Cardioinhibitory Reflex Syncope. Permanent Pacemaker Therapy or Cardioneuroablation? (PANACEA)

Institut d'Investigació Biomèdica de Bellvitge

Status: Enrolling

Conditions: Reflex Syncope

Treatments: Procedure: Cardioneuroablation; Device: Permanent pacemaker therapy

Study type: Interventional

Funder types: Other

Identifiers

NCT05855603

ICPS044/22

Details and patient eligibility

About

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.

Full 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.

Enrollment: 90 estimated patients

Sex: All

Ages: 40+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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90 participants in 2 patient groups

Cardioneuroablation

Experimental group

Description:

Bi-atrial ablation of GPs: CARDIONEUROABLATION (Group A, n = 45)

Treatment:

Procedure: Cardioneuroablation

Dual-chamber pacemaker

Active Comparator group

Description:

Implant of a dual-chamber CLS PACEMAKER\* (Group B, n = 45). \*or failing this, a dual-chamber pacemaker with RDR algorithm

Treatment:

Device: Permanent pacemaker therapy