Cardioinhibitory Reflex Syncope. Permanent Pacemaker Therapy or Cardioneuroablation?

Study Overview
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Brief Summary
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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
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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.

Official Title
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Recurrent Cardioinhibitory Reflex Syncope. PermANent PAcemaker Therapy or CardionEuroablation? A Multicenter RAndomized Clinical Trial

Conditions
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Reflex Syncope

Intervention / Treatment
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* Procedure: Cardioneuroablation
* Device: Permanent pacemaker therapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cardioneuroablation<br>Bi-atrial ablation of GPs: CARDIONEUROABLATION (Group A, n = 45) | Procedure: Cardioneuroablation<br>* Ganglionated plexi will be localized using an empirical anatomical approach and/or a fractionated electrogram-based strategy. Point-by-point ablation will be performed using radiofrequency energy and an irrigated tip contact force sensing ablation catheter in a power control mode (35-50 W; AI, 350-500; LSI, 4.5-5.5). The right superior GP (RSGP), left superior GP (LSGP) and posterior left GP (PMLGP) will be targeted during CNA. Radiofrequency applications in other GPs will be left at the discretion of the operator. At the end of the procedure, another EP study and atropine test will be performed. Clinical endpoints for completion of the CNA will be: 1) a HR increase >20% if the CNA was performed under general anesthesia/deep sedation; 2) improved electrophysiological parameters; 3) significant reduction in atropine response (HR increase <10% after atropine); and 4) in case of using extracardiac vagal stimulation, lack of response.<br>|
| Active Comparator: Dual-chamber pacemaker<br>Implant of a dual-chamber CLS PACEMAKER* (Group B, n = 45). *or failing this, a dual-chamber pacemaker with RDR algorithm | Device: Permanent pacemaker therapy<br>* All patients in the pacemaker group will receive a dual-chamber pacemaker that has the ability to be programmed in the DDD-CLS algorithm mode (or failing this, a dual-chamber pacemaker with RDR algorithm).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the efficacy of CNA in the treatment of cardioinhibitory reflex syncope in comparison to pacemaker therapy. | Differences in 12-month syncope-free survival between the 2 groups | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the incidence of complications in the short and long terms for CNA compared to pacemaker therapy | Pacemaker and CNA complication rates at 1 and 12 months | 1 and 12 months | 
| In patients undergoing CNA, evaluation of the degree of long-term reinnervation using the tilt table test (HUTT) | Changes in response to HUTT (type 1-3) at baseline, 1 and 12 months | 1 and 12 months | 
| In patients undergoing CNA, evaluation of the degree of long-term reinnervation using the atropine test | Changes in response (maximum heart rate) to atropine test at baseline, 1 and 12 months | 1 and 12 months | 
| To determine which of the 2 strategies, CNA or cardiac pacing, is superior at preventing a composite of syncope and presyncope | Differences in 12-month syncope- and presyncope-free survival between the 2 groups | 12 months | 
| Evaluations of changes in quality of life, comparing the two therapies | Using the Impact of Syncope on Quality-of-life questionnaire (University of Calgary). It consists of 9 questions with 6 choices and 3 questions with 5 choices. The overall maximum score is 57. The higher the score, the poorer the QOL is | 12 months | 
| To determine if CNA produces variations in the QTc interval | The QTc interval will be measured at minimum, average and maximum heart rate using a 24-hour holter monitoring | 12 months | 
| To determine if CNA produces variations in the burden of atrial or ventricular arrhythmias compared to pacemaker therapy | Arrhythmias will be detected by implantable loop recorder in the group A (CNA) vs. by the pacemaker itself in group B | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardioneuroablation, Permanent cardiac pacing, Vasovagal syncope