Feasibility and Efficacy of Tailoring Ablation Index to Left Atrial Wall Thickness During Atrial Fibrillation Ablation: The Ablate By-LAW Study
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Centro Medico Teknon

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Personalized Atrial Fibrillation Ablation with 
Ablation Index Adapted to Left Atrial Wall 
Thickness: The Ablate-by-LAW Study. 
TRIAL LOCAL IDENTIFIER: Ablation-by-LAW 
ClinicalTrials.gov ID: NCT04218604 
PROTOCOL VERSION: 2.3 (June 25th 2020) 
 
 
 
Protocol 
Version 
Date of change 
Description and comments 
Control 
1.2 
June 18th 2019 
Fused LAWT + Single-catheter, clinical FU added 
CT + BJ 
1.3 
September 16th 2019 
Anesthesia protocol (Appendix 4) + sample size calculation 
+ peri-procedural TEE addendum + new investigators 
added 
BJ 
1.4 
September 23rd 2019 
Figures added (Appendix 5) + minor text corrections 
BJ 
1.5 
October 1st 2019 
Principal investigators’ minor change 
BJ 
1.6 
October 16th 2019 
Minor text changes + split protocols (retrospective and 
prospective) 
BJ 
1.7 
October 21st 2019 
Minor text changes 
BJ 
1.8 
November 27th 2019 
Minor text changes + ADAS-3D list of collaborators + minor 
data collection sheet changes 
BJ 
1.9 
December 27th 2019 
Final participating centers & investigators + format 
optimization for international centers + English informed 
consent + minor text changes 
BJ 
2.0 
January 6th 2020 
ClinicalTrials.gov ID added 
BJ 
2.1 
February 12th 2020 
Minor text changes 
BJ 
2.2 
February 26th 2020 
Personalized ablation concept + new diagram, further 
explanation on esophagus segmentation using MDCT, 
CARTO data management by the core-lab, anesthetic 
protocol changes 
BJ 
2.3 
June 25th 2020 
Text changes and other centers’ queries solved. Sample 
size re-calculated 
BJ 
 
 
 

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1. INTRODUCTION 
 
Atrial fibrillation (AF) is the most common arrhythmia and constitutes an important public 
health burden, being a source of high morbidity and mortality. 1 Circumferential pulmonary 
vein isolation (PVI) has become a mainstay in the treatment of AF, particularly in 
symptomatic patients with paroxysmal AF (PAF) intolerant or refractory to medical 
treatment. 2 Dormant conduction and pulmonary vein reconnections are responsible for 
AF/atrial tachycardia (AT) recurrences owing to incomplete non-transmural ablation lesions 
that generate gaps on ablation lines. 3–5 
 
Local electrogram attenuation, catheter-tip temperature and impedance drop have been 
used as surrogates for lesion formation. Nevertheless, they correlate badly with contact 
force and therefore constitute bad predictors of lesion size 6. Radiofrequency (RF) power, 
duration of RF energy delivery, baseline impedance and contact force (CF) have been proven 
to be determinants of lesion formation. 7–9  
 
More complex formulae have been developed to assess real-time effect of RF delivery and 
predict threshold values that must be reached to reduce reconnections and achieve 
permanent PVI. Namely, Force-Time Integral (FTI) which is calculated in grams second (gs) 
and represents the area under the CF/time curve 10,11; and Ablation Index (AI) which is a 
complex weighed formula that integrates CF, RF time and RF power 12,13. In order to 
minimize PVI reconnection, FTI and AI threshold values have been studied. In general, these 
values must be higher in the roof and anterior wall as compared to the inferior and posterior 
wall probably related to a lower wall thickness. 14 
 
The CLOSE study 15 analyzed the utility of AI for the reduction of AF recurrences with 91.3% 
of the patients free from AF/AT/atrial flutter (AFL) at 12 months follow-up. The CLOSE 
protocol targeted an inter-lesion distance of 6 mm and AI ≥ 400 at the posterior wall and ≥ 
550 at the anterior wall. Nonetheless, in over 40% of patients, the target AI of 400 was not 
attained on the posterior wall owing to chest pain and/or intraesophageal temperature rise 
(IQR: 378–425 AU). The same 550 and 400 AI target values where used in a retrospective 
study comparing AI vs. CF-guided ablation resulting in significantly lower AT/AF recurrences 
on the AI arm. 13 Such targets where chosen based on a previous study that retrospectively 
analyzed the ablation settings at first AF ablation of patients having redo ablation. Mean AI 
and mean FTI being statistically lower for reconnected segments [mean AI: 395 (350–429) vs. 
422 (380–464), p=0.002; mean FTI: 311 (225–373) vs. 371 (260–502) gs, p=0.003]. 12 
 
The left atrial wall is a thin structure with heterogeneous thickness, ranging from < 1mm to > 
5 mm, with an important inter and intra-patient variability. 16 This variability in wall 
thickness is the result of a complex array of three-dimensional muscular strands. 17–19 A 
prospective study already showed that first pass PVI was limited by inability to create 

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transmural lesions in certain anatomical sites where left atrial wall thickness (LAWT) had 
been described as being higher in ex-vivo hearts. 18,20 LAWT was an independent predictor of 
reconnection, 21 dormant conduction 22 and AF recurrence after 12 months follow-up, 23 and 
it might even be a predictor of transition from paroxysmal to chronic AF. 24   
 
The relationship between FTI and AI values, LAWT and gap formation on the ablation line 
after PAF ablation was already studied in two small retrospective studies that used single-
point LAWT measurements. Nevertheless, the anatomical location of the measured points in 
the multidetector cardiac tomography (MDCT) may have not corresponded exactly to the 
real-time catheter position as seen with the CARTO Merge® (Biosense Webster, Diamond 
Bar, CA, USA) module. These studies showed that FTI/wall thickness and AI/wall thickness 
indexes have demonstrated to predict gaps on PVI lines. 25 Although this relationship might 
also be explained by the fact that the anatomical regions where tissue is thickest are also 
regions where catheter stability is more difficult to obtain. Therefore, AI is the most suitable 
index to look at since it also takes stability on account. 
 
Even though many limitations have been described on MDCT atrial wall thickness 
measurement for previous generations of scanners, modern machines allow for sub-
millimetric resolution. In fact, MDCT-derived LAWT measurements have been reliably 
validated on a porcine model. 26 3D LAWT maps have already been generated from contrast-
enhanced MDCT images, 27 although their integration on a 3D anatomical mapping system 
for clinical use has not been described yet.  
 
Of all the determinants of lesion creation, LAWT is one key element that has been evaluated 
in some retrospective analysis but is not yet used as per procedure to dose the 
radiofrequency delivery. Adapting AI to local LAWT would be very useful in standardizing the 
ablation procedure with parameters fitted to each patient, enabling the development of a 
personalized approach that will both: i) increase efficacy by performing transmural lesions to 
prevent the formation of conduction gaps in the initial lesion set, and ii) increase safety by 
preventing excessive RF delivery on thin wall areas which can lead to complications, like 
cardiac perforation or atrio-esophageal fistula. 
 
Further on, with regards to procedural safety, a recent study by Pambrun et al. 28 recruited 
100 patients with symptomatic, drug-refractory AF that underwent standard wide antral 
circumferential ablation to achieve PVI, divided into two groups: i) Control group, 
corresponding to 50 consecutive patients that followed a standard, two-catheter approach 
(CF ablation catheter plus circular mapping catheter); and ii) study group, conformed by 50 
consecutive patients that followed a single-catheter approach (without the need for a 
circular mapping catheter) to achieve PVI. The rationale for the use of this approach was 
based on prior studies that showed that the complete loss of pace capture directly along the 
circumferential ablation line correlates with entrance block in 95% of PV and can be 

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achieved without circular mapping catheter guidance. 
29,30 Moreover, pacing for 
unexcitability along the ablation line can identify potential sites with dormant conduction, 
and even excitable sites that would not have been identified using adenosine, 31 which, on 
the other hand, has not been able to improve the long-term success after AF ablation. 32 The 
study by Pambrun et al. 28 showed that antral exit block validated with a CF-sensing ablation 
catheter successfully predicts PVI, and it was demonstrated that this single-catheter 
approach for achieving PVI is feasible, cost-saving and non-inferior in terms of AF 
recurrences in the mid-term. However, the study was conducted only in patients with PAF, 
normal LA volumes and no prior AF ablation procedures. Thus, the potential usefulness of 
this cost-saving approach in a broader, ‘real life’ population is still unknown. We hypothesize 
that a single-catheter approach for RF-based PVI may be feasible, cost-saving and at least as 
safe and effective as the standard approach when used in all patients referred for AF 
ablation. 
 
Finally, one key element regarding procedural safety is the avoidance of a dreaded 
complication, the atrio-esophagueal fistula. 33 It is estimated to occur in <0.1% to 0.25% of 
AF ablation procedures, but, among causes of death after AF ablation, atrio-esophagueal 
fistula is the second most common along with stroke. 34 The relationship of the esophagus to 
the LA posterior wall and pulmonary veins is variable. It tends to be located farthest from 
the right superior pulmonary vein, but it can be close to any of the others, depending on its 
course, and may be within a few millimeters at the point of closest proximity. 35 Imaging of 
the esophagus may be performed as a component of an imaging study that is primarily 
designed to evaluate extraesophageal anatomy, such as during a cardiac MDCT. In a similar 
way as for LAWT measurements using MDCT, the distance (i.e. ‘tissue thickness’) between 
the posterior wall of the LA and the esophagus can be measured. 
 
We sought to evaluate the feasibility, safety, efficacy and reproducibility of performing atrial 
fibrillation ablation procedures with a fully personalized protocol that includes: i) the use of 
MDCT-derived LAWT information to select tailored point-by-point AI targets; ii) the use of a 
single-catheter strategy to minimize vascular-related complications; and iii) the integration 
of a MDCT-derived ‘fingerprinted’ esophagus image to modify the ablation lines to avoid too 
close proximity of RF applications. The study will be single-catheter-based, hypothesizing 
that this simplified and personalized approach is feasible, cost-saving and at least as safe and 
effective as the standard approach when used in all patients referred for AF ablation.  
 
 

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2. HYPOTHESIS AND OBJECTIVES 
2.1 Research hypothesis 
Personalized AF ablation using the ‘ablation-by-LAW’ protocol that uses point-by-point 
adapted AI values according to the local MDCT-derived LAWT, is feasible, safe and at least as 
effective as the current AF ablation standards. 
Ablation-by-LAW involves the use of tailored point-by-point AI values according to the local 
MDCT-derived LAWT, the use of a single-catheter strategy, and the integration of a MDCT-
derived ‘fingerprinted’ esophagus image to modify the ablation lines aiming to avoid too 
close RF applications, while performing the procedures using general anesthesia and a high-
rate, low-volume ventilation protocol. The following diagram constitutes a general overview 
of the protocol: 
 
 
 
 
 
Ablation-by-LAW
1. MDCT-derived
LAWT
Tailored, 
point-by-point 
AI targets
2. MDCT-derived
'fingerprinted' 
esophagus 
image
Tailored 
disposition of 
ablation lines
3. Single-
catheter strategy
Improved 
vascular safety
4. General 
anesthesia
+
HR-LV 
ventilation
Improved 
catheter 
stability & 
anatomical 
precision
Personalized AF Ablation 

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2.2 Study objectives 
2.2.1 Primary objective 
To determine if the proposed ablation-by-LAW protocol is non-inferior in terms of long-term 
clinical outcomes when compared to other AF ablation protocols using higher AI targets, not 
adapted to the LAWT. 
2.2.2 Secondary objectives 
• To determine if the ablation-by-LAW approach permits to be more efficient in terms 
of procedure time, RF time, and fluoroscopy time. 
• To evaluate the rate of complications using the ablation-by-LAW approach. 
• To analyze the reasons for not obtaining a first-pass isolation using the ablation-by-
LAW approach. 
 
 
 
 

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3. METHODS 
3.1 Study design 
Single-arm, international, multicenter, prospective study. 
 
3.2 Study setting 
Tertiary hospitals with an electrophysiology team of qualified investigators with proven 
experience in performing atrial fibrillation ablation. 
 
3.3 Eligibility criteria 
Patients will only be recruited if they fulfill the following inclusion criteria: 
• Age > 18 years. 
• Indication for paroxysmal atrial fibrillation ablation. 
• Signed informed consent. 
 
Patients will be excluded if they meet any of the following exclusion criteria: 
• Age < 18 years. 
• Pregnancy. 
• Previous AF REDO procedure. 
• Impossibility to perform a MDCT scan. 
• Concomitant investigation treatments. 
• Medical, geographical and social factors that make study participation impractical, 
and inability to give written informed consent. Patient's refusal to participate in the 
study. 
 
3.4 Interventions 
3.4.1 Pre-procedure MDCT scan  
A pre-procedural multi-detector cardiac tomography (MDCT) will have to be performed in all 
participant subjects and centers. In the case of Teknon Medical Center, this will be done 
using a RevolutionTM CT scanner (General Electric Healthcare). The images will be acquired 
during an inspiratory breath-hold using retrospective ECG-gating technique with tube 
current modulation set between 50% and 100 % of the cardiac cycle. CT angiographic images 
will be acquired during the injection of a 70 mL bolus of Iopromide 370 mg I/mL (Ultravist, 
Bayer Hispania, Barcelona, Spain) at a rate of 3mL/s. Other contrast agents or acquisition 
protocols will be permitted, according to the usual practice of the corresponding centers. 
Similar acquisition protocols will be adapted to the local practice and available CT scanner of 
each participant center. All the data will be transmitted to the core-lab (see section 3.4.2) for 

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post-processing and will be reconstructed into axial images with a slice thickness of 0.625 
mm. 
3.4.2 Image processing  
MDCT images of all centers will be anonymously sent using a secure data transfer server 
(eCRD platform developed by the contract research organization –CRO– Xolomon SL) and 
analyzed by the following core-lab: ADAS 3D Medical SL headquarters (Barcelona, Spain). 
The ADAS 3D LA™ software (ADAS 3D Medical SL, Barcelona, Spain) will be used to obtain 3D 
atrial wall thickness maps. All the images obtained in the remaining participating centers will 
be submitted to the core-lab using a secure server. In order to obtain the atrial wall 
thickness a 3-step algorithm will be applied: i) the endocardial layer is defined by means of a 
semi-automatic segmentation based on pixel intensity thresholds; ii) the epicardial layer is 
defined by a manually delineation in few slices followed by an interpolation in the missing 
slices; iii) Finally, the wall thickness at each endocardial point is computed as the distance 
between each endocardial point and its projection to the epicardial shell. These three steps 
result in a 3D thickness map that can be introduced into CARTO® navigation system 
(Biosense Webster, Diamond Bar, California, US). The color map uses a color scale to depict a 
range of thickness red being the thinnest (< 1 mm) and purple being the thickest (> 4 mm). 
Yellow, green and blue will be considered the intermediate values. 
The same post-processing protocol will be applied to compute the distance between each LA 
epicardial point and the boundaries of the esophagus, thus calculating the soft tissue 
thickness (i.e. separation in mm) between these two anatomic structures. The tissue 
thickness at each point will be color-coded in a similar way as for LAWT, and the 
‘fingerprinted’ esophagus image with the tissue thickness information will be also exported 
into CARTO® navigation system (Biosense Webster, Diamond Bar, California, US). Figure 3 in 
Appendix 4 shows an example of this fingerprinted esophagus, projected onto the LA 
posterior wall. 
3.4.3 Catheter-based radiofrequency ablation 
Procedures should be performed on uninterrupted oral anticoagulation and under general 
anesthesia aiming to complete neuromuscular relaxation (see Appendix 3), with 
hemodynamic monitoring using a radial arterial line. Single venous femoral access will be 
mandatory. Peri-procedural anticoagulation will be performed according to local protocols 
but always aiming to achieve an intraprocedural activated clotting time (ACT) of 300–350 
seconds. 
Transeptal puncture will be preferably guided by peri-procedural transesophageal 
echocardiography (TOE), which does not require for an additional venous puncture. Other 
imaging techniques, such as intracardiac echo, will be allowed to guide the puncture for 
those centers without TOE availability (it will have to be collected in the data collection 
sheet). After the puncture, the TOE probe must be removed from the esophagus to avoid 
tissue overheating during RF applications. The use of a transesophageal temperature probe 
will be allowed at operator’s discretion. PVI will be performed point-by-point, aiming to 

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complete a RF circle around the PV ostia (nephroid shape) on the 3-dimensional geometry 
using a Thermocool SmartTouch 3.5-mm irrigated tip contact force-sensing RF ablation 
catheter (Biosense Webster, Inc.). In case of a common ipsilateral vein ostium, the line must 
be drawn around the trunk. PVI will be started in all cases at the right PVs; PV isolation 
initiated from the right anterior ganglionated plexi (located at the supero-anterior area of 
the RSPV antrum) could effectively inhibit vagal response occurrence during subsequent RF 
applications by increasing the basal heart rate. 36 RF lines will be manually traced, aiming to 
avoid, if possible, the ‘fingerprinted’ image of the esophagus, projected on the LA posterior 
wall (see Appendix 4). Maximal interlesion distance will be 6 mm. VisiTag settings will be as 
follows: catheter position stability: minimum time 3 s, maximum range 4 mm; force over 
time: 25%, minimum force 3 g; lesion tag size: 3 mm. The irrigation flow rate must be set to 
2 ml/min during mapping and 17-30 ml/ min during ablation. AI targets are defined by local 
AWT on the thickness color map, as follows: Thickness < 1 mm (red): 300; 1-2 mm (yellow): 
350; 2-3 mm (green): 400; 3-4 mm (blue): 450; > 4 mm (purple): 500. The recommended 
power settings to reach these AI values will be, in general, 35W for the posterior wall and 
40W for the anterior wall. Wherever local AWT is > 3 mm (green and blue colors), an 
increased RF power (50W) will be permitted to reach the AI target faster, particularly if the 
catheter is placed in an unstable place. If the targeted AI value is not reached, another lesion 
reaching the target must be applied. 
Acute PVI will be confirmed after first pass with the single catheter method of 
demonstrating entry and exit block with the ablation catheter placed sequentially in each of 
the PVs or trunks. There is a minimum waiting time of 10 min after isolation of each 
ipsilateral PV pair; additional RF applications must be performed at reconnection sites until 
PVI is achieved. A carina line will have to be always performed for the right pulmonary veins, 
since there is anatomical 37 and electrophysiological evidence 38–40 for the presence of 
interconnections of the ipsilateral veins in up to of ⅔ of the patients referred for AF ablation. 
41 Additional substrate ablation to create left atrial linear lesions or any extra PV-trigger 
ablation like CFAE is not permitted. Atrial fibrillation that persists after PVI must be 
terminated with electrical cardioversion. In case other substrates have to be addressed in 
the same procedure (i.e. right atrial arrhythmias), the additional time, vascular accesses or 
catheters employed after PVI will not be taken into account for the purpose of the present 
study. 
Of note is that complete PVI will not be considered unless a second evaluating operator 
confirms the absence of ‘visual gaps’ along the ablation lines. This second operator may be 
any experienced professional involved in the procedure (nurse, engineer, technician, etc.) 
that is able to assess the presence of gaps in a reliable manner. The visual gaps will be 
defined as any solution of continuity between two RF lesions tagged using the VisiTag 
settings previously described and a 3-mm tag size. This confirmation will have to be 
indicated in ALL cases in the data collection sheet. Its absence will be a reason to exclude the 
case from the study. 
 

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3.5 Outcomes 
3.5.1 Primary endpoint 
The primary endpoint will be survival free of any atrial arrhythmia at 1-year follow-up. From 
this endpoint, important definitions must be taken into account: 
• AF recurrence will be considered only after the 3-month ‘blanking period’ (see 
below), whenever the patient refers clear symptoms of recurrence (fast, recurrent 
palpitations with abrupt onset and termination, lasting for several minutes or hours), 
if AF is documented in an electrocardiogram (ECG), or whether it is recorded in a 
Holter registry (> 30 seconds). 
• The ‘blanking period’ refers to the first 3-month period after the PVI procedure, 
where a transient increased risk of post-procedural atrial tachyarrhythmias is 
expected to occur due to pro-arrhythmogenic inflammatory changes after creating 
tissue RF lesions. 
3.5.2 Secondary endpoints 
3.5.2.1 Acute procedural outcomes 
• Procedure time (skin to skin) 
• Radiofrequency time 
• Number of applications (total/per RF line/per segment) 
• Fluoroscopy time  
• First-pass isolation rate 
• Early PV reconnections 
3.5.2.2 Peri-procedural complications 
The following procedure-related complications will be collected: 
• Death 
• Myocardial infarction 
• Diaphragmatic paralysis 
• Stroke or transient ischemic attack (TIA) 
• Other thromboembolic events 
• Cardiac perforation or tamponade 
• Vascular complications 
• Prolonged or repeat hospitalization 
• Heart block 
• PV stenosis >70% (as measured by cardiac CT) 
• Atrio-esophageal fistula 
• Pericarditis requiring intervention 
• Pneumothorax  
• Pulmonary edema 

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3.6 Variables 
3.6.1 Enrollment evaluation 
A complete evaluation will be performed in each patient at enrollment, including: 
1. Patient demographic data 
2. Clinical evaluation with a physical examination 
3. Medical and cardiovascular history  
4. NYHA functional class 
1. Medication list 
2. 12-Lead ECG 
3. Transthoracic echocardiography with 
a. LA diameter  
b. LVEF (biplane Simpson’s method) (%) 
4. Trans-esophageal echocardiography/Intra-cardiac echocardiography. 
 
3.6.2 Procedural evaluation 
5. MDCT wall thickness variables 
5.1. Mean LAWT (all of the atrial measures) 
5.2. Mean PVI RF line WT (only around the PV line) 
5.3. Normalized PVI RF line WT (point thickness/maximum PVI RF line thickness)  
5.4. Reconnection point mean WT (mean thickness on a 3mm radium around the point) 
5.5. Reconnection segment mean WT (mean thickness in each segment) 
5.6. Coefficient of variation of wall thickness on each segment (CV-WT) standard 
deviation of the wall thickness/mean WT 
5.7. Gaussian curvature (to have an idea of the heterogeneity of tissue) 
6. Procedural data of the first PVI 
6.1. PV anatomy (presence or absence of common vein ostia) 
6.2. RF time 
6.3. Acute reconnection sites  
7. Procedural data of the re-do intervention 
7.1. Reconnection sites according to an 8-segment model where the antral region of 
the PVs is divided into segments 
7.2. RF time 
7.3. EGM attenuation time 
 
3.7 Follow-up 
Clinical follow-up (FU) will include outpatient clinic visits at 3, 6 and 12 months after the 
ablation procedure. If no other contraindications, all antiarrhythmic drugs should be stopped 
at the 3-month FU visit (end of the ‘blanking period’; see ‘Outcomes’ section before). 12-
lead ECG and 24-hour ambulatory Holter monitoring will be performed in every scheduled 

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appointment. Successful ablation will be defined as the absence of clinical symptoms 
suggestive of AF recurrence, as well as the absence of documented AF in ECGs and/or 
Holter. 
 
3.8 Study timeline 
 
VISIT 
 
PROCEDURE 
Enrollment 
Baseline 
Ablation 
1 month 
6 months 
12 months 
Eligibility screen 
   
 
 
 
 
 
Informed consent 
   
 
 
 
 
 
Demographic Data 
 
   
 
 
 
 
Medical History 
 
   
 
 
 
 
Medication 
 
   
 
   
   
   
NYHA Class 
 
   
 
   
   
   
12-lead ECG 
 
   
 
   
   
   
24-h Holter 
 
(*) 
 
   
   
   
TTE 
 
   
 
 
 
   
TOE 
 
 
   
 
 
 
Allocation 
 
 
 
 
 
 
Ablation data 
 
 
   
 
 
 
Protocol Deviation 
✔(*) 
  (*) 
✔(*) 
✔(*) 
  (*) 
  (*) 
Adverse event 
  (*) 
  (*) 
  (*) 
✔(*) 
✔(*) 
  (*) 
Termination 
  (*) 
  (*) 
  (*) 
  (*) 
✔(*) 
  (*) 
 
3.9 Recruitment and agenda 
All participant centers are tertiary referral centers for AF ablation within their health care 
network. All patients who give consent for participation and fulfill the inclusion eligibility 
criteria will be consecutively enrolled. First patient will be included after approval of the 
protocol by ethics committee. We expect to include all the patients within a year period. The 

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12-month follow-up information of the last included patient should be available 
approximately 2 years after the first inclusion. 
 
3.10 Document and data control 
The principal investigator or delegate is responsible of the data collection on the electronic 
Case Report Forms (eCRFs). This eCRFs will be introduced using an electronic clinical 
research data capture (eCRD) platform developed by the contract research organization 
(CRO) Xolomon SL. The principal investigator will review all the data on the eCRFs and will 
sign to verify he has reviewed the data collected. Original anonymized paper support forms 
will be stored in a secure place and manner at each participating center. Anonymization 
codes will be stored in a safely manner by the local principal investigator. Access to the 
online study data (eCRFs) will be restricted through passwords. In addition, center 
coordinators will only have access to their own center’s data. Paper files will be physically 
stored until 5 years after the completion of the study. 

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3.10.1 Traceability of documents and data 
The investigator shall ensure accuracy, completeness, legibility and timeliness of the data 
reported to the principal investigator on the eCRFs and in all required reports. When copies 
of the original source document as well as print outs of original electronic source documents 
are retained, these shall be signed and dated by a member of the investigational site team 
with a statement that it is a true reproduction of the original source document. 
3.10.2 Recording data 
Source documents shall be created and maintained by the investigation site team 
throughout the clinical investigation. The data reported on the eCRFs shall be derived from, 
and be consistent with, these source documents, and any discrepancies shall be explained in 
writing. The eCRFs shall be signed and dated by the principal investigator or a delegated 
investigator. Any change or correction to data reported on a paper CRF shall be dated, 
initialed and explained if necessary, and shall not obscure the original entry. 
3.10.3 CARTO® data management 
CARTO® (Biosense Webster, Diamond Bar, California, US) studies of all centers will be 
exported and anonymously sent using a secure data transfer server (eCRD platform 
developed by CRO Xolomon SL) and analyzed by the following core-lab: ADAS 3D Medical SL 
headquarters (Barcelona, Spain). Ablation settings and RF applications will be thoroughly 
reviewed by an expert operator of the core-lab, to ensure compliance with the LAWT 
protocol. Any violation of this protocol will be considered enough reason to exclude the case 
from further analysis. 
3.10.4 Review of data 
The clinical investigation will be monitored by reviewing the eCRF submitted by the 
investigators. The following activities will occur: 
• All eCRFs will be reviewed for completeness and accuracy upon receipt by the 
principal investigator. 
• The investigator (co-investigator) and/or delegate will be contacted by the principal 
investigator regarding any missing or unclear data. 
 
3.11 Statistical analysis 
3.11.1 Sample size 
The sample size calculation has been based on the assumption that the proposed ablation 
protocol (‘LAWT’) is an acceptable alternative to the CLOSE protocol15 (non-inferiority), with 
the advantage of less radiofrequency applied and likely lower risk for complications. A non-
inferiority margin of 10% of clinical success (arrhythmia-free survival one year after the 
ablation procedure) will be considered to be the largest difference that is acceptable 

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between both protocols for LAWT to be adopted in clinical practice. Recruiting n = 106 
participants will be required to confer 90% power to reject the inferiority null hypothesis, 
that is, that the lower limit of a one-sided 95% confidence interval will be above the non-
inferiority limit of −0.05, indicating no difference between the arms. A drop-out rate of 10% 
is estimated, and included in the sample size calculation. 
3.11.2 Statistical methods 
All applicable statistical tests will be 2-sided and will be performed using a 5% significance 
level. Continuous variables will be reported as mean ± standard deviation, or median (range 
or interquartile range if data are skewed) if not normally distributed; these variables will be 
compared using Student’s t-test if normally distributed or Mann-Whitney U test if not 
normally distributed. Categorical variables will be expressed as total number (percentage) 
and will be compared by chi-squared test. For the primary endpoint, survival free from atrial 
arrhythmia, we will use the Kaplan-Meier survival analysis. A multivariable Cox proportional 
hazards model will be performed to investigate the effects of baseline characteristics in 
predicting ablation results, an adjustment will also be done by recruiting center. A receiver 
operating curve analysis will be performed to determine optimal cutoff LAWT values for 
predicting AF recurrence after ablation. All efforts will be done to limit missing data on 
outcome. Nevertheless, missing data will be reported on the final manuscript and, as much 
as possible, the reasons why data are missing will be documented. If missing, a simple 
imputation method will be applied and reported. 
 
3.12 Protocol deviation 
A protocol deviation is defined as a situation in which there is a non-compliance with the 
protocol. The following situations are considered protocol deviations and must be 
appropriately documented: 
1. Utilization of another method for guiding the ablation. 
2. Ablation of extra PV substrate. 
Investigators will be required to adhere to the investigational plan, signed investigator’s 
agreement, applicable national or local, laws and regulations, and any conditions required by 
the appropriate Ethics Committees or applicable regulatory authorities. The reporting of all 
the deviations will be performed through the eCRF application. In the event of repeated 
protocol deviation as determined by the principal investigator, a clinical research associate 
or clinical representative will attempt to secure compliance by one or more of the following 
actions: i) contacting the investigator by telephone, or ii) contacting the investigator in 
writing. 

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3.13 Harms 
Since all included patients must have an indication for AF ablation, no specific harms are 
expected in the context of the trial, as AI targets will be decreased at those ablation points 
with lower LAWT values. In fact, in a single-center, prospective series of 80 patients, whose 
results will be presented at the EHRA 2020 Congress, there were no procedure-related 
complications using this approach. All complications will be documented as secondary 
endpoints. 
 
 

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4. STUDY INVESTIGATORS AND PARTICIPATING CENTERS 
 
1. Antonio Berruezo, MD, PhD. Principal investigator. Heart Institute, Teknon Medical 
Center, Barcelona (Spain). Mail: antonio.berruezo@quironsalud.es   
2. Beatriz Jáuregui, MD. Co-investigator and responsible for study monitoring. Heart 
institute, 
Teknon 
Medical 
Center, 
Barcelona 
(Spain). 
Mail: 
beatriz.jauregui@quironsalud.es  
3. David Soto, PhD. Engineer and responsible for the Core Lab. Heart institute, Teknon 
Medical Center, Barcelona (Spain). Mail: sotin1985@gmail.com   
4. Juan Fernández-Armenta, MD, PhD. Co-investigator. Hospital Universitario Puerta 
del Mar, Cádiz (Spain). Mail: juanfdezarmenta@gmail.com  
5. Gerhard Hindricks, MD, PhD. Co-investigator. Heart Center Leipzig University 
Hospital, Leipzig (Germany). Mail: gerhard.hindricks@medizin.uni-leipzig.de  
6. Peter Zimetbaum, MD, PhD / André D‘Avila. Co-investigators. Beth Israel Deaconess 
Medical Center, Boston, MA (USA). Mail: pzimetba@bidmc.harvard.edu  
7. Saman Nazarian, MD, PhD. Co-investigator. Hospital of the University of 
Pennsylvania, Philadelphia, PA (USA). Mail: saman.nazarian@uphs.upenn.edu 
8. Philipp Sommer, MD, PhD. Co-investigator. Herz- und Diabeteszentrum Nordrhein-
Westfalen, Bad Oeynhausen (Germany). Mail: mail@philippsommer.de  
9. Giulio Zucchelli, MD, PhD. Co-investigator. Azienda Ospedaliero-Universitaria Pisana, 
Pisa (Italy). Mail: zucchelli76@gmail.com  
 
 
4.1 Coordinating clinical investigator 
This will be the principal investigator of the study and the person who will take the decision 
to submit the report for publication, and will have ultimate authority over all the activities: 
 
Antonio Berruezo, MD, PhD 
Teknon Medical Center 
C/Vilana, 12; 08022 Barcelona (Spain) 
Tel: (+34) 93 290 62 51 
Mail: antonio.berruezo@quironsalud.es  
 
4.2 Responsibilities of the coordinating center 
The Heart Institute at Teknon Medical Center (Barcelona, Spain) is the coordinating center 
that will manage the data and perform statistical analysis.  
 
 

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5. ETHICS AND DISSEMINATION 
5.1 Research ethics approval 
This protocol must be reviewed and approved by the local institutional review board (IRB) of 
each center. 
5.2 Risks 
There are no particular risks related to study participation. Nevertheless, there are risks 
related to the procedure itself, which is explained on the informed consent sheet. 
5.3 Protocol amendments 
Any modifications to the protocol which may impact on the conduct of the study, potential 
benefit of the patient or may affect patient safety, including changes of study objectives, 
study design, patient population, sample sizes, study procedures, or significant 
administrative aspects will require a formal amendment to the protocol. Such amendment 
must be approved by the IRB. 
5.4 Consent or assent 
Operators will introduce the trial to patients on the pre-operatory outpatient visit. 
Information sheets and consent forms will be provided to all screened patients at the time of 
the visit and consents will be collected at the time of hospitalization. 
5.5 Confidentiality 
All study-related information will be stored securely at the study site. All participant 
information will be stored in locked file cabinets in areas with limited access. All laboratory 
specimens, reports, data collection, process, and administrative forms will be identified by a 
coded ID [identification] number only to maintain participant confidentiality. All records that 
contain names or other personal identifiers, such as locator forms and informed consent 
forms, will be stored separately from study records identified by code number. All local 
databases will be secured with password-protected access systems. 
5.6 Access to data 
Project Principal Investigators will have direct access to their own site’s data sets, and will 
have access to other sites data by request. To ensure confidentiality, data dispersed to 
project team members will be blinded of any identifying participant information.  
5.7 Dissemination policy 
The study results will be released to the participating physicians, referring physicians, 
patients and the general medical community. 
 
 
 

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6. REFERENCES 
 
1.  
Kirchhof P, Kotecha D, Casadei B, et al. 2016 ESC Guidelines for the management of 
atrial fibrillation developed in collaboration with EACTS The Task Force for the 
management of atrial fibrillation of the European Society of Cardiology ( ESC ) 
Developed with the special contribution of the Europ. Eur Heart J. 2016. 
doi:10.1093/eurheartj/ehw210 
2.  
Calkins H, Hindricks G, Cappato R, et al. 2017 HRS / EHRA / ECAS / APHRS / SOLAECE 
expert consensus statement on catheter and surgical ablation of atrial fi brillation : 
Executive summary. J Arrhythmia. 2017;33(5):369-409. doi:10.1016/j.joa.2017.08.001 
3.  
Ouyang F, Tilz R, Chun J, et al. Long-Term Results of Catheter Ablation in Paroxysmal 
Lessons From a 5-Year Follow-Up. 2010:2368-2377. 
doi:10.1161/CIRCULATIONAHA.110.946806 
4.  
Cappato R, Negroni S, Pecora D, et al. Prospective assessment of late conduction 
recurrence across radiofrequency lesions producing electrical disconnection at the 
pulmonary vein ostium in patients with atrial fibrillation. Circulation. 
2003;108(13):1599-1604. doi:10.1161/01.CIR.0000091081.19465.F1 
5.  
Kuck K-H, Hoffmann BA, Ernst S, et al. Impact of Complete Versus Incomplete 
Circumferential Lines Around the Pulmonary Veins During Catheter Ablation of 
Paroxysmal Atrial Fibrillation: Results From the Gap-Atrial Fibrillation-German Atrial 
Fibrillation Competence Network 1 Trial. Circ Arrhythm Electrophysiol. 
2016;9(1):e003337. doi:10.1161/CIRCEP.115.003337 
6.  
Ikeda A, Nakagawa H, Lambert H, et al. Relationship between catheter contact force 
and radiofrequency lesion size and incidence of steam pop in the beating canine 
heart: electrogram amplitude, impedance, and electrode temperature are poor 
predictors of electrode-tissue contact force and lesion. Circ Arrhythm Electrophysiol. 
2014;7(6):1174-1180. doi:10.1161/CIRCEP.113.001094 
7.  
Thiagalingam A, D’Avila A, Foley L, et al. Importance of catheter contact force during 
irrigated radiofrequency ablation: evaluation in a porcine ex vivo model using a force-
sensing catheter. J Cardiovasc Electrophysiol. 2010;21(7):806-811. doi:10.1111/j.1540-
8167.2009.01693.x 
8.  
Barkagan M, Rottmann M, Leshem E, Shen C, Buxton AE, Anter E. Effect of Baseline 
Impedance on Ablation Lesion Dimensions. Circ Arrhythm Electrophysiol. 
2018;11(10):e006690. doi:10.1161/CIRCEP.118.006690 
9.  
Reddy VY, Dukkipati SR, Neuzil P, et al. Randomized, Controlled Trial of the Safety and 
Effectiveness of a Contact Force-Sensing Irrigated Catheter for Ablation of Paroxysmal 
Atrial Fibrillation: Results of the TactiCath Contact Force Ablation Catheter Study for 
Atrial Fibrillation (TOCCASTAR) S. Circulation. 2015;132(10):907-915. 
doi:10.1161/CIRCULATIONAHA.114.014092 
10.  
Shah DC, Lambert H, Nakagawa H, Langenkamp A, Aeby N, Leo G. Area under the real-
time contact force curve (force-time integral) predicts radiofrequency lesion size in an 
in vitro contractile model. J Cardiovasc Electrophysiol. 2010;21(9):1038-1043. 
doi:10.1111/j.1540-8167.2010.01750.x 
11.  
De Potter T, Van Herendael H, Balasubramaniam R, et al. Safety and long-term 
effectiveness of paroxysmal atrial fibrillation ablation with a contact force-sensing 
catheter: real-world experience from a prospective, multicentre observational cohort 
registry. Eur  Eur pacing, arrhythmias, Card Electrophysiol  J  Work groups Card pacing, 

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arrhythmias, Card Cell Electrophysiol Eur Soc Cardiol. 2018;20(FI_3):f410-f418. 
doi:10.1093/europace/eux290 
12.  
Das M, Loveday JJ, Wynn GJ, et al. Ablation index, a novel marker of ablation lesion 
quality: prediction of pulmonary vein reconnection at repeat electrophysiology study 
and regional differences in target values. Eur  Eur pacing, arrhythmias, Card 
Electrophysiol  J  Work groups Card pacing, arrhythmias, Card Cell Electrophysiol Eur 
Soc Cardiol. 2017;19(5):775-783. doi:10.1093/europace/euw105 
13.  
Hussein A, Das M, Chaturvedi V, et al. Prospective use of Ablation Index targets 
improves clinical outcomes following ablation for atrial fibrillation. J Cardiovasc 
Electrophysiol. 2017;28(9):1037-1047. doi:10.1111/jce.13281 
14.  
Das M, Loveday JJ, Wynn GJ, et al. Ablation index, a novel marker of ablation lesion 
quality: Prediction of pulmonary vein reconnection at repeat electrophysiology study 
and regional differences in target values. Europace. 2017;19(5):775-783. 
doi:10.1093/europace/euw105 
15.  
Taghji P, El Haddad M, Phlips T, et al. Evaluation of a Strategy Aiming to Enclose the 
Pulmonary Veins With Contiguous and Optimized Radiofrequency Lesions in 
Paroxysmal Atrial Fibrillation: A Pilot Study. JACC Clin Electrophysiol. 2018;4(1):99-108. 
doi:10.1016/j.jacep.2017.06.023 
16.  
Mahida S, Derval N, Sacher F, et al. Role of Electrophysiological Studies in Predicting 
Risk of Ventricular Arrhythmia in Early Repolarization Syndrome. J Am Coll Cardiol. 
2015;65(2). doi:10.1016/j.jacc.2014.10.043 
17.  
Papez JW. Heart musculature of the atria. Am J Anat. 1920;27(3):255-285. 
doi:10.1002/aja.1000270302 
18.  
Ho SY, Cabrera JA, Tran VH, Farre J, Anderson RH, Sanchez-Quintana D. Architecture 
of the pulmonary veins: relevance to radiofrequency ablation. Heart. 2001;86(3):265-
270. 
19.  
Ho SY, Sanchez-Quintana D. The importance of atrial structure and fibers. Clin Anat. 
2009;22(1):52-63. doi:10.1002/ca.20634 
20.  
Kistler PM, Ho SY, Rajappan K, et al. Electrophysiologic and anatomic characterization 
of sites resistant to electrical isolation during circumferential pulmonary vein ablation 
for atrial fibrillation: a prospective study. J Cardiovasc Electrophysiol. 
2007;18(12):1282-1288. doi:10.1111/j.1540-8167.2007.00981.x 
21.  
Inoue J, Skanes AC, Gula LJ, Drangova M. Effect of Left Atrial Wall Thickness on 
Radiofrequency Ablation Success. J Cardiovasc Electrophysiol. 2016;27(11):1298-1303. 
doi:10.1111/jce.13065 
22.  
Takahashi K, Okumura Y, Watanabe I, et al. Relation Between Left Atrial Wall 
Thickness in Patients with Atrial Fibrillation  and Intracardiac Electrogram 
Characteristics and ATP-Provoked Dormant Pulmonary Vein Conduction. J Cardiovasc 
Electrophysiol. 2015;26(6):597-605. doi:10.1111/jce.12660 
23.  
Suenari K, Nakano Y, Hirai Y, et al. Left atrial thickness under the catheter ablation 
lines in patients with paroxysmal atrial fibrillation: insights from 64-slice multidetector 
computed tomography. Heart Vessels. 2013;28(3):360-368. doi:10.1007/s00380-012-
0253-6 
24.  
Nakamura K, Funabashi N, Uehara M, et al. Left atrial wall thickness in paroxysmal 
atrial fibrillation by multislice-CT is  initial marker of structural remodeling and 
predictor of transition from paroxysmal to chronic form. Int J Cardiol. 
2011;148(2):139-147. doi:10.1016/j.ijcard.2009.10.032 

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25.  
Chikata A, Kato T, Sakagami S, et al. Optimal Force-Time Integral for Pulmonary Vein 
Isolation According to Anatomical  Wall Thickness Under the Ablation Line. J Am Heart 
Assoc. 2016;5(3):e003155. doi:10.1161/JAHA.115.003155 
26.  
Sun J-Y, Yun C-H, Mok GSP, et al. Left Atrium Wall-mapping Application for Wall 
Thickness Visualisation. Sci Rep. 2018;8(1):4169. doi:10.1038/s41598-018-22089-z 
27.  
Bishop M, Rajani R, Plank G, et al. Three-dimensional atrial wall thickness maps to 
inform catheter ablation procedures for atrial fibrillation. Eur  Eur pacing, 
arrhythmias, Card Electrophysiol  J  Work groups Card pacing, arrhythmias, Card Cell 
Electrophysiol Eur Soc Cardiol. 2016;18(3):376-383. doi:10.1093/europace/euv073 
28.  
Pambrun T, Combes S, Sousa P, et al. Contact-force guided single-catheter approach 
for pulmonary vein isolation: Feasibility, outcomes, and cost-effectiveness. Hear 
Rhythm. 2017. doi:10.1016/j.hrthm.2016.12.008 
29.  
Steven D, Reddy VY, Inada K, et al. Loss of pace capture on the ablation line: A new 
marker for complete radiofrequency lesions to achieve pulmonary vein isolation. Hear 
Rhythm. 2010. doi:10.1016/j.hrthm.2009.11.011 
30.  
Eitel C, Hindricks G, Sommer P, et al. Circumferential pulmonary vein isolation and 
linear left atrial ablation as a single-catheter technique to achieve bidirectional 
conduction block: The pace-and-ablate approach. Hear Rhythm. 2010. 
doi:10.1016/j.hrthm.2009.10.003 
31.  
Schaeffer B, Willems S, Sultan A, et al. Loss of Pace Capture on the Ablation Line 
during Pulmonary Vein Isolation versus “dormant Conduction”: Is Adenosine 
Expendable? J Cardiovasc Electrophysiol. 2015. doi:10.1111/jce.12759 
32.  
Jiang R, Chen M, Yang B, et al. Intraprocedural endpoints to predict durable 
pulmonary vein isolation: a randomized trial of four post-ablation techniques. EP Eur. 
2019. doi:10.1093/europace/euz301 
33.  
Kapur S, Barbhaiya C, Deneke T, Michaud GF. Esophageal injury and atrioesophageal 
fistula caused by ablation for atrial fibrillation. Circulation. 2017. 
doi:10.1161/CIRCULATIONAHA.117.025827 
34.  
Cappato R, Calkins H, Chen SA, et al. Prevalence and Causes of Fatal Outcome in 
Catheter Ablation of Atrial Fibrillation. J Am Coll Cardiol. 2009. 
doi:10.1016/j.jacc.2009.02.022 
35.  
Sánchez-Quintana D, Cabrera JA, Climent V, Farré J, De Mendonça MC, Ho SY. 
Anatomic relations between the esophagus and left atrium and relevance for ablation 
of atrial fibrillation. Circulation. 2005. doi:10.1161/CIRCULATIONAHA.105.551291 
36.  
Hu F, Zheng L, Liu S, et al. Avoidance of Vagal Response During Circumferential 
Pulmonary Vein Isolation: Effect of Initiating Isolation From Right Anterior 
Ganglionated Plexi. Circ Arrhythmia Electrophysiol. 2019. 
doi:10.1161/CIRCEP.119.007811 
37.  
Cabrera JA, Ho SY, Climent V, Fuertes B, Murillo M, Sánchez-Quintana D. 
Morphological evidence of muscular connections between contiguous pulmonary 
venous orifices: Relevance of the interpulmonary isthmus for catheter ablation in 
atrial fibrillation. Hear Rhythm. 2009. doi:10.1016/j.hrthm.2009.04.016 
38.  
Valles E, Fan R, Roux JF, et al. Localization of Atrial Fibrillation Triggers in Patients 
Undergoing Pulmonary Vein Isolation. Importance of the Carina Region. J Am Coll 
Cardiol. 2008. doi:10.1016/j.jacc.2008.07.025 
39.  
Udyavar AR, Chang SL, Tai CT, et al. The important role of pulmonary vein carina 
ablation as an adjunct to circumferential pulmonary vein isolation. J Cardiovasc 

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Electrophysiol. 2008. doi:10.1111/j.1540-8167.2008.01182.x 
40.  
Lin YJ, Tsao HM, Chang SL, et al. The distance between the vein and lesions predicts 
the requirement of carina ablation in circumferential pulmonary vein isolation. 
Europace. 2011. doi:10.1093/europace/euq500 
41.  
Squara F, Liuba I, Chik W, et al. Electrical connection between ipsilateral pulmonary 
veins: Prevalence and implications for ablation and adenosine testing. Hear Rhythm. 
2015. doi:10.1016/j.hrthm.2014.11.003 
 
 
 

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APPENDIX 1: Informed consent material 
ENGLISH VERSION 
 
PATIENT INFORMATION SHEET AND INFORMED CONSENT FOR A RESEARCH STUDY. 
 
Study title: Personalized Atrial Fibrillation Ablation with Ablation Index Adapted to Left Atrial Wall 
Thickness: The Ablate-by-LAW Study 
Name of the principal investigator: Antonio Berruezo, MD, PhD. 
Coordinating research center address: Teknon Medical Center (Barcelona, Spain) 
Número de teléfono de contacto: (+34) 93 290 62 51 
 
We ask that you participate in a research study. First, we want you to know that your participation is 
completely voluntary. This consent document contains important information about the research 
study. Please read it carefully before deciding to participate. No one can force you to participate and 
may leave the study at any time. If you agree to participate in it, you must sign this informed consent 
document. You will receive a signed copy of it to save. This study has been reviewed and approved 
by the Clinical Research Ethics Committee of the Hospital. 
 
1. WHAT IS THE OBJECTIVE OF THE STUDY? 
You are asked to participate in this study because you have a cardiac arrhythmia called atrial 
fibrillation (AF). Your medical team, according to the Arrhythmia Unit, believes that the best 
treatment for your disease is to conduct an electrophysiological study to ablate (eliminate) the 
arrhythmia by applying radiofrequency energy. Radiofrequency ablation of AF is a procedure that, by 
means of a catheter, seeks to apply radiofrequency energy in the junction areas (“ostia”) of the 
pulmonary veins with the left atrium until they are “electrically isolated”. This procedure has been 
routinely performed for more than 20 years, when it was described the origin of this arrhythmia at 
the ostia of the pulmonary veins. The effectiveness of an ablation procedure, per year, is around 80% 
for paroxysmal AF, in some cases requiring a second ablation procedure to isolate any point/s that 
could have reconnected any of the pulmonary veins with the atrium. 
Our objective, with the present study, is to demonstrate, on the one hand, that it is possible to adapt 
the level of radiofrequency energy applied at each point of the “ostia” of the pulmonary veins 
according to the thickness of the tissue, previously measured in a cardiac tomography (CT). Up to 
date, a series of standard parameters have been established with which radiofrequency is applied 
systematically but, just as not all patients do have the same body surface, e.g., they also do not have 
the same atria in terms of wall thickness. Applying standard parameters implies, in some cases, 
assuming a risk (very small, but present) of potentially lethal complications (e.g. perforation, atrio-
esophageal fistula) and, in others, not providing maximum benefit in terms of definitive electrical 
isolation of the pulmonary veins (and, therefore, assuming a higher recurrence rate). 
On the other hand, the study aims to achieve the same clinical benefits after ablation, minimizing the 
risk of complications by using only a single catheter (a procedure that we could consider “minimally 
invasive”) to apply radiofrequency and check the effective electrical isolation of the pulmonary veins. 
Among the risks of complications that are described for this type of procedure, and that could be 
minimized, are: Slight discomfort in the puncture area, or the appearance of a bruise that will almost 
always be reabsorbed spontaneously; less frequent there are other complications (phlebitis, venous 

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or arterial thrombosis, hemorrhage that requires transfusion, cardiac perforation with tamponade, 
pulmonary or systemic embolism, narrowing of the orifice opening of one of the pulmonary veins, 
diaphragmatic paralysis due to phrenic nerve injury or formation of a communication -fistula- 
between the left atrium and the esophagus), although some of them are serious and require urgent 
action (< 1 per 100); the risk of death is exceptional (< 1 per 1,000). 
 
2. WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY? 
If you decide not to participate in this research study, you will undergo the same tests and planned 
ablation procedure as it is routinely done in the hospital.  
 
3. WHAT ARE THE POSSIBLE BENEFITS OF PARTICIPATION IN THIS STUDY? 
The research team thinks that the participation in the study and, therefore, undergoing a 
personalized and minimally invasive AF ablation procedure, performed in a center with great 
experience and a very high number of procedures performed annually (> 350), in addition to not 
involving any additional risk, it will allow to report very useful information about the proposed 
protocol, permitting to evaluate the long-term efficacy of the ablation and, eventually, facilitating its 
future implementation by other Arrhythmia Units as a standard to benefit to other patients like you. 
 
4. IS PARTICIPATION IN THIS STUDY VOLUNTARY? 
Yes. Participation in this research study is voluntary. You can decide not to participate and you can 
also change your mind later and leave the study at any time, without affecting your clinical care. 
 
5. IF I PARTICIPATE IN THIS RESEARCH STUDY, HOW WILL MY PRIVACY BE PROTECTED? 
Access to your medical history and data derived from the procedure: 
The doctors, nurses and other center staff involved in this study will need to access your medical 
history, including medical records or previous results for the purposes of this study. By signing this 
consent form, you authorize them to this access and, if necessary, they can contact your GP or other 
health professionals to access your medical history during the study. In accordance with current 
regulations on data protection, you expressly consent to the access of your medical record data, as 
well as those resulting from your participation in the study in a personal data file under the 
responsibility of the Center. Access to your personal information will be restricted to the study 
doctor and his collaborators, health authorities and the Research Ethics Committee. By signing this 
consent, you consent to the use of the (previously anonymized) data derived from the pre-
procedural CT, in order to optimize the software used during the post-processing of the images 
(ADAS 3D LATM; ADAS 3D Medical SL, Barcelona, Spain), as well as to be able to develop a software 
platform that allows the automatization and standardization of the image post-processing. 
Confidentiality of information about your health: 
Your health information regarding the trial will be included in a database, but you will not be 
referred to by name or identified in any report or publication. 
Withdrawal from the study: 
If you decide to leave the study, tell your study doctor. In this case, the study staff will not collect 
new information about you. However, the information already collected may continue to be used as 
described above. If you have any questions about this topic, we recommend that you discuss it with 
your study doctor. 
Compliance with current legislation regarding confidentiality of your health information: 

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The research team is committed to ensuring compliance with the principles established in the local 
laws on Biomedical Research and on Protection of Personal Data and Guarantee of Digital Rights. 
Finally, the research team undertakes to facilitate the exercise by you of the rights of access, 
rectification, cancellation and opposition provided for the local Laws of Personal Data Protection and 
Guarantee of Digital Rights. The processing, communication and transfer of personal data of the 
participants will be in accordance with the provisions of the local Data Protection Regulations. If you 
have any questions about the handling of your data, you should contact your doctor at 
………..…………………………... In addition to the rights you already know (access, modification, opposition 
and cancellation of data) you can also limit the processing of data that is incorrect, request a copy or 
transfer the data that you have provided to the study to a third party (data portability). To exercise 
your rights, contact the principal investigator of the study. We remind you that the data cannot be 
deleted, even if you stop participating in the study, to guarantee the validity of the investigation and 
comply with the legal duties and medication authorization requirements. You also have the right to 
contact the Data Protection Agency if you are not satisfied. 
 
6. WHO SHOULD I TALK TO KNOW MY RIGHTS OR ASK QUESTIONS? 
Before signing this document, you should ask everything you do not understand. The study team will 
answer your questions before, during and after the study. If you think your question has not been 
fully answered or if you do not understand the answer, keep asking until you are satisfied. If you 
have any concerns or complaints about this study or the way it is being conducted, do not hesitate to 
discuss it with the study team. The phone numbers to contact the study team are listed on the first 
page of this document. 
 
I, ______________________________________________________________ (name and surname) 
 
• I have spoken with: ________________________________________________________________ 
• I have received enough information about the reason why I am asked to participate in the study. 
• I have been able to ask questions about the study. 
• I understand that my participation is voluntary. 
• I understand that I can withdraw from the study at any time, without having to give explanations, 
and without this having an impact on my medical care. 
• I consent to the collection and processing of my personal and medical data according to the 
specified conditions. 
• And I have expressed my agreement to participate. 
 
PARTICIPATING SUBJECT: 
 
__________________________________  
 
____________   
 
_________ 
Signature of participant  
 
 
 
 
   Date   
 
          Time 
 
INVESTIGATOR: 
 
__________________________________  
 
____________  
 
 _________ 
Signature of researcher  
 
 
 
        
   Date   
 
           Time 

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APPENDIX 2: Data collection sheet 
 
Name: ………………………………………………………………. Nº History: …………………………………. 
 
Date of birth: …………………………………………… Study code: ................. Center ………………………………. 
 
1. PROCEDURE AND PATIENT DATA  
 
FIRST OPERATOR……………………… Anesthetist…………………… EVALUATING OPERATOR……………………… 
DATE OF THE PROCEDURE...... /...... /...... 
HR ventilation Yes/No Rate ………… Tidal vol ………… 
 
Age: ......... Sex: Male //Female CHA2DS2-VASc = .... HAS-BLED:… Weight ..... Kg Height: ...... m  
CVRF: none // HBP // Dislipemia // DM-2 // Smoker // OSA // Sport (>4 h/week x 10 y) 
Underlying HD: none // Hypertensive // Ischemic // HOCM // Valvular // Other ......................... 
Conduction disturbances: none // LBBB // RBBB // LAHB // LPHB // Other: ................ 
Treatment: .................................................... OAC: ................................... Interrupted: Yes // NO // ¿? 
TEE LA Size (mm): ...........  LVEF: .......... Mitral annulus: ………... cm Other: ………………………………… 
PV anatomy: 4 indep.  // Left common // Right common // Accessory veins: ...................................... 
LAA Closure: YES // NO  Closure device type and size: …………………………………….  
 
2. PROCEDURAL DATA OF PVI: 
 
Number of femoral accesses: 1 / 2 (only 2 permitted in case of ICE use) 
Ablation lines adapted to fingerprinted esophagus: YES // NO (why: ………………………………..) 
Curve of the ablation catheter (SmartTouch®): Blue // Orange // Black 
Procedure time: ............ min  FAM + Merge time: ………… min  Transeptal time: ………. min 
Transeptal puncture technique:  TEE // ICE 
Fluoro time: ......... sec Fluoro dose: ……… mGy Fluoro dose (index): ….….. Gy/cm2 
RF power: anterior wall ......... W // posterior wall ......... W 
RF time: Right PV ......... s // Left PV ......... s 
Number of RF points: Left …..…  Right …….. 
Electrical cardioversion: Yes // No 
Acute complications: ………………………………………………………………. 
Was the procedure evaluated for the absence of gaps by the 2nd operator?: YES // NO 
 
 
 
 
 
 
 
 
 
 
 

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Select at which segment/s the subjacent rhythm was (entirely or predominantly) AF/AT: This is to 
assess in the future whether segments where rhythm disturbances are observed could influence 
catheter stability, quality of RF lesions and, ultimately, be a predictor of reconnections. 
 
 
 
Select at which segment/s FIRST PASS isolation was NOT ACHIEVED, an explain why: 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
 
 
Select at which segment/s ACUTE RECONNEXION was observed, an explain why: 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….……….………. 
 
 

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APPENDIX 3: Anesthetic protocol for ablation 
 
NOTE: This is a recommended anesthetic protocol, which may be adapted to the daily practice of 
the corresponding participating centers. The only essential requirement that must be met is to 
achieve a ‘high-rate, low-volume’ ventilation: respiratory rate > 40 rpm, and a tidal volume 
adapted to the patient's weight (in general, 3.5-4.0 ml/Kg). 
 
1. Standard Anesthetic Monitoring: 
 
• 
Non-invasive blood pressure (NIBP) an invasive blood pressure (IBP) 
• 
EKG 
• 
SpO2, inspired and tele-expiratory O2 
• 
Capnography: EtCO2 and inspired CO2 
• 
Standard mechanical ventilation monitoring: inspiratory peak pressure, airway plateau 
pressure, tele-expiratory pressure, tidal volume, respiratory rate, expired volume, pulmonary 
distensibility curve, arterial gasometry 
• 
Bispectral analysis for anesthetic depth (BIS), neuromuscular relaxation monitoring with 
train-of-four (TOF-Cuff Monitor®) 
• 
Optional brain Doppler: Peak middle cerebral artery flow (MCA), mean ACM flow and 
pulsatility index. 
 
2. Anesthetic induction: 
 
Midazolam: 1-2 mg, Fentanyl 2-3 mcg/Kg, Propofol 1.5-2 mg/Kg (holder), Rocuronium bromide: 0.6 
mg/kg. It can be considered as anesthetic inducer Etomidate 0.2-0.3 mg/Kg if there is severe 
ventricular dysfunction or any other reason that contraindicates the use of propofol. 
 
3. Endotracheal intubation: 
 
Once a TOF of 0% is corroborated, endotracheal intubation is performed. It is very important to 
consider the need to use difficult airway devices (DAV). There is some association between 
arrhythmias, OSAHS and difficult intubation. On-hand video-laryngoscope (Glidescope®) or similar 
device for advanced DAV management. 
 
4. Introduction of the Trans-esophageal Echocardiography (ETE) probe: 
 
Standard assessment, corroboration of preoperative data, discard thrombi in left atrial or atrial 
appendage, left atrial velocity measurement, interatrial septum analysis. Real-time progress guide of 
catheters and puncture in the appropriate area of the inter-atrial septum. Review of possible 
complications (rule out hemopericardium, cardiac valvular disease, etc.) 
 
5. Super-Protective Mechanical Ventilation Protocol with Short-Term Permissive Hypercapnia: 
 

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Once the patient is intubated, mechanical ventilation is established at Tidal Volume (Vt) of 8 mL/Kg 
and Respiratory Rate (RR) at 12-15 resp/min, FiO2 0.5 (oxygen/air) at 1 L/min for 10 min. Alveolar 
recruitment maneuvers are performed. Then change to the Super-Protective Pattern consisting of Vt 
3.5-4.0 mL/Kg and RR 45-55 resp/min; with FiO2 0.4, I:E relationship 1:1.5, and PEEP 0 mmHg. 
Systemic blood pressure and pulmonary systolic pressure, RV and LV function, tricuspid valve are 
evaluated. If there are no changes greater than 10% of baseline values, continue with Super-
Protective protocol. If PaCO2 greater than 60 mmHg is documented, a high flow of fresh gases 
(O2/FiO2 air 0,5 to 4 L/min) is administered to increase CO2 washing of the anatomical dead space. At 
the end of the Super-Protective protocol, alveolar recruitment maneuvers are performed before 
anesthetic awakening. 
 
Pre-operative relative contraindications to initiate the Super-Protective protocol: 
• 
Severe LV or RV dysfunction 
• 
Severe pulmonary hypertension 
• 
Moderate or severe CPOD with evidence of self-PEEP 
• 
Severe asthma 
• 
Chronic or severe metabolic acidosis 
• 
Hypercalcemia 
• 
Past history of severe migraines, neuralgia of trigeminal or atypical facial pain, 
hydrocephalus, patients with ventricular-peritoneal shunt valves, Parkinson's, epilepsy, 
vertigo, Ménière syndrome, narrow angle glaucoma, or stroke with considerable neurological 
sequelae. 
 
6. Maintenance of general anesthesia: 
 
Mixture of O2/air to FiO2 0.4 to 4 L/min, Sevoflurane 1-1.5Vol% or propofol 2 mcg/mL TCI (Schnider 
Model), Remifentanil 1.5-2.0 ng/mL TCI (Model Minto), Rocuronium 0.2 mg/Kg every 30 minutes. 
 
If PAIV decreases more than 20% with respect to the anesthetic pre-induction value, vasopressor 
boluses such as: Ephedrine 5-10mg, Phenylephrine 25-50 mcg or Norepinephrine 2.5-5 mcg can be 
used. 
 
It may be advisable to prepare phenylephrine perfusion at 0.1-0.5 mcg/Kg/min (10 mg in 100 mL of 
0.9% sol) to maintain perfusion pressure in case of hypotension. Alternatively, very diluted 
Noradrenaline (“Baby-Nora”: 4 mg/250 mL) infusion of 0.02-0.08 mcg/Kg/min can be used. 
 
7. Anesthetic weaning: 
 
After the TEE is removed (according to echocardiography protocol, after complications of 
interventional cardiological procedures or other types of incidence have been ruled out), gleras are 
gently aspirated and a state of residual muscle relaxation is corroborated. The safety target for 
reversal of neuromuscular relaxation is a 100% TOF, in case the patient presents TOF-ratio less than 
80%, Sugammadex 2 mg/Kg is administered. If TOF-ratio is greater than 80% and less than 100% it 
can be considered to use Sugammadex or neostigmine at 50 mcg/Kg. Paracetamol 1 g, 
dexketoprofen 50 mg and ondansetron 4 mg is given. 

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Once the patient has spontaneous breathing, adequate Vt and RR, SpO2 above 98% and BIS above 
80-90, is extinguished. It is transferred to a Semi-Critical Care Unit monitored or with nasal cannulas 
with FiO2 0.3 at 2 L/min. 
 

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APPENDIX 4: Representative figures 
 
Figure 1. Aspect of the left atrial (LA) anterior wall after MDCT imaging segmentation. An analysis 
of the LA wall thickness (LAWT) has been performed. The color map uses a color scale to depict a 
range of thickness; red being the thinnest (< 1 mm) and purple being the thickest (> 4 mm). Yellow 
(1-2 mm), green (2-3 mm) and blue (3-4 mm) will be considered the intermediate values. The full-
range color-coded LAWT map (left image) can be simplified using an adaptative binarization 
algorithm (right image) that helps selection the proper Ablation Index (AI) targets for each zone. 
 
 
 
 
Figure 2. Aspect of the LA posterior wall after MDCT imaging segmentation. Right image: Full-range 
color-coded LAWT map as seen in CARTO. Left image: Binarized color-coded LAWT map integrated in 
CARTO. 
 
 
 
 

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Figure 3. Integration of the anatomical position of the esophagus with respect to the LA posterior 
wall. The esophagus is segmented using the MDCT and its anatomical position is then integrated in 
CARTO, along with the LA anatomy (left image). The point-by-point distance between the esophagus 
body and the corresponding LA posterior wall is also calculated, color-coded and exported (right 
image), an information that can help selecting safer AI targets in this area. Lower image: The color-
coded distance map can be visualized in a semi-transparent mode that helps during RF applications.