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Comparison of the Efficacy and Safety of Cardioneuroablation to Permanent Pacing in Patients With an Implanted Pacemaker for Symptomatic Bradycardia. (GENTLE-PACE)

4

4th Military Clinical Hospital with Polyclinic, Poland

Status

Enrolling

Conditions

Bradycardia
Syncope

Treatments

Diagnostic Test: Extracardiac vagal stimulation
Diagnostic Test: Anamnesis
Diagnostic Test: Implantable loop recorder check
Diagnostic Test: Invasive electrophysiological study
Diagnostic Test: Pacemaker check
Procedure: Cardioneuroablation
Procedure: Implantation of the implantable loop recorder
Procedure: Redo cardioneuroablation
Diagnostic Test: Holter ECG

Study type

Interventional

Funder types

Other

Identifiers

NCT05896592
03/2023

Details and patient eligibility

About

Background Sinus node dysfunction (SND) and atrioventricular block (AVB) are significant diagnostic and therapeutic problems. The primary method of their treatment is cardiac pacemaker implantation (PM). Although PM remains the main therapeutic approach for most patients with SND/AVB, long-term PM therapy can be associated with various limitations, complications, and the need for device and electrode replacement. There is increasing evidence for the effectiveness of an alternative approach to functional bradycardia associated with excessive vagal activation - cardioneuroablation (CNA). The method leads to the alleviation or complete resolution of bradycardia symptoms, as well as reflex syncope, providing an opportunity to discontinue PM therapy.

Primary aims

1.Evaluation of the efficacy and safety of CNA as a therapy allowing for discontinuation of PM therapy in patients with SND or AVB.

Secondary aims

  1. Evaluation of the efficacy and safety of CNA as a therapy allowing for the optimization of PM therapy in patients with SND and AVB.
  2. Development of a diagnostic algorithm allowing for the identification of patients with SND and/or AVB suitable for CNA and discontinuation of PM and TLE therapy.
  3. In addition, blood samples will be collected for future analysis and biobanking.

Methodology

Inclusion criteria

  1. Patients up to 50 years old who underwent pacemaker implantation due to sinus node and/or atrioventricular node dysfunction
  2. Positive response to atropine test
  3. Age between 18-65 years
  4. Signed informed consent to participate in the study

Exclusion criteria

  1. Own heart rate <30/min
  2. Fainting after pacemaker therapy initiation
  3. Persistent and sustained atrial fibrillation
  4. History of myocarditis
  5. History of myocardial infarction
  6. History of cardiac surgery
  7. History of ablation procedures
  8. Congenital heart defects
  9. Congenital atrioventricular block
  10. Neuromuscular and neurodegenerative diseases
  11. Indications for expanding the pacemaker system to ICD/CRT-D
  12. Pregnancy
  13. Renal insufficiency with GFR <30 ml/min/1.73m2
  14. Age below 18 and above 65 years
  15. HAS-BLED score >/= 3 points

Randomization, study scheme Qualified patients will be randomly assigned (1:1:1) to group 1 undergoing first-stage invasive electrophysiology study (EPS), extracardiac vagus nerve stimulation (ECVS) and CNA with continued PM therapy and implantable loop recorder (ILR) implantation, to group 2 undergoing first-stage EPS and ECVS with continued PM therapy, ILR implantation, and no CNA, and to group 3 where patients will undergo observation only for the entire study. The follow-up time will be 18 months. Groups 1 and 2 will be blinded. Two months after the first invasive procedure, the secondary endpoint-stimulation rate in all groups will be assessed. In addition, a non-invasive evaluation of the efficacy of CNA and the incidence of syncope (MAS) and collapse (paraMAS) will take place in group 1, as well as an evaluation of the pacing percentage. After another month during the second hospitalization, the following will be performed: EPS and ECVS, and repeat CNA if ECVS does not show full parasympathetic cardiac denervation. In group 2, after 2 months, non-invasive tests will also be performed to assess and presence of MAS, paraMAS symptoms, and to assess pacing rates. After another month, during the second hospitalization, the following will be performed: EPS, ECVS and CNA. Group 1 and 2 patients will have their pacemaker set to VVI/AAI 30/min. Group 3 patients will then be evaluated for pacing rates and MAS, paraMAS symptoms. At the third visit, one month after the second invasive procedure in group 1 and 2 patients, the pacing percentage will be assessed. Patients with zero pacing percentage PM will be put on ODO/OVO/OAO-pacing off mode. Patients with a pacing percentage greater than zero PM will be set to their optimal mode. A pacing percentage of <0.1% will be treated as 0%, which will be confirmed in the ILR control. For the next 12 months, patients will be observed. During this period, at the next 4 visits repeated every 3 months, groups 1 and 2 will undergo a non-invasive assessment of CNA efficacy and bradycardia symptoms, while group 3 will be evaluated for MAS, paraMAS and pacing percentage assessment. At the 7th visit, the qualification of patients in groups 1 and 2 for discontinuation of continued pacing treatment will take place, with possible qualification for TLE.

Justification Early and late results of a new strategy which is CNA, indicate the possibility of developing an new approach that allows patients with functional bradycardia to decide whether to discontinue or optimize PM therapy. However, standardized approaches based on noninvasive and invasive techniques have not yet been validated and evaluated in a prospective, multicenter, randomized, controlled trial with long-term remote follow-up, including ILR.

Full description

Visit 1- Screening, recruitment, randomization.

  • ECG, PM check, NIEPS
  • change the stimulation mode to DDD 50/min, AV 220ms/ VVI 50/min/ AAI 50/min
  • atropine test
  • laboratory tests: complete blood count, creatinine, AST, ALT, TSH, fT3, fT4, NT-proBNP, beta-HCG, K
  • analysis of inclusion and exclusion criteria

Hospitalization 1-1 month from randomization Group 1- EPS, ECVS, CNA, ILR implantation Group 2- EPS, ECVS, ILR implantation Group 3- observation

Visit 2-3 months after randomization

Group 1 and 2:

  • History of MAS and paraMAS symptoms and the consequences of the procedures performed.
  • PM control with the assessment of the percentage of stimulation. Change settings and check PM - to assess the efficiency of own rhythm, patients will then have their pacemaker reprogrammed in DDD 50/min mode with AV 220ms or VVI 50/min. or AAI 50/min.
  • ECG
  • NIEPS
  • 24-hour Holter ECG monitoring
  • ILR control

Group 3 observation:

  • History of MAS and paraMAS symptoms.
  • PM control with the assessment of the percentage of stimulation.

Hospitalization 2-4 months from randomization Group 1 - EPS, ECVS, redo CNA if required Group 2 - EPS, ECVS, CNA Group 1 and 2 patients will have their pacemaker set to VVI/AAI 30/min. For patients of Groups 1 and 2 in whom the CNA proved to be ineffective, the PM will be programmed in the optimal mode for them.

Visit 3-6 months after randomization

Group 1 and 2:

  • History of MAS and paraMAS symptoms and the consequences of the procedures performed.
  • PM control with the evaluation of the percentage of stimulation. Changing settings and checking PM- to assess the efficiency of your own rhythm
  • ECG
  • NIEPS
  • 24 hour Holter ECG monitoring
  • ILR control Patients from groups 1 and 2, whose percentage of stimulation in PM control will be 0%, will have their PM reprogrammed to ODO/OVO/OAO - pacing off.

Group 3 observation:

  • History of MAS and paraMAS symptoms.
  • PM control with the assessment of the percentage of stimulation.

Visits 4, 5, 6 - consecutively 9, 12, 15 months after randomization

Groups 1 and 2:

  • Anamnesis for possible symptoms of bradycardia and undesirable effects of the procedure.
  • PM control
  • ECG
  • NIEPS
  • 24-hour Holter ECG monitoring
  • ILR control Patients in Groups 1 and 2 who experience symptoms of bradycardia correlated with bradycardia recorded in the ILR will resume pacing in the optimal mode for them.

During these visits, patients in Group 3 and Groups 1 and 2 who had their pacing restored/optimized will be interviewed for possible MAS and paraMAS symptoms, perform a physical examination, and check the PM with assessment of pacing percentage and pacing mode optimization.

Visit 7 - ending the study - 18 months from randomization.

Group 1 and 2:

  • Anamnesis for possible symptoms of bradycardia and undesirable effects of the procedure.
  • PM control
  • ECG
  • NIEPS
  • Atropine test
  • 24-hour Holter ECG monitoring
  • ILR control Patients from groups 1 and 2 without symptoms of bradycardia and without asymptomatic bradycardia <40/min recorded in the ILR, after assessment by the EP-HEART TEAM (a council of two cardiologist specialists), will be qualified for the end of permanent pacing therapy. Those patients with a low risk of TLE will be qualified for TLE.

During this visit, Group 3 and Group 1 and 2 patients with previously pacing restored/optimized will be interviewed for possible MAS and paraMAS symptoms, perform a physical examination and PM check with assessment of pacing percentage and pacing mode optimisation.

The ILR will be left in place until the battery runs out or will be removed sooner at the patient's request.

Enrollment

99 estimated patients

Sex

All

Ages

18 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  • Patients who underwent pacemaker implantation before 50 years old due to sinus node and/or atrioventricular node dysfunction
  • Positive response to atropine test
  • Age between 18-65 years
  • Signed informed consent to participate in the study

Exclusion criteria

  • Own heart rate <30/min
  • Fainting after pacemaker therapy initiation
  • Persistent and sustained atrial fibrillation
  • History of myocarditis
  • History of myocardial infarction
  • History of cardiac surgery
  • History of ablation procedures
  • Congenital heart defects
  • Congenital atrioventricular block
  • Neuromuscular and neurodegenerative diseases
  • Indications for expanding the pacemaker system to ICD/CRT-D
  • Pregnancy
  • Renal insufficiency with GFR <30 ml/min/1.73m2
  • Age below 18 and above 65 years
  • HAS-BLED score >/= 3 points

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

99 participants in 3 patient groups

Group 1
Experimental group
Description:
Group 1 will undergo EPS, ECVS, CNA with continuation of PM therapy and ILR implantation. Two months later pacing rate, will be assessed. In addition, there will be a non-invasive assessment of the effectiveness of CNA. After another month, EPS and ECVS will be performed and a re-CNA if the ECVS does not show full parasympathetic denervation of the heart. The pacemaker will be set to VVI or AAI 30/min. One month after the second invasive procedure, the pacing rate will be assessed. Patients with zero percentage of PM stimulation will be set to ODO/OVO/OAO-stimulation off mode. Patients will be monitored for the next 12 months. During the next 4 visits repeated every 3 months, patients in this group will undergo non-invasive assessment of the effectiveness of CNA and symptoms of bradycardia. At the 7th visit, patients in this group will be qualified to discontinue of the cardiac pacing treatment, with possible qualification for TLE.
Treatment:
Diagnostic Test: Holter ECG
Procedure: Redo cardioneuroablation
Procedure: Implantation of the implantable loop recorder
Diagnostic Test: Pacemaker check
Procedure: Cardioneuroablation
Diagnostic Test: Implantable loop recorder check
Diagnostic Test: Invasive electrophysiological study
Diagnostic Test: Anamnesis
Diagnostic Test: Extracardiac vagal stimulation
Group 2
Experimental group
Description:
Group 2 will undergo EPS and ECVS with continuation of PM therapy, ILR implantation, without CNA. Two months later pacing rate, will be assessed. After another month, EPS, ECVS and CNA will be made. The pacemaker will be set to VVI or AAI 30/min. One month after the second invasive procedure, patients in this group will have their pacing rate assessed. Patients with zero percentage of PM stimulation will be set to ODO/OVO/OAO-stimulation off mode. Patients will be monitored for the next 12 months. During next 4 visits repeated every 3 months, patients in this group will undergo a non-invasive assessment of the effectiveness of CNA and symptoms of bradycardia. At the 7th visit, the qualification for discontinuation of cardiac pacing treatment will take place, with possible qualification for TLE.
Treatment:
Diagnostic Test: Holter ECG
Procedure: Implantation of the implantable loop recorder
Diagnostic Test: Pacemaker check
Procedure: Cardioneuroablation
Diagnostic Test: Implantable loop recorder check
Diagnostic Test: Invasive electrophysiological study
Diagnostic Test: Anamnesis
Diagnostic Test: Extracardiac vagal stimulation
Group 3
Active Comparator group
Description:
Group 3 patients will only be observed for the duration of the study. The observation period will be 18 months. At subsequent visits 1, 3, 4, 6, 9, 12, 15 months after randomization, they will be assessed for the presence of MAS, paraMAS and assessment of the percentage of stimulation.
Treatment:
Diagnostic Test: Pacemaker check
Diagnostic Test: Anamnesis

Trial contacts and locations

2

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Central trial contact

Przemyslaw Skoczynski, PhD; Bruno Hrymniak, MD

Data sourced from clinicaltrials.gov

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