Efficacy of a Right-sided Ablation of the Anterior Ganglionated Plexus for Neurally Mediated Syncope
Efficacy of a Right-sided Ablation of the Anterior Ganglionated Plexus for Neurally Mediated Syncope
The third study on CardNM (CardNMH3 study) is a multicenter, double-blind, randomized trial
 with a sham control group investigating the efficacy and safety of a computed tomography
 (CT)-guided, right-sided ablation of the anterior ganglionated plexus to prevent recurrence
 of syncope in patients with neurally mediated syncope (NMS).

 The primary goal of the study is to determine whether a CT-guided, right-sided ablation of
 the anterior ganglionated plexus safely reduces the risk of recurrent episodes of syncope in
 patients with a history of recurrent NMS.

 Two-third of the patients will be randomized to the active arm and one-third to the control
 arm (sham).

 The study procedure is described in the 'detailed description' and 'intervention
 description'.

 Syncope burden, syncope occurrence and quality of life will be assessed by questionnaires at
 baseline and at 1, 3, 6 and 12 months. A 24-h rhythm registration will be performed at
 baseline and at 1-, 3- and 6-month follow-up to investigate the influence of the intervention
 on heart rate.

 The effect of CardNM on blood pressure and on chronotropic sinus node function will be
 evaluated in 2 additional substudies. Patients enrolled in the blood-pressure substudy will
 undergo a 24-h blood pressure monitoring at baseline and at 1, 3 and 6 months. Participants
 in the sinus node competence substudy will undergo a bicycle exercise test at baseline and at
 1, 3 and 6 months.

 Investigators aim to achieve complete follow-up for 110 patients who meet the study
 enrollment criteria. If syncope-free survival (primary endpoint) is significantly different
 between the 2 arms after the enrollment of fewer than 110 patients (minimum 55 patients),
 enrollment into the trial will be prematurely stopped. The study may also be terminated
 prematurely if safety concerns occur.
The efficacy of therapeutic strategies mentioned in the guidelines for patients with neurally
 mediated syncope (NMS) is limited. The first clinical study on cardiac denervation in humans
 was published in 2005. Derived from this first method, different approaches to
 cardioneuroablation (CNA) to treat NMS have been published. Such ablations are complex,
 bi-atrial, and extensive. Cardio-neuromodulation (CardNM) is a less extensive and right-sided
 approach to CNA, based on a tailored vagolysis of the sinoatrial node through partial
 ablation of the anterior right-ganglionated plexus. Evidence from a single-center,
 non-randomized, unblinded trial showed that CardNM was associated with a reduction in syncope
 burden exceeding 90%.

 This third study on CardNM (CardNMH3 study) is a multicenter, double-blind, randomized trial
 with a sham control group investigating the efficacy and safety of a computed tomography
 (CT)-guided, right-sided ablation of the anterior ganglionated plexus to prevent recurrence
 of syncope in patients with neurally mediated syncope.

 The primary goal of the study is to determine whether a CT-guided, right-sided ablation of
 the anterior ganglionated plexus safely reduces the risk of recurrent episodes of syncope in
 patients with a history of recurrent NMS.

 Two-thirds of the patients will be randomized to the active arm and one-third to the control
 arm (sham).

 In all patients, the endocardial site to potentially target during ablation will be annotated
 before the procedure by a target line (TL) on a computed tomographic image of the heart
 imported into the CARTO system (Biosense Webster, Diamond Bar, CA), as detailed in the
 'intervention description'.

 The study procedure will be performed under general anesthesia according to a standardized
 protocol. In all patients, a diagnostic electrophysiology study (EPS) and electroanatomical
 mapping of the right atrium and the surrounding veins will be performed first. This image
 will be merged with the CT image and the TL will be visible. Randomization will be performed
 electronically at this stage of the procedure.

 In patients assigned to the active arm, the TL will be targeted by ablation as detailed in
 the intervention description'.

 The ablation procedure is considered complete when one of the following conditions is
 fulfilled:

 1. 10 radiofrequency applications have been delivered;

 2. After 5 radiofrequency applications, the P-P interval is <70% of the baseline procedural
 P-P interval and remains >550 ms 5 min after the last radiofrequency application;

 3. ≥5 radiofrequency applications have been delivered and the operator estimates that no
 additional P-P interval shortening will be obtained by additional radiofrequency
 applications;

 4. 3 radiofrequency applications have been delivered and the P-P interval is <550 ms after
 the last radiofrequency application and remains stable after 5 min of waiting.

 In all patients, a pharmacological evaluation and new diagnostic EPS will be performed to
 further evaluate the sinus node and atrioventricular nodal intrinsic activity at the end of
 the procedure, either after the diagnostic part of the procedure in the sham group or after
 the ablation in the active arm.

 Syncope burden, syncope occurrence and quality of life will be assessed by questionnaires
 completed at baseline and at 1, 3, 6 and 12 months. A 24-h rhythm registration will be
 performed at baseline and at 1-, 3- and 6-month follow-up to investigate the influence of the
 intervention on heart rate.

 The effect of CardNM on blood pressure and on chronotropic sinus node function will be
 evaluated in 2 additional substudies. Patients enrolled in the blood-pressure substudy will
 undergo a 24-h blood pressure monitoring at baseline and at 1, 3 and 6 months. Participants
 in the sinus node competence substudy will undergo a bicycle exercise test at baseline and at
 1, 3 and 6 months.

 Investigators aim to achieve complete follow-up for 110 patients who meet the study
 enrollment criteria. If the syncope-free survival, the primary endpoint of the study, is
 significantly different between the 2 arms after the enrollment of fewer than 110 patients
 (minimum 55 patients), enrollment into the trial will be prematurely stopped. The study may
 also be terminated prematurely if safety concerns occur.
Inclusion Criteria:

 -  Patients must be in sinus rhythm and have ≥3 syncopes during the last 18 months* and a
 previous positive tilt table test (TTT) with a cardioinhibitory or mixed response
 (VASIS I, IIA or IIB classification).

 * syncopes occurring during TTT are not taken into account

 -  Patients have a 'preserved cholinergic SN reserve', defined as ≥20% sinus heart rate
 increment during a pharmacological test with atropine.

 Exclusion Criteria:

 -  <14 years age

 -  Any unstable medical condition, life expectancy <12 months

 -  Inability to provide consent or undergo follow-up

 -  Syncope due to a non-cardiac disease or due to an advanced neuropathy

 -  Moderate to severe valvular or subvalvular aortic stenosis or mitral stenosis

 -  Overt heart failure or left ventricular ejection fraction <45%

 -  Current pregnancy

 -  Chronotropic negative medications unless judged mandatory

 -  4 g amiodarone intake during the 2 months preceding enrollment

 -  Alternating RBBB and LBBB, HV interval >70 ms

 -  LBBB, bifascicular block (RBBB + LAHB, RBBB + LPHB)

 -  PR interval permanently >240 ms

 -  Pacemaker or automated implantable cardioverter defibrillator device

 -  Permanent AF, PAF or electrical cardioversion during the last 6 months

 -  Channelopathy

 -  Tilt table test with VASIS III response or with VASIS II response and AV-Block