Clinical trial NCT05855603: Cardioinhibitory Reflex Syncope. Permanent Pacemaker Therapy or Cardioneuroablation?
Official title: Recurrent Cardioinhibitory Reflex Syncope. PermANent PAcemaker Therapy or CardionEuroablation? A Multicenter RAndomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Reflex Syncope
Keywords: Cardioneuroablation
Permanent cardiac pacing
Vasovagal syncope
Lead sponsor: Institut d'Investigació Biomèdica de Bellvitge
Sponsor class: OTHER
First posted: 2023-05-11
Enrollment: 90
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Reflex syncope is the most common form of syncope. It can lead to injuries and affect quality of life. Nonpharmacological and medical therapies have limited effectiveness. In certain patients, cardiac pacing seem to be beneficial. More recently cardioneuroablation (CNA) has emerged as a novel therapy for reflex syncope. The investigators aim to determine whether CNA is more effective than cardiac pacing at reducing the rate of cardioinhibitory-type reflex syncope.

Detailed description: Reflex or neurally mediated syncope is the most common form of syncope in any setting and at all ages. It is associated with an autonomic imbalance in which vagal hyperactivity predominates, resulting in vasodilation or bradycardia or both, thereby producing a fall in global cerebral perfusion. It is divided into three types: vasovagal, situational, and carotid sinus syndrome.

Reflex syncope is benign and usually occurs in healthy people; however, very frequent syncope or events without prodromal symptoms can lead to injuries and affect long-term quality of life. Nonpharmacological and medical therapies proven effective in randomized clinical trials are scarce. In certain patients with frequent and burdensome cardioinhibitory reflex syncope, dual-chamber cardiac pacemakers seem to be beneficial. More recently, catheter-based cardiac autonomic modulation, or cardioneuroablation (CNA), has emerged as a novel therapy for reflex syncope, and positive results in small open-label cohort studies, and more recently in the first randomized study, have been reported.

The literature provides sufficient evidence that cardiac pacing should be considered in select patients affected by severe forms of reflex syncope with frequent recurrence and a high risk of injury. Current guidelines suggest that pacemaker therapy should be considered in patients aged more than 40 years with frequent recurrent reflex syncope when asystole has been documented, induced by either carotid sinus massage (CSM) or the head-up tilt test (HUTT), or recorded using an electrocardiogram (ECG) monitoring system (≥3 seconds if syncope, ≥6 seconds if asymptomatic).

Cardiac autonomic system modulation by endocardial ablation targeting atrial ganglionated plexi (GPs), or CNA, has been recently proposed as a novel therapy for reflex syncope.

Cardioneuroablation was introduced by Pachon et al. in 2005. In their initial study, twenty-one symptomatic patients with vasovagal syncope (6 patients), functional high-degree atrio-ventricular block (7 patients), and/or functional sinus node dysfunction (13 patients), were treated with CNA without complications. Follow-up for a mean of 9.2 months demonstrated symptom relief for all patients. After this initial description, several small studies and case series confirmed the efficacy of this approach. In a recent randomized prospective study, Piotrowski et al. documented that not only could CNA significantly reduce recurrences of syncopal episodes in patients with vasovagal syncope, it could also improve quality of life.

The primary strength of this therapeutic approach is that it avoids pacemaker implant, a procedure with a significant complication rate during long-term follow-up in a population composed predominantly of young and otherwise healthy patients.

The excellent results reproduced by many investigators worldwide suggest that CNA should be considered in patients with reflex syncope, especially those who display an important cardioinhibitory component of syncope. However, given that current evidence is limited, and the procedure carries potential risk, a randomized clinical trial to assess the true benefit of CNA and to compare this technique with pacemaker implantation should be performed. Results could guide the physician to the best current choice in this scenario.

Eligibility criteria: Inclusion Criteria:

* Aged more than 40 years.
* Having a 12-month history that includes at least two documented episodes of spontaneous reflex syncope or one episode that led to injury in addition to at least two presyncopal events, refractory to all recommended types of standard treatment.
* Bradycardia-syncope correlation (at least 3 seconds of asystole due to sinus arrest or atrio-ventricular block) confirmed by ECG during spontaneous syncope.
* If lacking ECG evidence during spontaneous syncope, a cardioinhibitory response (VASIS type 2A or 2B) on tilt test.
* Displaying indicators for pacing such as those suggested in the ESC guidelines for a class I recommendation for patients with reflex syncope.
* Significantly decreased quality of life due to syncope.
* Sinus rhythm on ECGs.
* Obtained written informed consent.

Exclusion Criteria:

* Intrinsic sinus or atrioventricular nodal disease with a proven indication for permanent pacemaker implantation.
* Evidence of structural heart disease.
* Contraindications to ablation in the right or left atrium.
* Life expectancy \<12 months.
* Lacking willingness to comply with the randomization procedure.

Primary outcomes:
measure: To determine the efficacy of CNA in the treatment of cardioinhibitory reflex syncope in comparison to pacemaker therapy.
timeFrame: 12 months
Secondary outcomes:
measure: To evaluate the incidence of complications in the short and long terms for CNA compared to pacemaker therapy
timeFrame: 1 and 12 months
measure: In patients undergoing CNA, evaluation of the degree of long-term reinnervation using the tilt table test (HUTT)
timeFrame: 1 and 12 months
measure: In patients undergoing CNA, evaluation of the degree of long-term reinnervation using the atropine test
timeFrame: 1 and 12 months
measure: To determine which of the 2 strategies, CNA or cardiac pacing, is superior at preventing a composite of syncope and presyncope
timeFrame: 12 months
measure: Evaluations of changes in quality of life, comparing the two therapies
timeFrame: 12 months
measure: To determine if CNA produces variations in the QTc interval
timeFrame: 12 months
measure: To determine if CNA produces variations in the burden of atrial or ventricular arrhythmias compared to pacemaker therapy
timeFrame: 12 months
Other outcomes:
Locations:
city: San Juan De Alicante
country: Spain
facility: Hospital Universitario San Juan de Alicante
state: Alicante
city: Castellón De La Plana
country: Spain
facility: Hospital Universitari General de Castellón
state: Castellón
city: Vigo
country: Spain
facility: Hospital Universitario Álvaro Cunqueiro de Vigo
state: Pontevedra
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario de Bellvitge
city: Girona
country: Spain
facility: Hospital Universitari Dr. Josep Trueta
city: Santa Cruz de Tenerife
country: Spain
facility: Hospital Universitario Nuestra Señora de Candelaria
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
Study officials:
affiliation: Hospital Universitario de Bellvitge
name: Rodolfo San Antonio, MD, PhD
role: STUDY_CHAIR
References:
citation: Pachon JC, Pachon EI, Cunha Pachon MZ, Lobo TJ, Pachon JC, Santillana TG. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results. Europace. 2011 Sep;13(9):1231-42. doi: 10.1093/europace/eur163. Epub 2011 Jun 28.
citation: Aksu T, Gupta D, D'Avila A, Morillo CA. Cardioneuroablation for vasovagal syncope and atrioventricular block: A step-by-step guide. J Cardiovasc Electrophysiol. 2022 Oct;33(10):2205-2212. doi: 10.1111/jce.15480. Epub 2022 Apr 9.
citation: Piotrowski R, Baran J, Sikorska A, Krynski T, Kulakowski P. Cardioneuroablation for Reflex Syncope: Efficacy and Effects on Autonomic Cardiac Regulation-A Prospective Randomized Trial. JACC Clin Electrophysiol. 2023 Jan;9(1):85-95. doi: 10.1016/j.jacep.2022.08.011. Epub 2022 Aug 28.