<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03811639</url>
  </required_header>
  <id_info>
    <org_study_id>65/PB/2015</org_study_id>
    <nct_id>NCT03811639</nct_id>
  </id_info>
  <brief_title>Changes in Cardiac Autonomic Nervous System Following Atrial Fibrillation Ablation.</brief_title>
  <acronym>ABLANSAF</acronym>
  <official_title>ABLation-induced Changes in Cardiac Autonomic Nervous System in Patients With Atrial Fibrillation: Radiofrequency Versus Cryoballoon Techniques. The ABLANSAF Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre of Postgraduate Medical Education</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre of Postgraduate Medical Education</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aim. To compare changes in cardiac autonomic tone caused by radio-frequency versus&#xD;
      cryoballoon ablation and to assess their value in predicting the outcome.&#xD;
&#xD;
      Study group. In this prospective randomized study 126 consecutive patients with paroxysmal AF&#xD;
      undergoing first ablation of AF using radio-frequency (RF) or cryoballoon (CB) technique will&#xD;
      be recruited. Patients will undergo several ECG and autonomic tests before and after the&#xD;
      procedure. The follow-up will last one year.&#xD;
&#xD;
      Measurements:&#xD;
&#xD;
        1. Standard 12-lead ECG a day before and 1-2 days after the procedure will be performed.&#xD;
           The SR and P wave duration as well as the difference (∆) in SR and P wave duration&#xD;
           before and after ablation will be analyzed.&#xD;
&#xD;
        2. A 24-hour Holter ECG will be performed at baseline (1-2 days before ablation) and 7-day&#xD;
           Holter ECG will be performed 3, 6 and 12 months after the procedure. Minimal, maximal&#xD;
           and mean heart rate (HR) as well as HRV parameters will be analyzed. The differences (∆)&#xD;
           in these variables between baseline and post-ablation Holter ECG recordings will be&#xD;
           analyzed.&#xD;
&#xD;
        3. Autonomic parameters (HR, HRV parameters and baroreceptor reflex sensitivity as well as&#xD;
           hemodynamic parameters (stroke volume (SV), cardiac output (CO), total peripheral&#xD;
           resistance (TPR)) will be also examined before and after orthostatic stress. This will&#xD;
           be performed using tilt table test and non-invasive measurement of autonomic and&#xD;
           hemodynamic parameters before and shortly after (1-3 days) the procedure.&#xD;
&#xD;
        4. Quality of life will be assessed using the AFSS scale and EHRA scale at baseline and 3,&#xD;
           6 and 12 months after ablation.&#xD;
&#xD;
        5. Follow-up will last 12 months. Efficacy of ablation will be assessed during outpatients&#xD;
           visits and using 7-day Holter ECG recordings 3, 6 and 12 months after the procedure. The&#xD;
           analyzed outcomes will include symptomatic recurrences of AF, hospitalizations due to&#xD;
           AF, redo procedures i occurrence of asymptomatic AF on Holter ECG monitoring.&#xD;
&#xD;
        6. All the above listed parameters and ablation efficacy will be compared between the RF&#xD;
           and CB groups.&#xD;
&#xD;
      Anticipated results.&#xD;
&#xD;
        1. Ablation significantly effects the parameters of cardiac autonomic control&#xD;
&#xD;
        2. These effects are more pronounced in the CB group compared with the RF group&#xD;
&#xD;
        3. Changes in autonomic indices have value in predicting ablation efficacy in both analyzed&#xD;
           groups.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ABLation-induced changes in cardiac Autonomic Nervous System in patients with Atrial&#xD;
      Fibrillation: radiofrequency versus cryoballoon techniques (the ABLANSAF study).&#xD;
&#xD;
      Introduction. The primary goal of ablation for atrial fibrillation (AF) is pulmonary vein&#xD;
      isolation (PVI). The second mechanism of action of ablation is modification of cardiac&#xD;
      autonomic tone by ablation of atrial ganglionated plexi, mainly of their parasympathetic&#xD;
      component. Data in literature concerning this topic is scares. A few studies showed that&#xD;
      ablation-induced changes in heart rate variability (HRV) or sinus rate (SR) predict the&#xD;
      outcome. However, these data are preliminary and have not yet been included into clinical&#xD;
      practice. Moreover, whether these effects depend on the technique used - radio-frequency (RF)&#xD;
      ablation or cryoballoon (CB) ablation, has not yet been examined.&#xD;
&#xD;
      Aim. To compare the changes in cardiac autonomic tone caused by RF versus CB ablation and to&#xD;
      assess their value in predicting the outcome after the procedure.&#xD;
&#xD;
      Hypothesis. We hypothesised that both techniques cause significant changes in cardiac&#xD;
      autonomic innervation, however, these changes are significantly more pronounced following CB&#xD;
      rather than RF ablation.&#xD;
&#xD;
      Methods. Study group. In this prospective randomised study 126 consecutive patients with&#xD;
      paroxysmal AF undergoing first ablation of AF using RF or CB technique will be recruited.&#xD;
      Patients will undergo several ECG and autonomic tests before and after the procedure. The&#xD;
      follow-up will last one year.&#xD;
&#xD;
      Ablation The RF and CB ablation will be performed using standard approach. A patient will be&#xD;
      randomly selected to RF or CB ablation. The only parameter influencing randomisation will be&#xD;
      the presence of the common trunk of the left PV (visualised by computed tomography or&#xD;
      rotational angiography) which is regarded as relative contraindication to CB because of&#xD;
      anatomical difficulties in the positioning of balloon. In such cases the decision as to the&#xD;
      type of procedure will be left to the discretion of the operator.&#xD;
&#xD;
      The CB PVI will be conducted in standard manner. Briefly, after injection of local&#xD;
      anesthetic, both femoral veins is punctured. One long sheath (8.5 F Swartz, St. Jude, Saint&#xD;
      Paul, USA) to cross interatrial septum is inserted in the right femoral vein. Another two&#xD;
      short sheaths were inserted in the left femoral vein for the intracardiac echocardiographic&#xD;
      probe (8 or 10 Fr Acunav, Acuson, Siemens, Berlin) and diagnostic catheter introduced into&#xD;
      the coronary sinus. After crossing the septum and introducing guidewire into the left&#xD;
      superior pulmonary vein (LSPV), long sheath is replaced with steerable sheath (14 F.,&#xD;
      Flexcath, Medtronic, Minneapolis, USA) and CB (28 mm, second generation) is introduced into&#xD;
      the left atrium. Next, the Achieve (20 mm diameter) mapping catheter, (Medtronic, Milwaukee,&#xD;
      USA) is placed in the LSPV ostium, CB inflated and contrast injected to confirm proper&#xD;
      occlusion of LSPV. When PVI is achieved during first freezing lasting 180 - 240 sec and&#xD;
      confirmed by PV potentials (PVP) disappearance within 60 seconds by recordings from the&#xD;
      Achieve catheter, no second cryoapplication is performed. In case of incomplete occlusion,&#xD;
      persistence or very late disappearance of PVP, suboptimal temperatures achieved (less than&#xD;
      -36C) or very short thawing time, CB is repositioned and another cryo-application is&#xD;
      delivered. Next, CB-PVI of the left inferior pulmonary vein (LIPV), right superior pulmonary&#xD;
      vein (RSPV) and right inferior pulmonary vein (RIPV) is performed. Pacing of the right&#xD;
      phrenic nerve is performed during CB of the right veins to avoid phrenic nerve palsy.&#xD;
&#xD;
      The RF ablation is performed in a standard manner using 3-D electro-anatomical system CARTO-3&#xD;
      (Biosense Webster, USA) and Smarttouch ablation catheter. Two separate transseptal punctures&#xD;
      are performed under intracardiac echocardiography guidance. After reconstruction of the left&#xD;
      atrial geometry using merging of the computed tomography or rotational angiography image with&#xD;
      the CARTO map, the point-by-point PVI of each vein is performed. The ablation index is used&#xD;
      to ensure the quality of RF applications. The Lasso circular catheter (Biosense Webster, USA)&#xD;
      is used to assess PVI and diagnostic catheter placed in the coronary sinus is used for pacing&#xD;
      manoeuvres.&#xD;
&#xD;
      Measurements:&#xD;
&#xD;
        1. Standard 12-lead ECG a day before and 1-2 days after the procedure will be performed.&#xD;
           The SR and P wave duration as well as the difference (∆) in SR and P wave duration&#xD;
           before and after ablation will be analysed.&#xD;
&#xD;
        2. A 24-hour Holter ECG will be performed at baseline (1-2 days before ablation) and 7-day&#xD;
           Holter ECG will be performed 3, 6 and 12 months after the procedure. Minimal, maximal&#xD;
           and mean heart rate (HR) as well as time-domain HRV parameters (SDNN, SDANN, pNN50,&#xD;
           rMSSD) and frequency-domain HRV indices (LF, HF, LF/HF) will be analysed. The&#xD;
           differences (∆) in these variables between baseline and post-ablation Holter ECG&#xD;
           recordings will be analysed.&#xD;
&#xD;
        3. Autonomic parameters (HR, frequency-domain HRV parameters and baro-reflex sensitivity&#xD;
           (BRS) using sequential method) as well as hemodynamic parameters (stroke volume (SV),&#xD;
           cardiac output (CO), total peripheral resistance (TPR)) will be also examined before and&#xD;
           after orthostatic stress. This will be performed using tilt table test (70 degrees) and&#xD;
           non-invasive measurement of autonomic and hemodynamic parameters (cardiac impedance&#xD;
           method) using the Task Force system, before (1-2 days) and shortly after (1-3 days) the&#xD;
           procedure. The 5-min ECG recordings will be used to calculate the values of autonomic&#xD;
           and haemodynamic parameters. Also ∆ of these parameters will be computed. The values&#xD;
           measured before and after ablation, before and after tilt testing as well ∆ will be&#xD;
           compared.&#xD;
&#xD;
        4. Quality of life will be assessed using the AFSS scale and EHRA scale at baseline and 3,&#xD;
           6 and 12 months after ablation.&#xD;
&#xD;
        5. Follow-up will last 12 months. Efficacy of ablation will be assessed during outpatients&#xD;
           visits and using 7-day Holter ECG recordings 3, 6 and 12 months after the procedure. The&#xD;
           analysed outcomes will include symptomatic recurrences of AF, hospitalisations due to&#xD;
           AF, redo procedures i occurrence of asymptomatic AF on Holter ECG monitoring. Efficacy&#xD;
           of the procedure will be assessed and defined as (1) complete efficacy - no symptoms&#xD;
           attributed to AF and no AF on Holter ECG monitoring; (2) symptomatic efficacy - no&#xD;
           symptoms attributed to AF but AF episodes &gt; 30 sec recorded on Holter ECG monitoring;&#xD;
           (3) partial efficacy - recurrences of symptomatic AF, however, of lower intensity,&#xD;
           defined as improvement of at least 1 degree in the EHRA scale and improvement in the&#xD;
           AFSS scale; and (4) no effects - no change in symptoms compared with the pre-ablation&#xD;
           periods.&#xD;
&#xD;
        6. All the above listed parameters and ablation efficacy will be compared between the RF&#xD;
           and CB groups.&#xD;
&#xD;
      Statistical analysis. The results will be presented as mean±SD (normally distributed&#xD;
      variables) or median values (not normally distributed variables). The changes between&#xD;
      baseline and parameters obtained after ablation as well as before and after tilt testing will&#xD;
      be performed using paired two-tailed Student t-test, Mann-Whitney or ANOVA tests where&#xD;
      appropriate. The results obtained in the RF versus CB groups will be compared using unpaired&#xD;
      Student t-test. The predictive value of examined parameters in identifying responders to&#xD;
      ablation will be assessed using the ROC curves and by computing sensitivity, specificity,&#xD;
      positive and negative predictive value. Multivariate analysis will be performed to identify&#xD;
      parameters independently associated with ablation efficacy. A p value &lt; 0.05 will be&#xD;
      considered significant.&#xD;
&#xD;
      The estimated number of patients sufficient to detect significant difference between the RF&#xD;
      and CB groups is 126 based on the assumption that ablation-induced changes in cardiac&#xD;
      autonomic parameters will differ between the RF and CB groups by 20% (alfa error = 0.05 and&#xD;
      beta error = 0.2) Anticipated results.&#xD;
&#xD;
        1. Ablation significantly effects the parameters of cardiac autonomic control&#xD;
&#xD;
        2. These effects are more pronounced in the CB group compared with the RF group&#xD;
&#xD;
        3. Changes in autonomic indices have value in predicting ablation efficacy in both analysed&#xD;
           groups.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2015</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">November 30, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Comparison of changes in autonomic heart regulation caused by radio-frequency ablation and cryoballoon ablation</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Heart rate-induced changes in the RF and CB groups.</measure>
    <time_frame>1-2 days before and 2-3 days after ablation heart rate will be recorded</time_frame>
    <description>The baseline and tilt-induced heart rate (beats/min) measured before and after ablation will be compared between the RF and CB groups</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Heart rate variability (SDNN)-induced changes in the RF and CB groups.</measure>
    <time_frame>1-2 days before and 2-3 days after ablation SDNN parameter will be recorded</time_frame>
    <description>The baseline and tilt-induced heart rate variability (SDNN) (msec) measured before and after ablation will be compared between the RF and CB groups</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Baroreflex sensitivity-induced changes in the RF and CB groups.</measure>
    <time_frame>1-2 days before and 2-3 days after ablation baroreflex sensitivity will be recorded</time_frame>
    <description>The baseline and tilt-induced baroreflex sensitivity (msec/mmHg) measured before and after ablation will be compared between the RF and CB groups</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy of RF versus CB ablation (ECG symptomatic AF recurrences)</measure>
    <time_frame>One year</time_frame>
    <description>Efficacy of RF versus CB ablation will be compared using repetitive Holter ECG monitoring and documented on ECG symptomatic AF recurrences during one year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ablation-induced changes in heart rate predicting ablation efficacy</measure>
    <time_frame>One year</time_frame>
    <description>Ablation-induced change in heart rate (beats/min) will be analyzed as a predictor of ablation efficacy during one-year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ablation-induced changes in heart rate variability predicting ablation efficacy</measure>
    <time_frame>One year</time_frame>
    <description>Ablation-induced change in heart rate variability (SDNN) (msec) will be analyzed as a predictor of ablation efficacy during one-year follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ablation-induced changes in baroreflex sensitivity predicting ablation efficacy</measure>
    <time_frame>One year</time_frame>
    <description>Ablation-induced change in baroreflex sensitivity (msec/mmHg) will be analyzed as a predictor of ablation efficacy during one-year follow-up</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">126</enrollment>
  <condition>Atrial Fibrillation</condition>
  <arm_group>
    <arm_group_label>RF ablation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients treated with point-by-point radio-frequency ablation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cryoballoon ablation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients treated with cryoballoon ablation</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Radio-frequency ablation</intervention_name>
    <description>Ablation for atrial fibrillation</description>
    <arm_group_label>RF ablation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Cryoballoon ablation</intervention_name>
    <description>Ablation for atrial fibrillation</description>
    <arm_group_label>Cryoballoon ablation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Paroxysmal AF&#xD;
&#xD;
          -  First AF ablation&#xD;
&#xD;
          -  Sinus rhythm before and after the procedure at the time of ECG and tilt table testing.&#xD;
&#xD;
          -  No change in medication affecting cardiac autonomic nervous system before and after&#xD;
             ablation.&#xD;
&#xD;
          -  Obtained written informed consent to participate in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any of inclusion criterion not met&#xD;
&#xD;
          -  Pacing system implanted&#xD;
&#xD;
          -  Additional ablation to PVI like cavo-tricuspid isthmus ablation or linear lesions in&#xD;
             the left atrium.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Piotr Kulakowski, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Postgraduate Medical School, Grochowski Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Cardiology, Postgraduate Medical School, Grochowski Hospital</name>
      <address>
        <city>Warsaw</city>
        <zip>04-073</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <reference>
    <citation>Hsieh MH, Chiou CW, Wen ZC, Wu CH, Tai CT, Tsai CF, Ding YA, Chang MS, Chen SA. Alterations of heart rate variability after radiofrequency catheter ablation of focal atrial fibrillation originating from pulmonary veins. Circulation. 1999 Nov 30;100(22):2237-43. doi: 10.1161/01.cir.100.22.2237.</citation>
    <PMID>10577997</PMID>
  </reference>
  <results_reference>
    <citation>Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Augello G, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004 Jan 27;109(3):327-34. doi: 10.1161/01.CIR.0000112641.16340.C7. Epub 2004 Jan 5.</citation>
    <PMID>14707026</PMID>
  </results_reference>
  <results_reference>
    <citation>Yamada T, Yoshida N, Murakami Y, Okada T, Yoshida Y, Muto M, Inden Y, Murohara T. Vagal modification can be a valid predictor of late recurrence of paroxysmal atrial fibrillation independent of the pulmonary vein isolation technique. Circ J. 2009 Sep;73(9):1606-11. doi: 10.1253/circj.cj-09-0158. Epub 2009 Jul 17.</citation>
    <PMID>19609042</PMID>
  </results_reference>
  <results_reference>
    <citation>Yamada T, Yoshida N, Murakami Y, Okada T, Yoshida Y, Muto M, Inden Y, Murohara T. The difference in autonomic denervation and its effect on atrial fibrillation recurrence between the standard segmental and circumferential pulmonary vein isolation techniques. Europace. 2009 Dec;11(12):1612-9. doi: 10.1093/europace/eup330. Epub 2009 Oct 29.</citation>
    <PMID>19875397</PMID>
  </results_reference>
  <results_reference>
    <citation>Yamaguchi Y, Kumagai K, Nakashima H, Saku K. Long-term effects of box isolation on sympathovagal balance in atrial fibrillation. Circ J. 2010 Jun;74(6):1096-103. doi: 10.1253/circj.cj-09-0899. Epub 2010 May 8.</citation>
    <PMID>20467150</PMID>
  </results_reference>
  <results_reference>
    <citation>Oswald H, Klein G, Koenig T, Luesebrink U, Duncker D, Gardiwal A. Cryoballoon pulmonary vein isolation temporarily modulates the intrinsic cardiac autonomic nervous system. J Interv Card Electrophysiol. 2010 Oct;29(1):57-62. doi: 10.1007/s10840-010-9491-7. Epub 2010 Jun 16.</citation>
    <PMID>20556498</PMID>
  </results_reference>
  <results_reference>
    <citation>Lim PB, Malcolme-Lawes LC, Stuber T, Koa-Wing M, Wright IJ, Tillin T, Sutton R, Davies DW, Peters NS, Francis DP, Kanagaratnam P. Feasibility of multiple short, 40-s, intra-procedural ECG recordings to detect immediate changes in heart rate variability during catheter ablation for arrhythmias. J Interv Card Electrophysiol. 2011 Nov;32(2):163-71. doi: 10.1007/s10840-011-9580-2. Epub 2011 Jun 7.</citation>
    <PMID>21647641</PMID>
  </results_reference>
  <results_reference>
    <citation>Wang K, Chang D, Chu Z, Yang Y, Gao L, Zhang S, Xia Y, Dong Y, Yin X, Cong P, Jia J. Denervation as a common mechanism underlying different pulmonary vein isolation strategies for paroxysmal atrial fibrillation: evidenced by heart rate variability after ablation. ScientificWorldJournal. 2013 Aug 24;2013:569564. doi: 10.1155/2013/569564. eCollection 2013.</citation>
    <PMID>24058286</PMID>
  </results_reference>
  <results_reference>
    <citation>Seaborn GE, Todd K, Michael KA, Baranchuk A, Abdollah H, Simpson CS, Akl SG, Redfearn DP. Heart rate variability and procedural outcome in catheter ablation for atrial fibrillation. Ann Noninvasive Electrocardiol. 2014 Jan;19(1):23-33. doi: 10.1111/anec.12098. Epub 2013 Sep 24.</citation>
    <PMID>24112475</PMID>
  </results_reference>
  <results_reference>
    <citation>Kang KW, Kim TH, Park J, Uhm JS, Joung B, Hwang C, Lee MH, Pak HN. Long-term changes in heart rate variability after radiofrequency catheter ablation for atrial fibrillation: 1-year follow-up study with irrigation tip catheter. J Cardiovasc Electrophysiol. 2014 Jul;25(7):693-700. doi: 10.1111/jce.12398. Epub 2014 Mar 28.</citation>
    <PMID>24575794</PMID>
  </results_reference>
  <results_reference>
    <citation>Mori H, Kato R, Ikeda Y, Goto K, Tanaka S, Asano S, Shiki Y, Nagase T, Iwanaga S, Nishimura S, Muramatsu T, Matsumoto K. Analysis of the heart rate variability during cryoballoon ablation of atrial fibrillation. Europace. 2018 Aug 1;20(8):1259-1267. doi: 10.1093/europace/eux225.</citation>
    <PMID>29016780</PMID>
  </results_reference>
  <results_reference>
    <citation>Yu HT, Kim TH, Uhm JS, Kim JY, Joung B, Lee MH, Pak HN. Prognosis of high sinus heart rate after catheter ablation for atrial fibrillation. Europace. 2017 Jul 1;19(7):1132-1139. doi: 10.1093/europace/euw142.</citation>
    <PMID>27256421</PMID>
  </results_reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 29, 2018</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>February 8, 2021</last_update_submitted>
  <last_update_submitted_qc>February 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 9, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Centre of Postgraduate Medical Education</investigator_affiliation>
    <investigator_full_name>Prof. Piotr Kulakowski</investigator_full_name>
    <investigator_title>Professor, head of Electrophysiology Department</investigator_title>
  </responsible_party>
  <keyword>ablation, atrial fibrillation, autonomic nervous system</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atrial Fibrillation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All study data will be available to other researchers or reviewers.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>During the study and up to 5 years after study termination</ipd_time_frame>
    <ipd_access_criteria>Data will be available for researchers who are interested in this field and to reviewers if they ask for data during reviewing process</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03811639
org study id: 65/PB/2015
nct id: NCT03811639
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Comparison of changes in autonomic heart regulation caused by radio-frequency ablation and cryoballoon ablation
primary purpose: Treatment
masking: None (Open Label)
measure: Heart rate-induced changes in the RF and CB groups.
time frame: 1-2 days before and 2-3 days after ablation heart rate will be recorded
description: The baseline and tilt-induced heart rate (beats/min) measured before and after ablation will be compared between the RF and CB groups
measure: Heart rate variability (SDNN)-induced changes in the RF and CB groups.
time frame: 1-2 days before and 2-3 days after ablation SDNN parameter will be recorded
description: The baseline and tilt-induced heart rate variability (SDNN) (msec) measured before and after ablation will be compared between the RF and CB groups
measure: Baroreflex sensitivity-induced changes in the RF and CB groups.
time frame: 1-2 days before and 2-3 days after ablation baroreflex sensitivity will be recorded
description: The baseline and tilt-induced baroreflex sensitivity (msec/mmHg) measured before and after ablation will be compared between the RF and CB groups
measure: Efficacy of RF versus CB ablation (ECG symptomatic AF recurrences)
time frame: One year
description: Efficacy of RF versus CB ablation will be compared using repetitive Holter ECG monitoring and documented on ECG symptomatic AF recurrences during one year follow-up
measure: Ablation-induced changes in heart rate predicting ablation efficacy
time frame: One year
description: Ablation-induced change in heart rate (beats/min) will be analyzed as a predictor of ablation efficacy during one-year follow-up
measure: Ablation-induced changes in heart rate variability predicting ablation efficacy
time frame: One year
description: Ablation-induced change in heart rate variability (SDNN) (msec) will be analyzed as a predictor of ablation efficacy during one-year follow-up
measure: Ablation-induced changes in baroreflex sensitivity predicting ablation efficacy
time frame: One year
description: Ablation-induced change in baroreflex sensitivity (msec/mmHg) will be analyzed as a predictor of ablation efficacy during one-year follow-up
arm group label: RF ablation
arm group type: Active Comparator
description: Patients treated with point-by-point radio-frequency ablation
arm group label: Cryoballoon ablation
arm group type: Experimental
description: Patients treated with cryoballoon ablation
intervention type: Procedure
intervention name: Radio-frequency ablation
description: Ablation for atrial fibrillation
arm group label: RF ablation
intervention type: Procedure
intervention name: Cryoballoon ablation
description: Ablation for atrial fibrillation
arm group label: Cryoballoon ablation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Piotr Kulakowski, MD
role: Study Chair
affiliation: Postgraduate Medical School, Grochowski Hospital
facility: 
country: Poland
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PMID: 10577997
citation: Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Augello G, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation. 2004 Jan 27;109(3):327-34. doi: 10.1161/01.CIR.0000112641.16340.C7. Epub 2004 Jan 5.
PMID: 14707026
citation: Yamada T, Yoshida N, Murakami Y, Okada T, Yoshida Y, Muto M, Inden Y, Murohara T. Vagal modification can be a valid predictor of late recurrence of paroxysmal atrial fibrillation independent of the pulmonary vein isolation technique. Circ J. 2009 Sep;73(9):1606-11. doi: 10.1253/circj.cj-09-0158. Epub 2009 Jul 17.
PMID: 19609042
citation: Yamada T, Yoshida N, Murakami Y, Okada T, Yoshida Y, Muto M, Inden Y, Murohara T. The difference in autonomic denervation and its effect on atrial fibrillation recurrence between the standard segmental and circumferential pulmonary vein isolation techniques. Europace. 2009 Dec;11(12):1612-9. doi: 10.1093/europace/eup330. Epub 2009 Oct 29.
PMID: 19875397
citation: Yamaguchi Y, Kumagai K, Nakashima H, Saku K. Long-term effects of box isolation on sympathovagal balance in atrial fibrillation. Circ J. 2010 Jun;74(6):1096-103. doi: 10.1253/circj.cj-09-0899. Epub 2010 May 8.
PMID: 20467150
citation: Oswald H, Klein G, Koenig T, Luesebrink U, Duncker D, Gardiwal A. Cryoballoon pulmonary vein isolation temporarily modulates the intrinsic cardiac autonomic nervous system. J Interv Card Electrophysiol. 2010 Oct;29(1):57-62. doi: 10.1007/s10840-010-9491-7. Epub 2010 Jun 16.
PMID: 20556498
citation: Lim PB, Malcolme-Lawes LC, Stuber T, Koa-Wing M, Wright IJ, Tillin T, Sutton R, Davies DW, Peters NS, Francis DP, Kanagaratnam P. Feasibility of multiple short, 40-s, intra-procedural ECG recordings to detect immediate changes in heart rate variability during catheter ablation for arrhythmias. J Interv Card Electrophysiol. 2011 Nov;32(2):163-71. doi: 10.1007/s10840-011-9580-2. Epub 2011 Jun 7.
PMID: 21647641
citation: Wang K, Chang D, Chu Z, Yang Y, Gao L, Zhang S, Xia Y, Dong Y, Yin X, Cong P, Jia J. Denervation as a common mechanism underlying different pulmonary vein isolation strategies for paroxysmal atrial fibrillation: evidenced by heart rate variability after ablation. ScientificWorldJournal. 2013 Aug 24;2013:569564. doi: 10.1155/2013/569564. eCollection 2013.
PMID: 24058286
citation: Seaborn GE, Todd K, Michael KA, Baranchuk A, Abdollah H, Simpson CS, Akl SG, Redfearn DP. Heart rate variability and procedural outcome in catheter ablation for atrial fibrillation. Ann Noninvasive Electrocardiol. 2014 Jan;19(1):23-33. doi: 10.1111/anec.12098. Epub 2013 Sep 24.
PMID: 24112475
citation: Kang KW, Kim TH, Park J, Uhm JS, Joung B, Hwang C, Lee MH, Pak HN. Long-term changes in heart rate variability after radiofrequency catheter ablation for atrial fibrillation: 1-year follow-up study with irrigation tip catheter. J Cardiovasc Electrophysiol. 2014 Jul;25(7):693-700. doi: 10.1111/jce.12398. Epub 2014 Mar 28.
PMID: 24575794
citation: Mori H, Kato R, Ikeda Y, Goto K, Tanaka S, Asano S, Shiki Y, Nagase T, Iwanaga S, Nishimura S, Muramatsu T, Matsumoto K. Analysis of the heart rate variability during cryoballoon ablation of atrial fibrillation. Europace. 2018 Aug 1;20(8):1259-1267. doi: 10.1093/europace/eux225.
PMID: 29016780
citation: Yu HT, Kim TH, Uhm JS, Kim JY, Joung B, Lee MH, Pak HN. Prognosis of high sinus heart rate after catheter ablation for atrial fibrillation. Europace. 2017 Jul 1;19(7):1132-1139. doi: 10.1093/europace/euw142.
PMID: 27256421
responsible party type: Principal Investigator
investigator affiliation: Centre of Postgraduate Medical Education
investigator full name: Prof. Piotr Kulakowski
investigator title: Professor, head of Electrophysiology Department
mesh term: Atrial Fibrillation
sharing ipd: Yes
ipd description: All study data will be available to other researchers or reviewers.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: During the study and up to 5 years after study termination
ipd access criteria: Data will be available for researchers who are interested in this field and to reviewers if they ask for data during reviewing process