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

Primary Purpose

Reflex Syncope

Status
Not yet recruiting
Phase
Not Applicable
Locations
Spain
Study Type
Interventional
Intervention
Cardioneuroablation
Permanent pacemaker therapy
Sponsored by
Institut d'Investigació Biomèdica de Bellvitge
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Reflex Syncope focused on measuring Cardioneuroablation, Permanent cardiac pacing, Vasovagal syncope

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Hospital Universitario San Juan de Alicante
  • Hospital Universitari General de Castellón
  • Hospital Universitario Álvaro Cunqueiro de Vigo
  • Hospital del Mar
  • Hospital de la Santa Creu i Sant Pau
  • Hospital Universitario de Bellvitge
  • Hospital Universitari Dr. Josep Trueta
  • Hospital Universitario Nuestra Señora de Candelaria
  • Hospital Universitari i Politècnic La Fe
  • Hospital Clínico Universitario Lozano Blesa

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Cardioneuroablation

Dual-chamber pacemaker

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
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
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
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
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
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

Full Information

First Posted
April 20, 2023
Last Updated
May 3, 2023
Sponsor
Institut d'Investigació Biomèdica de Bellvitge
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1. Study Identification

Unique Protocol Identification Number
NCT05855603
Brief Title
Cardioinhibitory Reflex Syncope. Permanent Pacemaker Therapy or Cardioneuroablation?
Acronym
PANACEA
Official Title
Recurrent Cardioinhibitory Reflex Syncope. PermANent PAcemaker Therapy or CardionEuroablation? A Multicenter RAndomized Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
June 2023 (Anticipated)
Primary Completion Date
June 2026 (Anticipated)
Study Completion Date
September 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Institut d'Investigació Biomèdica de Bellvitge

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Reflex Syncope
Keywords
Cardioneuroablation, Permanent cardiac pacing, Vasovagal syncope

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cardioneuroablation
Arm Type
Experimental
Arm Description
Bi-atrial ablation of GPs: CARDIONEUROABLATION (Group A, n = 45)
Arm Title
Dual-chamber pacemaker
Arm Type
Active Comparator
Arm Description
Implant of a dual-chamber CLS PACEMAKER* (Group B, n = 45). *or failing this, a dual-chamber pacemaker with RDR algorithm
Intervention Type
Procedure
Intervention Name(s)
Cardioneuroablation
Intervention Description
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.
Intervention Type
Device
Intervention Name(s)
Permanent pacemaker therapy
Intervention Description
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).
Primary Outcome Measure Information:
Title
To determine the efficacy of CNA in the treatment of cardioinhibitory reflex syncope in comparison to pacemaker therapy.
Description
Differences in 12-month syncope-free survival between the 2 groups
Time Frame
12 months
Secondary Outcome Measure Information:
Title
To evaluate the incidence of complications in the short and long terms for CNA compared to pacemaker therapy
Description
Pacemaker and CNA complication rates at 1 and 12 months
Time Frame
1 and 12 months
Title
In patients undergoing CNA, evaluation of the degree of long-term reinnervation using the tilt table test (HUTT)
Description
Changes in response to HUTT (type 1-3) at baseline, 1 and 12 months
Time Frame
1 and 12 months
Title
In patients undergoing CNA, evaluation of the degree of long-term reinnervation using the atropine test
Description
Changes in response (maximum heart rate) to atropine test at baseline, 1 and 12 months
Time Frame
1 and 12 months
Title
To determine which of the 2 strategies, CNA or cardiac pacing, is superior at preventing a composite of syncope and presyncope
Description
Differences in 12-month syncope- and presyncope-free survival between the 2 groups
Time Frame
12 months
Title
Evaluations of changes in quality of life, comparing the two therapies
Description
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
Time Frame
12 months
Title
To determine if CNA produces variations in the QTc interval
Description
The QTc interval will be measured at minimum, average and maximum heart rate using a 24-hour holter monitoring
Time Frame
12 months
Title
To determine if CNA produces variations in the burden of atrial or ventricular arrhythmias compared to pacemaker therapy
Description
Arrhythmias will be detected by implantable loop recorder in the group A (CNA) vs. by the pacemaker itself in group B
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rodolfo San Antonio, MD, PhD
Phone
932607500
Ext
2710
Email
rsanantonio@bellvitgehospital.cat
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rodolfo San Antonio, MD, PhD
Organizational Affiliation
Hospital Universitario de Bellvitge
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Universitario San Juan de Alicante
City
San Juan De Alicante
State/Province
Alicante
ZIP/Postal Code
03550
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
José Moreno-Arribas, MD, PhD
First Name & Middle Initial & Last Name & Degree
José Moreno-Arribas, MD, PhD
Facility Name
Hospital Universitari General de Castellón
City
Castellón De La Plana
State/Province
Castellón
ZIP/Postal Code
12004
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clara Gunturiz, MD
First Name & Middle Initial & Last Name & Degree
Clara Gunturiz, MD
Facility Name
Hospital Universitario Álvaro Cunqueiro de Vigo
City
Vigo
State/Province
Pontevedra
ZIP/Postal Code
36312
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Enrique García-Campo, MD
First Name & Middle Initial & Last Name & Degree
Enrique García-Campo, MD
Facility Name
Hospital del Mar
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ermengol Vallès, MD, PhD
First Name & Middle Initial & Last Name & Degree
Ermengol Vallès, MD, PhD
First Name & Middle Initial & Last Name & Degree
Ben Casteigt, MD
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
ZIP/Postal Code
08025
Country
Spain
Facility Name
Hospital Universitario de Bellvitge
City
Barcelona
ZIP/Postal Code
08907
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rodolfo San Antonio, MD, PhD
Phone
932607500
Ext
2710
Email
rsanantonio@bellvitgehospital.cat
First Name & Middle Initial & Last Name & Degree
Rodolfo San Antonio, MD, PhD
First Name & Middle Initial & Last Name & Degree
Ignasi Anguera, MD, PhD
First Name & Middle Initial & Last Name & Degree
Valentina Faga, MD
First Name & Middle Initial & Last Name & Degree
Marcos Rodríguez García, MD, PhD
Facility Name
Hospital Universitari Dr. Josep Trueta
City
Girona
ZIP/Postal Code
17007
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emilce Trucco, MD
First Name & Middle Initial & Last Name & Degree
Emilce Trucco, MD
First Name & Middle Initial & Last Name & Degree
Markus Linhart, MD, PhD
First Name & Middle Initial & Last Name & Degree
Eva M Benito, MD
Facility Name
Hospital Universitario Nuestra Señora de Candelaria
City
Santa Cruz de Tenerife
ZIP/Postal Code
38010
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Luis Álvarez-Acosta, MD
First Name & Middle Initial & Last Name & Degree
Luis Álvarez-Acosta, MD
First Name & Middle Initial & Last Name & Degree
Diego Valdivia, MD
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maite Izquierdo, MD, PhD
First Name & Middle Initial & Last Name & Degree
Maite Izquierdo, MD, PhD
Facility Name
Hospital Clínico Universitario Lozano Blesa
City
Zaragoza
ZIP/Postal Code
50009
Country
Spain
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Javier Ramos-Maqueda, MD, PhD
First Name & Middle Initial & Last Name & Degree
Javier Ramos-Maqueda, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
21712276
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.
Results Reference
result
PubMed Identifier
35362165
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.
Results Reference
result
PubMed Identifier
36114133
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.
Results Reference
result

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Cardioinhibitory Reflex Syncope. Permanent Pacemaker Therapy or Cardioneuroablation?

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