NeuroArrhythmias Area Registry of AIAC (NAARA) Syncope-Asystole Latency Time in Tilt Table Test (SALT-TILT) Study
Conditions: Syncope, Pacemaker, Asystole, Neurally Mediated Syncope
Sponsor: Azienda Ospedaliera di Bolzano

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NeuroArrhythmias Area Registry of AIAC (NAARA) 
Syncope-Asystole Latency Time in Tilt Table Test 
(SALT-TILT) study 
 
 
Principal Investigators: 
Unterhuber Dr. Matthias 
Tomaino Dr. Marco 
Central hospital of Bolzano, Department of Cardiology 
Via Lorenz Böhler, 5, 39100 Bolzano BZ 
 
Co-Investigators: 
Strano Dr. Stefano 
Sette Dr.ssa Antonella 
Marcheselli Dr. Andrea 
Di Maggio Dr.ssa Debora 
Attena Dr. Emilio 
Gallo Dr. Antonio 
 
 
 
 
 
 
Protocol Version 1.2 
06.12.2023 

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Summary 
1. Synopsis ......................................................................................................... 2 
2. Scientific background ........................................................................................ 4 
4. Primary objective ............................................................................................. 4 
5 Methods ........................................................................................................... 4 
5.1 Design and trial population ........................................................................... 4 
5.2.1 Primary endpoint ................................................................................... 5 
5.2.2 Secondary endpoints .............................................................................. 5 
5.2.3 Adverse events ..................................................................................... 5 
.3 
Inclusion and exclusion criteria ..................................................................... 5 
• 
Inclusion criteria ..................................................................................... 5 
• 
Patients eligible for invasive treatment according to the ESC Guidelines for 
pacing 2021 .................................................................................................. 5 
• 
Written informed consent ......................................................................... 5 
5.3.2 Exclusion criteria ................................................................................... 5 
5.4 Monitoring .................................................................................................. 6 
5.4.1 Hemodynamic parameters ...................................................................... 6 
5.4.2 Other parameters and data assessed ....................................................... 6 
5.4.4 Video Tilt Table Test procedure ................................................................ 7 
5.5 Follow-up ................................................................................................... 8 
6. Statistics ......................................................................................................... 9 
6.1 Statistical Analysis ....................................................................................... 9 
7. Organisatory .................................................................................................... 9 
7.1 Investigating center ..................................................................................... 9 
7.2 Clinical Investigation .................................................................................... 9 
8. Ethical Aspects ................................................................................................ 10 
8.1 General aspects and risk-benefit relationship .................................................. 10 
8.2 Informed Consent ....................................................................................... 10 
8.3 Documentation of the data assessed ............................................................. 11 
8.4 Adverse events .......................................................................................... 11 
8.5 Ethic commission ........................................................................................ 11 
8.6 Insurance .................................................................................................. 11 
10. Signature ...................................................................................................... 11 
11. Literature ..................................................................................................... 12 
 
 
 

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1. SYNOPSIS 
 
Title 
NeuroArrhythmias Area Registry of AIAC (NAARA) Syncope-Asystole 
Latency Time in Tilt Table Test (SALT-TILT) study 
Background 
Syncope is a common presenting condition. Pacemaker implantation 
can significantly reduce syncope recurrence in reflex syncope. Still, 
despite accurate selection, a substantial part of the patients treated 
with pacemaker suffers of syncope recurrence. It is thought that an 
accentuated vasodepressive component could hinder the effective 
pacing in patients by disallowing adeguate cerebral perfusion during 
the reflex, relativizing the anti-bradycardia function of the 
pacemaker to prevent syncope. 
Objectives 
The aim of this study is to compare the Syncope Asystole Latency 
time (SALT) using Video Tilt Table Testing (VTTT) to assess the time 
intercourse between the effective transitory loss of evoked by VTTT 
and the asystole recorded on ECG during the test in patients eligible 
for invasive treatment. To date, it is not known if there is a 
connection between the time when a patient faints to the occurrence 
of asystole in the ECG and its reversibility when treated with a 
pacemaker. Thus, patients with syncope recurrence despite optimal 
guideline – directed therapy will be compared to patients without 
recurrence to explore the existence of a potential SALT cut-off. 
Endpoints 
Primary:  
• 
Syncope – asystole latency time (SALT) in patients with 
syncope recurrence despite guideline-directed invasive 
treatment 
Secondary:  
• 
Recurrence of syncope in patients treated with different 
pacemaker configurations (DDD-CLS, DDD-RDR, DDDrr) and 
Neurocardioablation 
• 
Recurrences of syncope in treated patients selected by loop 
recorder, Carotid Sinus Massage and VTTT 
Sample size 
Prospective, observational study with first analysis when 68 patients 
reached 12 months of follow up 
Design 
Prospective, observational, multicenter study 
Patients with severe syncope presentation and guideline-directed 
workup and treatment are followed up for 24 months  

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Inclusion 
criteria 
• 
Patients with severe reflex syncope and eligible for invasive 
treatment strategies according to the ESC Guidelines for pacing 
2021[6] 
Exclusion 
criteria 
• 
Other condition which explains syncope cause other than reflex 
syncope 
• 
Structural heart disease (valvular, ischaemic, cardiomyopathies) 
• 
Pregnancy 
Institution 
Ospedale centrale di Bolzano- 
Cardiologia 
Via Lorenz Böhler, 5, 39100 Bolzano BZ 
Investigators 
Principal Investigator 
Dr. Marco Tomaino 
Ospedale centrale di Bolzano- 
Cardiologia 
Via Lorenz Böhler, 5, 39100 Bolzano BZ  
Tel:  
Email: marco.tomaino@sabes.it 
 
Co-Investigators 
Unterhuber Dr. Matthias 
Sette Dr.ssa Antonella 
Marcheselli Dr. Andrea 
Di Maggio Dr.ssa Debora 
Attena Dr. Emilio 
Gallo Dr. Antonio 
 
Time 
schedule 
 
• 
Start 10/2023 
• 
First analysis (64 patients, 12 months FU) 11.2025 
 
 
 
 
 

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2. SCIENTIFIC BACKGROUND 
Syncope is a common leading affection and is responsible for 1-3% [1-2] of the 
presentations in emergency departments and up to 3% of inpatient admissions. The 
phenomenon of syncope poses often a diagnostic and therapeutic challenge for the 
attending physician and is often misdiagnosed or underdiagnosed. After an accurate 
evaluation, patients can be treated with pacemaker implantation when the syncope cause 
is a cardioinhibition with documented asystole during the syncopal event according to the 
current ESC Guidelines for pacing 2021 [6]. When accurately selected, patients benefit 
from pacemaker therapy with a significant reduction of syncope recurrence in the follow 
up. However, a substantial portion of the patients (approx. 25%) experience recurrence 
of syncope despite optimal pacemaker therapy[3,4]. The underlying mechanism is not 
well understood and object of the current study.  
 
3. Definitions 
• 
Syncope: Transient Loss of Consciousness due to a cerebral hypoperfusion 
characterized by a rapid onset, short duration and spontaneous and complete 
recovery of the affected person. 
 
 
4. PRIMARY OBJECTIVE 
The main goal of the study is to evaluate the time elapsed between the T-LOC during Video 
Tilt Table Testing and the asystole at the ECG using a national registry and to assess its 
predictive value in patients undergoing invasive treatment. The hypothesis is that a 
vasodepressive component could lessen the effect of pacing in a patient, leading to cerebral 
hypoperfusion and syncope despite maintaining a stable rhythm. 
5 METHODS 
5.1 Design and trial population 
• 
Prospective, multi-center observational study with 2 year follow-up of patients eligible 
for invasive treatment of reflex syncope. 
 
 
 
 

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5.2 Endpoints and safety 
5.2.1 Primary endpoint 
• 
Syncope to asystole latency time (SALT) and its prognostic value regarding freedom of 
syncope recurrence after pacemaker implantation 
5.2.2 Secondary endpoints  
• 
Recurrence of syncope in patients treated with different pacemaker configurations 
(DDD-CLS, DDD-RDR, DDDrr) and Neurocardioablation 
• 
Recurrences of syncope in treated patients selected by CSM or loop recorder and 
negative or positive vasodepressive VTTT 
 
5.2.3 Adverse events  
• 
Acute: any major procedure-related adverse cardiac events or pacemaker-related 
complications  
 
Follow-up: 24 months 
• 
Assessment of all cardiac events leading to hospitalization or change of treatment 
strategy 
• 
Recurrence of syncope  
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Inclusion and exclusion criteria 
• 
Inclusion criteria 
• 
Patients eligible for invasive treatment according to the ESC Guidelines for pacing 2021 
• 
Written informed consent 
 
5.3.2 Exclusion criteria 
• 
Other condition which explains syncope cause other than reflex syncope 
• 
Structural heart disease (valvular, ischaemic, cardiomyopathies) 
• 
Pregnancy 
• 
Patient denial to be recorded on video during tilt table test 
 
5.3.3 Inclusion process 
The inclusion of patients should happen at any time when a patient is guided to the doctor’s 
attention for syncope. All patients with reflex syncope eligible for an invasive treatment 
according to the ESC Guidelines for pacing 2021 should be included. If after guideline-
directed implantable loop recorder insertion no cardioinhibition has been made, the patient 

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is included automatically in the registry. Informed consent must be obtained and can be 
withdrawn at any time. In case of consent withdrawal, the collected data will be removed 
from the database. 
5.4 Monitoring 
5.4.1 Hemodynamic parameters 
Systolic and diastolic arterial blood pressure (SBP/DBP) as well as heart rate must be 
measured in all patients according to the ESC Guidelines.  
5.4.2 Other parameters and data assessed 
Baseline data: comorbidities are assessed (diabetes mellitus, renal failure, valve 
disease, hyperthyroidisms etc.) and echocardiography performed to assess eligibility 
and to exclude other causes of syncope. 
 
Medication received, i.e., current antihypertensive medication. 
 
Laboratory parameters: serum creatinine (Crea), potassium (K), thyroid-stimulating 
hormone (TSH), blood count (BC - leucocytes, erythrocytes, hemoglobin, 
thrombocytes) have to be documented according to the standard of care protocols. 
 
Electrocardiogram (12-lead): All patients have to undergo at least one 12-lead 
Electrocardiogram in the context of syncope-workup according to the ESC Guidelines 
for pacing 2021. 
 
Procedural 
data: 
Invasive 
treatment 
(pacemaker 
implantation 
and/or 
neurocardioablation) must be documented with pacemaker modus (e.g. DDD), and 
procedure data has to be documented according to the local standard of care 
protocol. 
 
Complications: proactive assessment of possible complications related to 
pacemaker implantation or neurocardioablation (any physician on the ward as well 
as investigators). 
 
 
 
 
 

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5.4.3 Parameters assessment upon follow-up 
Study 
assessments 
 
Baseline* 
post 
at dis- 
charge 
12M 
 
(phone call or 
clinical 
esamination) 
24M 
 
 
(phone call or 
clinical esamination) 
Consent Process 
X 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
Medical and 
Cardiovascular  
History 
X 
 
 
X 
X 
Medications 
X 
 
X 
 
 
Physical 
Assessment and 
Office Blood 
Pressure 
X 
 
X 
 
 
12-Lead ECG 
X 
 
 
 
 
Serum 
creatinine1) 
X 
 
 
 
 
Estimated GFR1) 
X 
 
 
 
 
Blood sample 
X 
 
 
 
 
Adverse Event 
 
X 
X 
X 
X 
Withdrawal/ 
Termination 
 
X 
X 
X 
X 
 
5.4.4 Video Tilt Table Test procedure 
The Video-Tilt-Table-Test set-up uses a personal computer (PC) to capture screen video 
data from a non-invasive-beat-to-beat (NIBTB) hemodynamic blood pressure (BP) device, 
combined with video recording of a patient. Using this technique, TTT can be performed 
with any routine protocol with the addition of video information of the patient enabling the 
physician to review the images and to assess the exact moment of T-LOC of the patient in 
concomitance to the ECG tracing. This novel technique does not pose new risks or novel 
interventions and does not affect the patient.  
 
 

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5.4.4 Pacemaker implantation for reflex syncope 
Permanent pacemaker therapy may be effective if asystole is a dominant 
feature of reflex syncope. Establishing a relationship between symptoms and 
bradycardia should be the goal of the clinical evaluation of patients with 
syncope and a normal baseline ECG. The efficacy of pacing depends on the 
clinical setting. In patients with reflex syncope, cardiac pacing should be 
considered in severe forms of reflex syncope with frequent recurrences 
associated with a high risk of injury. Therefore, the ESC guidelines suggest to 
implant a pacemaker in these individuals selected by carotid sinus massage, 
tilt table testing and / or loop recorder in class IA.  
Pacemaker implantation is a procedure commonly used to treat bradycardia 
episodes, consisting in the insertion of pacing leads into the heart chambers, 
connected to a generator with a microcomputer which is inserted under the 
skin in the subclavian region.  
 
Study workflow 
 
Figure: Flow chart of the study. VTTT: Video Tilt Table Test, CSM: Carotid Sinus Massage, 
ILR: Implantable Loop Recorder. 
5.5 Follow-up  
All patients are followed at 12 and 24 months after the index visit.  
 

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6. STATISTICS 
6.1 Statistical Analysis 
Normality of data distribution is tested with the Shapiro–Wilk test. Normally distributed 
continuous variables will be tested using Student’s t-test or 
if non-normally distributed medians with interquartile range. Mann–Whitney U test will be 
used for non-normally distributed data, while Fisher’s exact test will be used for 
dichotomous variables. Receiver Operating Curves plotted to discover potential ideal cut-
offs and Kaplan–Meier estimates will be used to estimate hazard ratios. 
 
6.2 Sample size 
Since the explored syncope-to-asystole time has never been assessed before, power 
calculations to estimate the needed sample size are not easily feasible. However, the 
combination of Video-assisted Tilt Testing and precise ECG tracing during syncope allows 
for very precise syncope-to-asystole time measurements. Therefore, assuming values of 
-5 seconds to 5 seconds of syncope-to-asystole time seems reasonable. Starting from a 
25% recurrence rate in pacemaker-treated cohorts [3,4], allowing a 95% minimum 
acceptable probability of preventing Type I errors and 80% power and a standard 
deviation of ±10s, 16 patients with recurrences are needed. Thus, 16 patients with 
recurrences +48 patients without recurrences should suffice to be hypothesis generating. 
Therefore, a first analysis will be carried out at the reach of 64 included patients. 
7. ORGANISATORY 
7.1 Investigating center 
Südtiroler Sanitätsbetrieb - Azienda Sanitaria dell’Alto Adige 
Lorenz Böhler-Straße 5 39100 Bozen - Via Lorenz Böhler 5 39100 Bolzano 
Sekretariat/Segreteria (Gebäude W/Padiglione W) 0471909950-9951-9985 
Sekretariat/Segreteria (Hauptgebäude/Padiglione Centrale) 0471908335 
7.2 Clinical Investigation 
Principal Investigator 
Dr. Marco Tomaino 
Ospedale centrale di Bolzano- 
Cardiologia 
Via Lorenz Böhler, 5, 39100 Bolzano BZ  
Tel:  
Email: marco.tomaino@sabes.it 
 

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Co-Investigators 
Unterhuber Dr. Matthias 
Strano Dr. Stefano 
Sette Dr.ssa Antonella 
Marcheselli Dr. Andrea 
Di Maggio Dr.ssa Debora 
Attena Dr. Emilio 
Gallo Dr. Antonio 
 
The investigators have a clear track record of designing, conducting and analyzing clinical 
trials and fulfill the required standards.  
 
Participating physicians 
All physicians working at the cardiac care unit as well as all electrophysiologists trained 
adequately to pursue syncope work-up. 
 
 
Time schedule 
• 
Start 10/2023 
8. ETHICAL ASPECTS  
8.1 General aspects and risk-benefit relationship 
The trial is conducted according to: 
• 
Requirements of GCP (Good Clinical Practice) 
• 
And according to principle of the Declaration of Helsinki.  
 
As pacemaker implantation strategy is a standard treatment option the risk- benefit ratio 
can be considered as positive. Furthermore, the treatment is in line with the current 
guidelines and does not introduce new treatment options to the syncope work-up. 
8.2 Informed Consent 
After screening for eligibility, patients are thoroughly and comprehensively informed about 
all aspects of the study, specific potential complications and potential disadvantages. In 
particular, the patient will be assured that consenting for participation in the study can be 
withdrawn at any time. Further, the refusal of participation will not have any influence on 
further treatment of the patient. Appropriate consenting includes signing of the attached 
consent form by both the patient and consenting physician (attached). 

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8.3 Documentation of the data assessed 
All clinical data, results of diagnostic tests and procedures and patients’ consent forms 
are archived within the Case Reporting Forms. The content of the Case Reporting Forms 
should be consistent with patient’s clinical notes.  All patients’ data will be anonymized 
and electronically saved. No patients’ names, birthdate, or initials will be used. All data 
will be used only for the purpose of the study and will be accessible only for the 
investigators. Data will be treated according to the legal requirements concerning the 
confidential medical communication. Data will be kept for 10 years after study 
completion. 
8.4 Adverse events 
Adverse events will be assessed and documented in the patient’s clinical notes at any time 
and in the case reporting for at the follow-ups.  
8.5 Ethic commission 
The protocol and patients’ consent form will be submitted for approval to the local ethics 
committee of the University of Bozen. All relevant changes to the protocol have to be 
approved by the ethics committee. 
8.6 Insurance 
Concerning the general procedural risk, the individual patients are insured in the the 
context of the stay in hospital by the hospital operator.  
 
 
10. SIGNATURE 
 
Protocol approved. 
 
 
Bolzano, 14/07/2023 
 
 
 
 
Dr. Marco Tomaino, Dr. Matthias Unterhuber,  
 
 

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11. LITERATURE 
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analysis of a metropolitan area registry. Neuroepidemiology. 2002 Nov-Dec;21(6):287-
91. doi: 10.1159/000065525. PMID: 12411731. 
2. Olde Nordkamp LR, van Dijk N, Ganzeboom KS, Reitsma JB, Luitse JS, Dekker LR, 
Shen WK, Wieling W. Syncope prevalence in the ED compared to general practice and 
population: a strong selection process. Am J Emerg Med. 2009 Mar;27(3):271-9. doi: 
10.1016/j.ajem.2008.02.022. PMID: 19328369. 
3. Brignole M, Russo V, Arabia F, Oliveira M, Pedrote A, Aerts A, Rapacciuolo A, Boveda 
S, Deharo JC, Maglia G, Nigro G, Giacopelli D, Gargaro A, Tomaino M; BioSync CLS trial 
Investigators. Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. 
Eur Heart J. 2021 Feb 1;42(5):508-516. doi: 10.1093/eurheartj/ehaa936. PMID: 
33279955; PMCID: PMC7857694. 
4. Brignole M, Donateo P, Tomaino M, Massa R, Iori M, Beiras X, Moya A, Kus T, Deharo 
JC, Giuli S, Gentili A, Sutton R; International Study on Syncope of Uncertain Etiology 3 
(ISSUE-3) Investigators. Benefit of pacemaker therapy in patients with presumed 
neurally mediated syncope and documented asystole is greater when tilt test is negative: 
an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-
3). Circ Arrhythm Electrophysiol. 2014 Feb;7(1):10-6. doi: 10.1161/CIRCEP.113.001103. 
Epub 2013 Dec 12. PMID: 24336948. 
5. Tomaino M, Romeo C, Vitale E, Kus T, Moya A, van Dijk N, Giuli S, D'Ippolito G, Gentili 
A, Sutton R; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) 
Investigators. Physical counter-pressure manoeuvres in preventing syncopal recurrence 
in patients older than 40 years with recurrent neurally mediated syncope: a controlled 
study from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3)†. 
Europace. 2014 Oct;16(10):1515-20. doi: 10.1093/europace/euu125. Epub 2014 Jun 6. 
PMID: 24906609. 
6. Glikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, Barrabés 
JA, Boriani G, Braunschweig F, Brignole M, Burri H, Coats AJS, Deharo JC, Delgado V, 
Diller GP, Israel CW, Keren A, Knops RE, Kotecha D, Leclercq C, Merkely B, Starck C, 
Thylén I, Tolosana JM; ESC Scientific Document Group. 2021 ESC Guidelines on cardiac 
pacing and cardiac resynchronization therapy. Eur Heart J. 2021 Sep 14;42(35):3427-
3520. doi: 10.1093/eurheartj/ehab364. Erratum in: Eur Heart J. 2022 May 
1;43(17):1651. PMID: 34455430. 
7. Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, Fedorowski A, Furlan 
R, Kenny RA, Martín A, Probst V, Reed MJ, Rice CP, Sutton R, Ungar A, van Dijk JG; ESC 
Scientific Document Group. 2018 ESC Guidelines for the diagnosis and management of 

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syncope. Eur Heart J. 2018 Jun 1;39(21):1883-1948. doi: 10.1093/eurheartj/ehy037. 
PMID: 29562304.