Clinical trial NCT05896592: Comparison of the Efficacy and Safety of Cardioneuroablation to Permanent Pacing in Patients With an Implanted Pacemaker for Symptomatic Bradycardia.
Official title: A Multicenter, Randomized, Double-blind, Research Study comparinG the Efficacy and Safety of cardioneuroablaTion vs Permanent Pacing in Patients With an implantabLE PACEmaker for Symptomatic Bradycardia.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Bradycardia
Syncope
Keywords: cardioneuroablarion
functional bradycardia
pacemaker treatment discontinuation
Lead sponsor: 4th Military Clinical Hospital with Polyclinic, Poland
Sponsor class: OTHER
First posted: 2023-06-09
Enrollment: 99
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Primary efficacy endpoints- Composite endpoint
timeFrame: 18 months
measure: Primary safety endpoints- Composite endpoint
timeFrame: 18 months
Secondary outcomes:
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary efficacy endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
measure: Secondary safety endpoint
timeFrame: 18 months
Other outcomes:
Locations:
city: Radom
country: Poland
facility: Mazowiecki Specialist Hospital
state: Mazowieckie
city: Katowice
country: Poland
facility: Medical University of Silesia
state: Śląskie
Study officials:
affiliation: 4th Military Clinical Hospital with Polyclinic, Poland
name: Przemyslaw Skoczynski, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: 4th Military Clinical Hospital with Polyclinic, Poland
name: Dariusz Jagielski, PhD
role: STUDY_DIRECTOR
References:
citation: Glikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, Barrabes JA, Boriani G, Braunschweig F, Brignole M, Burri H, Coats AJS, Deharo JC, Delgado V, Diller GP, Israel CW, Keren A, Knops RE, Kotecha D, Leclercq C, Merkely B, Starck C, Thylen I, Tolosana JM; ESC Scientific Document Group. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J. 2021 Sep 14;42(35):3427-3520. doi: 10.1093/eurheartj/ehab364. No abstract available. Erratum In: Eur Heart J. 2022 May 1;43(17):1651. doi: 10.1093/eurheartj/ehac075.
citation: Rudbeck-Resdal J, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK. Aetiologies and temporal trends of atrioventricular block in young patients: a 20-year nationwide study. Europace. 2019 Nov 1;21(11):1710-1716. doi: 10.1093/europace/euz206.
citation: Chung MK, Fagerlin A, Wang PJ, Ajayi TB, Allen LA, Baykaner T, Benjamin EJ, Branda M, Cavanaugh KL, Chen LY, Crossley GH, Delaney RK, Eckhardt LL, Grady KL, Hargraves IG, True Hills M, Kalscheur MM, Kramer DB, Kunneman M, Lampert R, Langford AT, Lewis KB, Lu Y, Mandrola JM, Martinez K, Matlock DD, McCarthy SR, Montori VM, Noseworthy PA, Orland KM, Ozanne E, Passman R, Pundi K, Roden DM, Saarel EV, Schmidt MM, Sears SF, Stacey D, Stafford RS, Steinberg BA, Youn Wass S, Wright JM. Shared Decision Making in Cardiac Electrophysiology Procedures and Arrhythmia Management. Circ Arrhythm Electrophysiol. 2021 Dec;14(12):e007958. doi: 10.1161/CIRCEP.121.007958. Epub 2021 Dec 6.
citation: Pachon JC, Pachon EI, Pachon JC, Lobo TJ, Pachon MZ, Vargas RN, Jatene AD. "Cardioneuroablation"--new treatment for neurocardiogenic syncope, functional AV block and sinus dysfunction using catheter RF-ablation. Europace. 2005 Jan;7(1):1-13. doi: 10.1016/j.eupc.2004.10.003.
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: 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.
citation: Tulecki L, Polewczyk A, Jachec W, Nowosielecka D, Tomkow K, Stefanczyk P, Kosior J, Duda K, Polewczyk M, Kutarski A. A Study of Major and Minor Complications of 1500 Transvenous Lead Extraction Procedures Performed with Optimal Safety at Two High-Volume Referral Centers. Int J Environ Res Public Health. 2021 Oct 3;18(19):10416. doi: 10.3390/ijerph181910416.
citation: Sidhu BS, Gould J, Bunce C, Elliott M, Mehta V, Kennergren C, Butter C, Deharo JC, Kutarski A, Maggioni AP, Auricchio A, Kuck KH, Blomstrom-Lundqvist C, Bongiorni MG, Rinaldi CA; ELECTRa Investigators Group. The effect of centre volume and procedure location on major complications and mortality from transvenous lead extraction: an ESC EHRA EORP European Lead Extraction ConTRolled ELECTRa registry subanalysis. Europace. 2020 Nov 1;22(11):1718-1728. doi: 10.1093/europace/euaa131.