................................................................................................... 18 
8.2.2. 
Method ..................................................................................................... 18 
8.2.3. 
D-dimer assay .......................................................................................... 18 
8.3. ATE Score ................................................................................................... 19 
8.4. CHADS2 and CHA2DS2VASC scores .......................................................... 19 
9. 
Clinical data collection and procedure description ............................................... 20 
9.1. Study calendar ............................................................................................ 20 
9.2. Data collection requirements ....................................................................... 20 
9.3. Screening .................................................................................................... 20 
9.4. Enrolment .................................................................................................... 20 
9.5. Visit 1 ........................................................................................................... 21 
9.6. Patient exit ................................................................................................... 21 
9.7. Constraints related to the research.............................................................. 21 
9.8. Blood sample collection ............................................................................... 21 
10. Study follow-up ......................................................................................................... 23 
10.1. 
Protocol deviations ................................................................................... 23 
10.2. 
Adverse event reporting ........................................................................... 23 
10.2.1. 
Definition ............................................................................................... 23 
10.2.2. 
Description of expected SAE ................................................................ 25 
10.2.3. 
Event review and reporting ................................................................... 25 
10.2.3.1. 
Event review ...................................................................................... 25 
10.2.3.2. 
Reporting ........................................................................................... 25 
10.2.4. 
Information for data collection ............................................................... 25 

 
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10.2.5. 
Quality control ....................................................................................... 25 
10.2.1. 
Audit and inspection .............................................................................. 26 
11. Study conclusion and statistical consideration .................................................... 27 
11.1. 
Sample size rationale ............................................................................... 27 
11.2. 
Statistical analysis plan ............................................................................ 27 
12. Ethical and legal aspects ......................................................................................... 28 
12.1. 
Access right to files and source data ........................................................ 28 
12.1.1. 
Data access .......................................................................................... 28 
12.1.2. 
Source data........................................................................................... 28 
12.1.3. 
Data confidentiality ................................................................................ 28 
12.2. 
Ethical conduct of the study ..................................................................... 28 
12.3. 
Study funding and insurance .................................................................... 29 
12.4. 
Publication Policy ..................................................................................... 29 
12.5. 
Confidentiality ........................................................................................... 29 
12.6. 
Data archiving .......................................................................................... 29 
13. References ................................................................................................................ 30 
14. Appendices ............................................................................................................... 33 
 
 
 
 
 

 
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1. 
Definitions and abbreviations 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ATE 
Atrial Thrombus Exclusion 
e-CRF 
Electronic Case Report Form 
INR 
International Normalized Ratio 
IRB/EC  
Institutional review board/ethics committee
LMWH 
Low molecular weight heparin  
MRI 
Magnetic resonance imaging  
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TEE 
Transoesophageal echocardiography 
VKA 
Vitamin K antagonists 

 
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2. 
Contacts 
 
 
Study director
 
Sponsor
Dr Antoine MILHEM 
Cardiology department 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle 
: +33 546 456 683  
Antoine.MILHEM@ch-larochelle.fr 
Mme Caroline ALLIX-BEGUEC  
Unité de recherche clinique 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle, France 
 : +33 516 494 246  
Caroline.ALLIX-BEGUEC@ch-larochelle.fr 
 
 
 
 
 
Methodologist / Statistician
 
Clinical research assistant
Pr Pierre INGRAND 
Unité de biostatistique 
Université de Poitiers  
6, rue de la milétrie 
86073 POITIERS Cedex 9 
: +33 549 454 645 
pierre.ingrand@univ-poitiers.fr 
Mme Virginie LAURENCON 
Unité de recherche clinique 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle, France 
 : +33 516 494 955 /  : +33 516 494 762  
Virginie.LAURENCON@ch-larochelle.fr 
 
 
 
 
 
Laboratory
 
Collaborator
Dr An ALLANO 
Laboratoire 
Groupe Hospitalier de la Rochelle Ré Aunis 
Rue du Dr Schweizer 
17019 La Rochelle, France 
 : +33 516 494 743 
Hong-An.ALLANO@ch-larochelle.fr 
 
Mme Aliénor AUBY 
Mme Audrey CARLO 
Stago 
3 allée Thérésa 
92600 Asnières sur Seine, France 
 : +33 146 882 347 
alienor.auby@stago.com ;  
 : +33 285 376 268 
audrey.carlo@stago.com 
 
 

 
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3. 
Scientific justification and general description 
3.1. 
Background 
3.1.1. 
Pathology 
Atrial fibrillation is the most common heart rhythm disorder, and is associated with increased 
mortality and morbidity, including through its thromboembolic complications. The invasive 
treatment of atrial fibrillation by catheter ablation is indicated in symptomatic and recurrent 
forms. Catheter ablation of atrial fibrillation is one of the most complex procedures in 
electrophysiology. Thromboembolic events are part of the complications and are responsible 
for cerebral (stroke or transient ischemic attack), coronary and peripheral arterial ischemia. 
Emboli may be due to thrombus or air, and their incidence varies between 0.28 and 2.8 % 
(1–5). 
Cruoric embolisms are the most alarming on clinical level, and the most difficult to prevent. 
Several mechanisms are involved: 
- 
Thrombus may result from blood coagulation cascades secondary to the 
introduction and handling of catheters (6). Ren et al reported an incidence of 10 % 
of left intra-auricular thrombus detected on transept sheaths or circular catheters 
(LASSO) introduced during ablation despite an effective anticoagulation (activated 
clotting time > 250 s). These thrombi have been detected with cardiac 
echocardiography (7). An important anticoagulation, activated clotting time 
> 300 s and infusion of the transseptal sheaths with a high flow rate (> 180 ml/h), 
significantly reduces the formation of thrombus and the occurrence of 
thromboembolic events  (8). 
- 
Endothelial lesions secondary to radiofrequency applications are also responsible 
for blood coagulation. The incidence of thromboembolic events is important when 
asymptomatic ischemic brain lesions are investigated by magnetic resonance 
imaging (MRI) after the ablation procedures. The type of energy used to create 
the ablation lesion affects this incidence. A study examined the effect of atrial 
fibrillation ablation technique on thromboembolic events. The number of recent 
asymptomatic ischemic lesions seen in MRI was greater in patients with atrial 
fibrillation ablation by non-irrigated multi-electrode radio-frequency compared to 
those who had cryotherapy ablation or conventional radiofrequency catheter 
ablation (9). These strokes were more often found in the vertebrobasilar territory, 
which is strongly suggestive of a cardioembolic origin.  

 
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- 
The thromboembolic mechanism may also correspond to the detachment of a pre-
existing thrombus localized in the left atrium. The incidence of these thrombi is 
close to 2 % in the pre-procedural period, with values ranging from 1.2 % to 3.6 % 
(10–15).  
The embolic risk is limited by performing imaging tests in order to eliminate the presence of a 
left atrial thrombus. The reference examination is the transoesophageal echocardiography 
which is an unpleasant examination. 
 
3.1.2. 
Description of the ATE score to be validated 
A preliminary study, EXTRALUCID-d (NCT02199080), included 2,494 patients hospitalized 
for an atrial fibrillation ablation. It studied a combined clinical-biological score, the Atrial 
Thrombus Exclusion (ATE), associating thromboembolic risk factors (hypertension, cardiac 
insufficiency, history of stoke) and d-dimer level for the prediction of intra-atrial thrombus. 
The primary outcome was the number of intra-atrial thrombus diagnosed by 
transoesophageal echocardiography. A zero ATE score, defined by no cardiac insufficiency, 
no hypertension, no history of stroke, and D-dimer < 270 ng/mL, had a negative predictive 
value of 100% for the diagnosis of intra-atrial thrombus. 
 
3.1.3. 
Description of the reference method 
Transoesophageal echocardiography is performed routinely in more than 72 % of centres 
that perform atrial fibrillation ablation (16). It has a low morbidity. Most studies reporting 
transoesophageal echocardiography complications concerned examinations performed at 
cardiovascular operating room (17). Insertion and manipulation of the probe can damage the 
oropharynx, oesophagus or stomach. Two mechanisms of oesophageal lesions have been 
described, the first being a direct trauma occurring after insertion or manipulation of the 
endoscope. The second comes from the probe thermal energy. A multicentre study in 
cardiology described 10,419 transoesophageal echocardiographies where 88.7 % of patients 
were conscious and most of them did not receive sedation. In 1.9 % of cases, the probe 
could not be inserted because of a lack of patient cooperation (98.5 %) or due to anatomical 
reasons (1.5 %). In 0.88 % of the cases, when the endoscope was introduced, the 
examination had to be interrupted due to poor tolerance of the endoscope, pulmonary or 
cardiac complications or haemorrhage. Pre-transoesophageal echocardiography sedation 
complications 
have 
been 
described: 
hypoxia 
and 
transient 
hypotension 
(18). 
Transoesophageal echocardiography is recommended prior to any left atrium ablation in 
patients with persistent atrial fibrillation or with paroxysmal atrial fibrillation lasting longer than 

 
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48 hours when anticoagulation has not been satisfactory for more than three weeks. The 
most recent recommendations on atrial fibrillation ablation (19) state that it was not 
possible to find a consensus on the indication of transoesophageal echocardiography 
in patients under well-conducted anticoagulant therapy. 
 
3.2. 
Study hypothesis and expected results 
This study is lead in an independent population from the previous EXTRALUCID-d study in 
order to confirm the accuracy of the ATE score. 
 
3.3. 
Overall risk/benefit assessment 
We believe that the benefit / risk balance is very favourable, given that the risk of the study is 
negligible. The confirmation of an excellent negative predictive value of the ATE score would 
prevent one transoesophageal echocardiography out of three during the period of 
preoperative endocardial ablation of atrial fibrillation. 
 
3.4. 
Justification of low interventional level 
In addition to current practice, this study involves blood sampling. The collected volume 
complies with the conditions described by law for low interventional level (« Arrêté du 2 
décembre 2016 fixant la liste des recherches mentionnées au 2o de l’article L.1121-1 du 
code de la santé publique » for French law). 
 

 
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4. 
Validation study objectives 
4.1. 
Primary objective  
 
The objective is to confirm the negative predictive value, sensitivity and specificity of the ATE 
score for the exclusion of cardiac thrombus. 
 
4.2. 
Secondary objectives  
 
• 
To determine the prevalence of atrial thrombi in the study population, 
• 
To determine the negative predictive value of the CHADS2VASC score of cardiac 
thrombus risk in the study population, 
• 
To determine the negative predictive value of the CHADS2 score of cardiac thrombus 
risk in the study population, 
To collect a biobank of plasma samples to further confirm the study performances with other 
D-dimer assays in the future. 
 

 
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5. 
Outcomes 
5.1. 
Primary outcome 
 
The primary outcome is the number of patients with atrial thrombus diagnosed by pre-
procedural transoesophageal echocardiography. 
 
Detection of spontaneous echocardiographic contrast will not be considered for the primary 
outcome. In case of cardiac thrombus, data will be recorded and transmitted to the sponsor 
after de-identification. The maximum time between transoesophageal echocardiography and 
ablation will be 48 hours. It may also be performed at the beginning of the procedure. The 
detection of a thrombus prohibits the realization of catheter ablation. In other words, if there 
is any doubt about the existence of a thrombus (equivocal image) the primary outcome is the 
contraindication to the intervention. If necessary, this definition may be reviewed according to 
the evolution of ultrasound images and the diagnosis (persistence of the initial image under 
increased anticoagulant treatment, decision of the medical team to practice intervention). 
This revision of the diagnosis will be decided by the medical team in charge of the patient. 
 
 
5.2. 
Secondary outcome 
 
• 
Number of atrial thrombi in the study population 
• 
Number of patients with atrial thrombus among patients with a zero CHADS2VASC 
score (no congestive heart failure, hypertension, diabetes mellitus, vascular disease 
[previous myocardial infarction, peripheral arterial disease or aortic plaque],  history of 
stroke or transient ischemic attack, age under 75, and male) 
• 
Number of patients with atrial thrombus among patients with a zero CHADS2 score 
(no congestive heart failure, hypertension, diabetes mellitus, history of stroke or 
transient ischemic attack, and age under 75) 
 
 

 
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6. 
Study design 
 
This is a European multicentre prospective diagnostic accuracy study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 : Study design. TEE: transoesophageal echocardiography 
 
 
 
 
 
Screening
Patients hospitalized for ablation of atrial 
fibrillation or symptomatic left atrial tachycardia
Excluded
• 
Contraindication to TEE 
• 
TEE made in another centre than the 
centre of ablation 
• 
Vulnerable patient 
• 
Refusal to participate in the study 
Enrolment
Blood sample for d-dimer assay
Visit 1
Transoesophageal echocardiography result

 
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7. 
Study population 
7.1. 
 Inclusion / Exclusion criteria for intended population 
Inclusion criteria 
• 
Adult patients  
• 
Patients hospitalized for ablation of atrial fibrillation or symptomatic left atrial 
tachycardia. 
• 
Affiliated person or beneficiary of a social security system 
• 
Who have signed or orally given an informed consent according to local regulation, 
 
Exclusion criteria 
• 
Contraindication to transoesophageal echocardiography, 
• 
Transoesophageal echocardiography made in another centre than the centre of 
ablation, 
• 
Pregnant women, parturient mothers and nursing mothers, 
• 
Lives in an institution on court or authority order,  
• 
Severely altered psychological health, 
• 
Persons leaving in health or social establishment,  
• 
Minors, 
• 
Under guardianship, 
• 
Persons unable to give their consent, 
• 
Refusal to participate in the study. 
 
 
7.2. 
Feasibility and recruitment modalities 
 
The investigating centres have the following characteristics: 
• 
The number of ablation of atrial fibrillation is greater than 50 per year, 
• 
Transoesophageal echocardiography is performed routinely before any ablation of 
atrial fibrillation. 
Investigating centres compliance with those characteristics will be documented upon 
selection.  
In each centre, patient eligible for atrial fibrillation or left flutter ablation will be screened. In 
agreement with the physician performing the procedure, the study will be explained and 
proposed to the eligible patients by an investigator at the admission or at the pre-ablation 
consultation. It is strongly recommended to include patients consecutively in order to limit 

 
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selection bias. We plan to open circa 25 centres in France and Europe, with an average of 
120 patients per centre. The provisional duration of enrolment is 30 months. 
 
 

 
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8. 
Material and Methods 
8.1. 
Transoesophageal echocardiography 
Transoesophageal echocardiography is performed according to the guidelines of the 
European Association of Cardiovascular Imaging (20). 
It is performed at most within 48 hours before intervention.  
Images must be stored locally for the duration of the study. 
 
 
8.2. 
D-dimer assay 
8.2.1. 
Material 
STA - Liatest D-Di Plus will be used following the recommendations in its package insert on 
STAGO instruments. The STAGO instrument type used in each investigating centre will be 
documented (type and version) along with the name and lot of reagents (STA – Liatest D-Di 
Plus and its associated quality control plasmas).  
 
8.2.2. 
Method 
 
Blood sample (maximum 7.2 ml) will be collected for the determination of d-dimer level and 
for storage. It will be collected at the same time as standard biological intake and no more 
than 48 hours before surgery. 
 
8.2.3. 
D-dimer assay 
As STA-Liatest D-Di Plus assay reagents are pre-calibrated, the pre-calibration parameters 
will be used in each investigating centre. These will be entered on the analyzer through 
barcode scanning of the Assay Value insert, as described on the STA-Liatest D-Di Plus 
package insert. 
As requested in by the Standard Operating Procedure, quality control (QC) samples will be 
run to ensure accuracy and reproducibility of the device each time a patient sample will have 
to be tested. Results of these QC have to fall within their acceptance ranges prior to testing 
any patient sample and will be collected along with patient’s results. 
 
 
 
 

 
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8.3. 
ATE Score 
 
Condition 
Score 
Hypertension 
1 
Heart failure 
1 
History of stroke 
1 
High plasma d-dimer level (> 270 ng/ml)
1 
 
A zero ATE score is expected to exclude intra-atrial thrombi. 
 
 
 
8.4. 
CHADS2 and CHA2DS2VASC scores 
 
 
 
CHADS2 and CHA2DS2VASc scores are stroke risk stratification schemes based on a risk 
factor approach (21–23). 
 

 
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9. 
Clinical data collection and procedure description 
9.1. 
Study calendar 
Duration of inclusion: 30 months 
Duration by subject: 48 hours at most (from enrolment to transoesophageal 
echocardiography result) 
Total expected duration of the study: 30 months 
 
9.2. 
Data collection requirements 
 
 
Screening 
(0 to 3 months) 
Inclusion 
Visit 1  
(0 to 48 hours)
Inclusion/exclusion criteria 
 (T) 
 
 
Informed consent 
 
 (T) 
 
Medical history and demographics 
 
 (S) 
 
Blood sample for D-dimer level assay 
 
 (T) 
 
Transoesophageal echocardiography 
 
 
 (S) 
 
(T) Related to the clinical trial 
(S) Standard care 
Quality control samples results for D-dimer assay will also be documented. 
 
9.3. 
Screening 
Atrial fibrillation diagnosis may be based on a 12 lead electrocardiogram (ECG) 
characterized by absence of discrete P waves and an irregularly irregular ventricular rate. In 
most patients, a single ECG is sufficient to secure the diagnosis, assuming the patient is in 
AF at the time of the ECG. In some patients it may also be diagnosed using a heart rhythm 
recording such as a telemetry strip, Holter monitor, or an event monitor. 
 
Women of childbearing age must have a negative beta-hCG blood test. 
 
Patients with a programmed hospitalization for ablation of atrial fibrillation or symptomatic left 
atrial tachycardia are eligible to the study. The investigator verifies the eligibility criteria. 
 
9.4. 
Enrolment 
During the inclusion visit, the investigator informs the participant and answers all questions 
about the objectives, nature of constraints, foreseeable risks and expected benefits of the 

 
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research. He also specifies the rights of the participant and verifies the eligibility criteria. Oral 
consent of the patient will be recorded in the medical file.  
 
Medical history, clinical data and demographics are collected (hypertension, diabetes, 
congestive heart failure, age, history of stroke, peripheral arterial disease and diagnosis). 
 
Peripheral blood sample is collected for d-dimer assay.  
 
9.5. 
Visit 1 
The transoesophageal echocardiography is performed no more than 48 hours before 
ablation or during the ablation procedure. The vacuity of the left atrial appendage or the 
presence of a thrombus is specified on the transoesophageal echocardiography report. A 
spontaneous contrast and emptying velocity may be mentioned but these data are optional. 
Pictures of the left atrial appendage are recorded on CD if a thrombus is diagnosed. 
 
9.6. 
Patient exit 
Patients may be exited from the study under the following circumstances: 
- 
Included in the trial in violation of the inclusion and/or exclusion criteria 
- 
Patient chooses to withdraw  
- 
Patient death before transoesophageal echocardiography 
 
9.7. 
Constraints related to the research  
The person can participate in another interventional study if the related intervention starts 
after the transoesophageal echocardiography. There is no exclusion period during which the 
participant cannot participate in another study after completing this one. 
 
9.8. 
Blood sample collection 
Peripheral blood sample is collected for d-dimer assay at the inclusion. 
 
The following requirements will be followed for the collection: 
- 
Blood samples will be collected in 0.109M (i.e., 3.2%) trisodium citrate anticoagulant, 
1 volume of citrate for 9 volumes of blood, in accordance with CLSI Guideline H21-A5 
Collection, Transport, and Processing of Blood Specimens for Testing Plasma-
Coagulation Assays and Molecular Haemostasis Assays (Vol.28; No.5)(24). Two will 
be collected to allow sufficient plasma volume for the study. 

 
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- 
Blood samples will be centrifuged within 4 hours after blood draw at 2,000-2,500g for 
15 minutes at a temperature close to 18°C, and then plasma samples will be divided 
in at least 4 aliquots of 0.6 ml each. 
- 
Each aliquot will be de-identified (i.e., only an anonymous number will be available in 
the data collection form in order to ensure patient anonymity). 
- 
One aliquot will be tested fresh (within 6 hours after blood collection).  
- 
The remaining plasma samples will be frozen and stored at -70°C or colder (as soon 
as possible and no more than 2 hours after plasma collection). 
Frozen samples will be used to constitute a plasma bank. It will be used to confirm results 
with the STA-Liatest DDi Plus and to assess other d-dimer assays with kits currently under 
development. Samples will be kept for 10 years. After which, the samples will be destroyed 
by incineration. Under no circumstances will these samples be used in other studies. 

 
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10. 
Study follow-up 
10.1. 
Protocol deviations 
A deviation is defined as an event where the exact instructions written in this protocol, the 
clinical trial agreement or the applicable regulations have not been followed. Deviations are 
classified by occurrence, i.e., sporadic vs. repeated and seriousness, i.e., major vs. minor.  
Major deviations may impact subject safety, alter the risk/benefit ratio, compromise the 
integrity of the study data, and/or affect subjects’ willingness to participate in the study.  
Minor deviations do not impact subject safety, compromise the integrity of the study data, or 
affect subjects’ willingness to participate in the study. 
Investigators are required to obtain prior approval from the sponsor before initiating 
deviations from the protocol, except where necessary to protect the life or physical well-
being of a subject in an emergency. Such approval will be documented in writing and 
maintained in study files. Prior approval is generally not expected in situations where 
unforeseen circumstances are beyond the investigator’s control; however, the event is still 
considered a deviation and must be recorded in the subject Case Report Form. 
Protocol deviations will be reported to the sponsor using suitable forms, regardless of 
whether medically justifiable, pre-approved by the sponsor or taken to protect the subject in 
an emergency.  
Investigators must also adhere to procedures for reporting study deviations to IRB/EC in 
accordance with their specific IRB/EC reporting policies and procedures. 
The monitor will discuss deviations with relevant site personnel, and will document them on 
monitoring visit reports.  If needed, a Note to File will be issued and filed in the relevant file 
and a copy sent to the sponsor.  
The sponsor will review records of deviations and will consider the need for corrective and 
preventive action and further external reporting to regulatory authorities. A summary report 
classifying and summarizing the deviations per type will be issued and reviewed by the 
sponsor personnel.   
Deviations will be summarized and included in the study report. Assessment and discussion 
of their potential impact / lack of impact on study results will be addressed. 
 
10.2. 
Adverse event reporting 
10.2.1. 
Definition 
 
Adverse Device Effect (ADE): adverse event related to the use of a medical device. 

 
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Note 1: This definition includes any adverse event resulting from insufficient or inadequate 
instructions for use or the deployment, implantation, installation, or operation, or any 
malfunction of the medical device. 
Note 2: This definition includes any event resulting from user error or from intentional misuse 
of the medical device 
 
Adverse Event (AE): Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
person, whether or not related to the medical device 
Note 1: This definition includes events related to the medical device or the comparator 
Note 2: This definition includes events related to the procedure involved 
Note 3: For users or other persons, this definition is restricted to the medical device. 
 
Serious Adverse Event (SAE): An Adverse Event that: 
a) Led to death, 
b) Led to serious deterioration in health of the subject, that either resulted in 
- 
life-threatening illness or injury 
- 
permanent physical impairment 
- 
in-patient hospitalization or prolongation of existing hospitalization 
- 
medical or surgical intervention to prevent permanent physical impairment  
c) Led to foetal distress, foetal death or congenital abnormality or birth defect. 
 
Note: Planned hospitalization for a pre-existing condition without serious deterioration in 
health is not considered as a serious event. 
 
Serious Adverse Device Effect (SADE) (ISO14155-2011): Adverse device effect that has 
resulted in any of the consequences of a serious adverse event. 
 
Procedure-Related Adverse Event: An event that occurs due to the procedure and cannot 
be directly attributed to a particular device or implant tool. 
 
Unanticipated Serious Adverse Device Effect: serious adverse device effect which by its 
nature, incidence, severity or outcome has not been identified in the current version of the 
risk analysis report. 
 
 

 
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10.2.2. 
Description of expected SAE 
 
SAE related to atrial rhythm disorder: 
• 
Congestive Heart Failure 
• 
Cardiogenic shock 
• 
Intra-atrial thrombus 
• 
Cardioembolic stroke  
• 
Myocardial infarction and unstable angina for patients with ischemic disease 
 
SAE related to medical treatment: 
• 
Hemorrhage 
• 
Ventricular rhythm disorder 
• 
Bleeding or pain at the femoral puncture point 
• 
Bradycardia 
• 
Anticoagulant overdose  
 
10.2.3. 
Event review and reporting 
10.2.3.1. 
Event review 
Upon the signature of the consent, the investigator is responsible for the collection of all 
adverse events. He reports all serious and non-serious adverse events (biological and 
clinical) that occur between the signature of the consent and the end of patient participation. 
 
10.2.3.2. 
Reporting 
Adverse reactions/adverse reactions/incidents should be reported in accordance with local 
requirements. 
 
10.2.4. 
Information for data collection 
All information required by the protocol must be recorded on the case report forms and an 
explanation must be provided for each missing data. The data must be collected as it is 
obtained and transcribed in these case report forms clearly and legibly. 
Data will be collected through electronic case report forms. 
 
10.2.5. 
Quality control 
A clinical researcher mandated by the sponsor visits each research centre on a regular 
basis, when the research is set up, once or several times during the course of research, 

 
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according to the rhythm of the inclusions and at the end of the research. During these visits 
and in accordance with the risk-based monitoring plan (participant, logistics, impact, 
resources), the following elements will be reviewed: 
- 
informed consent, 
- 
compliance with the research protocol and the procedures defined therein, 
- 
quality of the data collected in the CRF: accuracy, missing data, consistency of data 
with source documents (medical records, appointment books, originals of laboratory 
results, etc.) 
A monitoring report will be written after each visit. 
Visits will be on-site or through teleconferences or webconferences. 
 
10.2.1. 
Audit and inspection 
The centre can be audited at any time by persons appointed by the sponsor and independent 
of the persons conducting the research. Its objective is to verify the safety of the participants 
and the respect of their rights, the respect of the applicable regulations and the reliability of 
the data. 
An inspection may also be carried out by a competent authority (ANSM for France or EMA in 
the context of a European trial). 
The audit, as well as the inspection, can happen at all research stages, from the 
development of the protocol to the publication of the results and the classification of the data 
used or produced during the research. 
The investigators agree to comply with the sponsor requirements for an audit and the 
competent authority for a research inspection. 
 
 

 
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11. 
Study conclusion and statistical consideration 
11.1. 
Sample size rationale 
 
Given the low rate of atrial thrombi (about 2 % of patients eligible to atrial fibrillation ablation), 
this study requires a high number of participants in order to allow reliable estimation of 
diagnostic performance. 
To detect a 0.5 % deviation between two negative predictive values (binomial test), 2,000 
patients are required for a power of 70 %; 2,400 patients for a power of 80 %; and 3,000 
patients for a power of 90%. 
Due to the high enrolment capacities of this multicentre study and its simplicity for the 
centres involved, it was chosen to focus on the power of the study and to retain a sample 
size of 3,000 patients. 
 
11.2. 
Statistical analysis plan 
 
The analysis will be performed at the end of the trial. There is no interim analysis planned. 
 
The index test is the ATE score. A zero score is a negative result, while a score above zero 
is a positive result. 
The reference test is the transoesophageal echocardiography. The negative condition is the 
absence of thrombus, and the positive condition is the presence of thrombus. 
 
Demographics, medical history, clinical characteristics and diagnosis will be presented in 
tables with descriptive statistics for each sub-population (positive and negative condition) and 
for the entire analysed population, as follows: 
• 
For quantitative variables: mean and standard deviation,  
 
 
 
• 
For qualitative variables: count, percentage (excluding missing denominator data) and 
95% confidence intervals. 
 
ATE score sensitivity, specificity, positive predictive value, negative predictive value, and 
95% confidence intervals will be calculated. 
Primary objective will be met, if these parameters are similar with the ones obtained during 
the first study. 
The ATE score will be considered clinically relevant if a negative predictive value of 100 % is 
obtained for a zero score. 

 
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12. 
Ethical and legal aspects 
12.1. 
Access right to files and source data 
12.1.1. 
Data access 
Acceptance of participation in the protocol implies that the investigators will make available 
the individual documents and data strictly necessary for monitoring, quality control and audit 
to those who have access to these documents in accordance with the laws and regulations in 
force. 
 
12.1.2. 
Source data 
Source data are all information in original documents or in authenticated copies of these 
documents relating to clinical examinations, observations or other research activities 
necessary for the evaluation of the research. The documents in which the source data are 
stored are called the source documents. 
 
12.1.3. 
Data confidentiality 
In accordance with current legislation, those with direct access to the source data will take all 
necessary precautions to ensure the confidentiality of information about experimental data, 
and participating patients and, in particular, their identity and the results obtained. These 
persons, in the same way as the investigators themselves, are subject to professional 
secrecy. 
During and after the research, the data collected from the patients and forwarded to the 
sponsor by the investigators (or other specialists) will be made anonymous. They must in no 
case show clearly the names of the concerned persons or their address. 
The sponsor will ensure that each participating patient to the research has given his consent 
for access to his individual data. 
 
12.2. 
Ethical conduct of the study 
The sponsor and the investigators ensure that this research is carried out in accordance with 
Law No. 2012-300 of March 5th 2012 on research involving the human person and in 
agreement with good clinical practice (ICH version 4 of November 9th 2016 and Decision of 
November 24th 2006) and the Helsinki Declaration (which can be found in its full version at 
http://www.wma.net). 
The research shall be conducted in accordance with this Protocol. Except in emergency 
situations requiring specific therapeutic procedures, the investigators undertake to comply 
with the protocol in all respects. 

 
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This research has been approved by a French Committee for the Protection of persons and 
other local ethics committees for sites selected out of France. 
The data recorded are subject to a computerized treatment in compliance with the law n°78-
17 of January 6th 1978 relating to data processing, files and freedoms as amended by Law 
2004-801 of August 6th 2004. 
This research falls within the framework of the "Reference Methodology" (MR-001) in 
application of the article 54 paragraph 5 of the amended law of January 6th 1978 relating to 
information, files and freedoms. This change was approved by decision of January 5th 2006, 
updated on July 21st 2016. The Groupe Hospitalier de la Rochelle Ré Aunis has signed a 
commitment to conform to this "Reference Methodology". 
  
12.3. 
Study funding and insurance 
 
The Groupe Hospitalier de la Rochelle Ré Aunis, sponsor of this research, has contracted 
civil liability insurance n°156.549 with sham, Société Hospitalière d’Assurances Mutuelles, 18 
rue Edouard Rochet – 69372 Lyon cedex 8, in accordance with the French Public Health 
Code. 
 
12.4. 
Publication Policy 
Please refer to study agreement 
 
12.5. 
Confidentiality 
Please refer to study agreement 
 
12.6. 
Data archiving 
The investigator should arrange for the archiving of the study documentation file and the raw 
data from their hospital for at least 15 years after the Close-out visit if not specified in the 
study agreement. 
Patient hospital files and other source data should be kept for the maximum period of time 
permitted by the hospital, institution or private practice, but not less than 15 years. 
 

 
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13. 
References  
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complications of pulmonary vein catheter ablation for atrial fibrillation: A multicenter 
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Pappone C, Rosanio S, Augello G, Gallus G, Vicedomini G, Mazzone P, et al. 
Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for 
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97. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0735109703005771 
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4.  
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Paroxysmal Atrial Fibrillation: Segmental Pulmonary Vein Ostial Ablation Versus Left 
Atrial Ablation. Circulation. 2003;108(19):2355–60.  
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Mansour M, Ruskin J, Keane D. Efficacy and safety of segmental ostial versus 
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HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of 
Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, 
Patient Management and Follow-up, Definitions, Endpoints, and Research Trial 
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Recommendations for transoesophageal echocardiography: EACVI update 2014. Eur 
Heart J Cardiovasc Imaging. 2014;15(4):353–65.  
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of Clinical Classification Schemes Results From the National Registry of Atrial 
Fibrillation. Jama. 2001;285(22):2864–70.  
22.  
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Selecting patients with atrial fibrillation for anticoagulation: Stroke risk stratification in 
patients taking aspirin. Circulation. 2004;110(16):2287–92.  
23.  
Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining Clinical Risk 
Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a 
Novel Risk Factor-Based Approach: The Euro Heart Survey on Atrial Fibrillation. 
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5th ed. 2008. 48 p.  
 
 
 

 
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14. 
Appendices 
• 
Protocol summary: English version 
• 
Protocol summary: French version 
• 
Consent form: French version 
• 
Case Report form 
• 
Investigators list 
• 
STA-Liatest DDI Plus package insert (English version, September 2017)