Clinical trial NCT03811639: Changes in Cardiac Autonomic Nervous System Following Atrial Fibrillation Ablation.
Official title: ABLation-induced Changes in Cardiac Autonomic Nervous System in Patients With Atrial Fibrillation: Radiofrequency Versus Cryoballoon Techniques. The ABLANSAF Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Atrial Fibrillation
Keywords: ablation, atrial fibrillation, autonomic nervous system
Lead sponsor: Centre of Postgraduate Medical Education
Sponsor class: OTHER
First posted: 2019-01-22
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Comparison of changes in autonomic heart regulation caused by radio-frequency ablation and cryoballoon ablation
Primary purpose: TREATMENT

Brief summary: Aim. To compare changes in cardiac autonomic tone caused by radio-frequency versus cryoballoon ablation and to assess their value in predicting the outcome.

Study group. In this prospective randomized study 126 consecutive patients with paroxysmal AF undergoing first ablation of AF using radio-frequency (RF) or cryoballoon (CB) technique will be recruited. Patients will undergo several ECG and autonomic tests before and after the procedure. The follow-up will last one year.

Measurements:

1. Standard 12-lead ECG a day before and 1-2 days after the procedure will be performed. The SR and P wave duration as well as the difference (∆) in SR and P wave duration before and after ablation will be analyzed.
2. A 24-hour Holter ECG will be performed at baseline (1-2 days before ablation) and 7-day Holter ECG will be performed 3, 6 and 12 months after the procedure. Minimal, maximal and mean heart rate (HR) as well as HRV parameters will be analyzed. The differences (∆) in these variables between baseline and post-ablation Holter ECG recordings will be analyzed.
3. Autonomic parameters (HR, HRV parameters and baroreceptor reflex sensitivity as well as hemodynamic parameters (stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR)) will be also examined before and after orthostatic stress. This will be performed using tilt table test and non-invasive measurement of autonomic and hemodynamic parameters before and shortly after (1-3 days) the procedure.
4. Quality of life will be assessed using the AFSS scale and EHRA scale at baseline and 3, 6 and 12 months after ablation.
5. Follow-up will last 12 months. Efficacy of ablation will be assessed during outpatients visits and using 7-day Holter ECG recordings 3, 6 and 12 months after the procedure. The analyzed outcomes will include symptomatic recurrences of AF, hospitalizations due to AF, redo procedures i occurrence of asymptomatic AF on Holter ECG monitoring.
6. All the above listed parameters and ablation efficacy will be compared between the RF and CB groups.

Anticipated results.

1. Ablation significantly effects the parameters of cardiac autonomic control
2. These effects are more pronounced in the CB group compared with the RF group
3. Changes in autonomic indices have value in predicting ablation efficacy in both analyzed groups.

Detailed description: ABLation-induced changes in cardiac Autonomic Nervous System in patients with Atrial Fibrillation: radiofrequency versus cryoballoon techniques (the ABLANSAF study).

Introduction. The primary goal of ablation for atrial fibrillation (AF) is pulmonary vein isolation (PVI). The second mechanism of action of ablation is modification of cardiac autonomic tone by ablation of atrial ganglionated plexi, mainly of their parasympathetic component. Data in literature concerning this topic is scares. A few studies showed that ablation-induced changes in heart rate variability (HRV) or sinus rate (SR) predict the outcome. However, these data are preliminary and have not yet been included into clinical practice. Moreover, whether these effects depend on the technique used - radio-frequency (RF) ablation or cryoballoon (CB) ablation, has not yet been examined.

Aim. To compare the changes in cardiac autonomic tone caused by RF versus CB ablation and to assess their value in predicting the outcome after the procedure.

Hypothesis. We hypothesised that both techniques cause significant changes in cardiac autonomic innervation, however, these changes are significantly more pronounced following CB rather than RF ablation.

Methods. Study group. In this prospective randomised study 126 consecutive patients with paroxysmal AF undergoing first ablation of AF using RF or CB technique will be recruited. Patients will undergo several ECG and autonomic tests before and after the procedure. The follow-up will last one year.

Ablation The RF and CB ablation will be performed using standard approach. A patient will be randomly selected to RF or CB ablation. The only parameter influencing randomisation will be the presence of the common trunk of the left PV (visualised by computed tomography or rotational angiography) which is regarded as relative contraindication to CB because of anatomical difficulties in the positioning of balloon. In such cases the decision as to the type of procedure will be left to the discretion of the operator.

The CB PVI will be conducted in standard manner. Briefly, after injection of local anesthetic, both femoral veins is punctured. One long sheath (8.5 F Swartz, St. Jude, Saint Paul, USA) to cross interatrial septum is inserted in the right femoral vein. Another two short sheaths were inserted in the left femoral vein for the intracardiac echocardiographic probe (8 or 10 Fr Acunav, Acuson, Siemens, Berlin) and diagnostic catheter introduced into the coronary sinus. After crossing the septum and introducing guidewire into the left superior pulmonary vein (LSPV), long sheath is replaced with steerable sheath (14 F., Flexcath, Medtronic, Minneapolis, USA) and CB (28 mm, second generation) is introduced into the left atrium. Next, the Achieve (20 mm diameter) mapping catheter, (Medtronic, Milwaukee, USA) is placed in the LSPV ostium, CB inflated and contrast injected to confirm proper occlusion of LSPV. When PVI is achieved during first freezing lasting 180 - 240 sec and confirmed by PV potentials (PVP) disappearance within 60 seconds by recordings from the Achieve catheter, no second cryoapplication is performed. In case of incomplete occlusion, persistence or very late disappearance of PVP, suboptimal temperatures achieved (less than -36C) or very short thawing time, CB is repositioned and another cryo-application is delivered. Next, CB-PVI of the left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV) and right inferior pulmonary vein (RIPV) is performed. Pacing of the right phrenic nerve is performed during CB of the right veins to avoid phrenic nerve palsy.

The RF ablation is performed in a standard manner using 3-D electro-anatomical system CARTO-3 (Biosense Webster, USA) and Smarttouch ablation catheter. Two separate transseptal punctures are performed under intracardiac echocardiography guidance. After reconstruction of the left atrial geometry using merging of the computed tomography or rotational angiography image with the CARTO map, the point-by-point PVI of each vein is performed. The ablation index is used to ensure the quality of RF applications. The Lasso circular catheter (Biosense Webster, USA) is used to assess PVI and diagnostic catheter placed in the coronary sinus is used for pacing manoeuvres.

Measurements:

1. Standard 12-lead ECG a day before and 1-2 days after the procedure will be performed. The SR and P wave duration as well as the difference (∆) in SR and P wave duration before and after ablation will be analysed.
2. A 24-hour Holter ECG will be performed at baseline (1-2 days before ablation) and 7-day Holter ECG will be performed 3, 6 and 12 months after the procedure. Minimal, maximal and mean heart rate (HR) as well as time-domain HRV parameters (SDNN, SDANN, pNN50, rMSSD) and frequency-domain HRV indices (LF, HF, LF/HF) will be analysed. The differences (∆) in these variables between baseline and post-ablation Holter ECG recordings will be analysed.
3. Autonomic parameters (HR, frequency-domain HRV parameters and baro-reflex sensitivity (BRS) using sequential method) as well as hemodynamic parameters (stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR)) will be also examined before and after orthostatic stress. This will be performed using tilt table test (70 degrees) and non-invasive measurement of autonomic and hemodynamic parameters (cardiac impedance method) using the Task Force system, before (1-2 days) and shortly after (1-3 days) the procedure. The 5-min ECG recordings will be used to calculate the values of autonomic and haemodynamic parameters. Also ∆ of these parameters will be computed. The values measured before and after ablation, before and after tilt testing as well ∆ will be compared.
4. Quality of life will be assessed using the AFSS scale and EHRA scale at baseline and 3, 6 and 12 months after ablation.
5. Follow-up will last 12 months. Efficacy of ablation will be assessed during outpatients visits and using 7-day Holter ECG recordings 3, 6 and 12 months after the procedure. The analysed outcomes will include symptomatic recurrences of AF, hospitalisations due to AF, redo procedures i occurrence of asymptomatic AF on Holter ECG monitoring. Efficacy of the procedure will be assessed and defined as (1) complete efficacy - no symptoms attributed to AF and no AF on Holter ECG monitoring; (2) symptomatic efficacy - no symptoms attributed to AF but AF episodes \> 30 sec recorded on Holter ECG monitoring; (3) partial efficacy - recurrences of symptomatic AF, however, of lower intensity, defined as improvement of at least 1 degree in the EHRA scale and improvement in the AFSS scale; and (4) no effects - no change in symptoms compared with the pre-ablation periods.
6. All the above listed parameters and ablation efficacy will be compared between the RF and CB groups.

Statistical analysis. The results will be presented as mean±SD (normally distributed variables) or median values (not normally distributed variables). The changes between baseline and parameters obtained after ablation as well as before and after tilt testing will be performed using paired two-tailed Student t-test, Mann-Whitney or ANOVA tests where appropriate. The results obtained in the RF versus CB groups will be compared using unpaired Student t-test. The predictive value of examined parameters in identifying responders to ablation will be assessed using the ROC curves and by computing sensitivity, specificity, positive and negative predictive value. Multivariate analysis will be performed to identify parameters independently associated with ablation efficacy. A p value \< 0.05 will be considered significant.

The estimated number of patients sufficient to detect significant difference between the RF and CB groups is 126 based on the assumption that ablation-induced changes in cardiac autonomic parameters will differ between the RF and CB groups by 20% (alfa error = 0.05 and beta error = 0.2) Anticipated results.

1. Ablation significantly effects the parameters of cardiac autonomic control
2. These effects are more pronounced in the CB group compared with the RF group
3. Changes in autonomic indices have value in predicting ablation efficacy in both analysed groups.

Eligibility criteria: Inclusion Criteria:

* Paroxysmal AF
* First AF ablation
* Sinus rhythm before and after the procedure at the time of ECG and tilt table testing.
* No change in medication affecting cardiac autonomic nervous system before and after ablation.
* Obtained written informed consent to participate in the study.

Exclusion Criteria:

* Any of inclusion criterion not met
* Pacing system implanted
* Additional ablation to PVI like cavo-tricuspid isthmus ablation or linear lesions in the left atrium.

Primary outcomes:
measure: Heart rate-induced changes in the RF and CB groups.
timeFrame: 1-2 days before and 2-3 days after ablation heart rate will be recorded
measure: Heart rate variability (SDNN)-induced changes in the RF and CB groups.
timeFrame: 1-2 days before and 2-3 days after ablation SDNN parameter will be recorded
measure: Baroreflex sensitivity-induced changes in the RF and CB groups.
timeFrame: 1-2 days before and 2-3 days after ablation baroreflex sensitivity will be recorded
Secondary outcomes:
measure: Efficacy of RF versus CB ablation (ECG symptomatic AF recurrences)
timeFrame: One year
measure: Ablation-induced changes in heart rate predicting ablation efficacy
timeFrame: One year
measure: Ablation-induced changes in heart rate variability predicting ablation efficacy
timeFrame: One year
measure: Ablation-induced changes in baroreflex sensitivity predicting ablation efficacy
timeFrame: One year
Other outcomes:
Locations:
city: Warsaw
country: Poland
facility: Department of Cardiology, Postgraduate Medical School, Grochowski Hospital
Study officials:
affiliation: Postgraduate Medical School, Grochowski Hospital
name: Piotr Kulakowski, MD
role: STUDY_CHAIR
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