FIRE AND ICE: Comparative Study of Two Ablation Procedures in Patients With Atrial Fibrillation

A Controlled, Prospective, Non-Inferiority, Parallel-Group, Randomised, Interventional, Open, Blinded Outcome Assessment (PROBE-Design), Multi-centre Trial, Comparing Efficacy and Safety of Isolation of the PVs With a Cryoballoon Catheter vs a Radiofrequency Ablation With a ThermoCool Catheter in Patients With PAF

Comparing efficacy and safety of isolation of the pulmonary veins (PV) using a Cryoballoon catheter versus a radiofrequency ablation with a ThermoCool catheter in patients with paroxysmal atrial fibrillation.

Study Overview

• Status: Completed
• Conditions: Symptomatic Paroxysmal Atrial Fibrillation (PAF)
• Intervention / Treatment: Procedure: Electrical isolation of the pulmonary veins; Procedure: Electrical isolation of pulmonary veins

Detailed Description

The purpose of this randomized clinical trial is to compare the efficacy and safety of isolating the PVs with either the cryoballoon or a RF ablation technique with a ThermoCool catheter, a system which can be regarded as standard for ablation. In total 762 patients with paroxysmal atrial fibrillation has been randomized for either radiofrequency (RF) or cryoballoon. With both techniques, PV isolation will be performed. Primary end point of the trial is the time to first recurrence of atrial arrhythmias or prescription of anti-arrhythmic drugs after a blanking period of three months. Treatment success will be evaluated by using weekly electrocardiography (ECG) monitoring (transtelephonic transmission/Tele-ECG) and using Holter electrocardiograms.

• Study Type: Interventional
• Enrollment (Actual): 769
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Czechia
  • Prague, Czechia, 515030
    • Na Homolce Hospital, Cardiology
• France
  • Créteil, France, 94010
    • Hospital Henri Mondor CHU, Service de Cardiologie
  • Lyon, France, 69677
    • CHU Lyon, Départment de Rythmologie, Hospital Cardiologique Pradel
  • Neuilly Sur Seine, France, 92200
    • Centre Chirurgical Ambroise Pare
  • Toulouse, France, 31076
    • La Clinique Pasteur, 45 Avenue de Lombez
• Germany
  • Bad Krozingen, Germany, 79189
    • Herz-Zentrum Bad Krozingen
  • Bad Neustadt/Saale, Germany, 97616
    • Klinik für Kardiologie II mit interventioneller Elektrophysiologie
  • Frankfurt, Germany, 60431
    • Cardioangiologisches Centrum Bethanien - CCB
  • Greifswald, Germany, 17475
    • Universitätsklinikum Greifswald Elektrophysiologie
  • Hamburg, Germany, 20099
    • Asklepios Klinik St. Georg
  • Konstanz, Germany, 78464
    • Herz-Zentrum-Bodensee Konstanz
• Hungary
  • Budapest, Hungary, 1122
    • Semmelweis University of Medicine, Kardiovaskuläres Zentrum
• Italy
  • Milan, Italy, 20138
    • Cardiac Arrhythmia Research Centre Department of Cardiovascular Medicine Centro Cardiologico Monzino University of Milan
• Netherlands
  • Zwolle, Netherlands, 8011
    • Isala Klinieken loc. Weezenlanden Diagram Clinical Resarch
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic, University of Barcelona
  • Madrid, Spain, 28040
    • Arrhythmia Unit Hospital Clinico San Carlos
  • Malaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria, Department of Cardiology, Campus Teatinos sn
  • Valencia, Spain, 46014
    • Hospital Clinico Universtitario, Cardiology Department Arrhythmia Unit
• Switzerland
  • Basel, Switzerland, 4031
    • Universitätsspital Basel, Elektrophysiologie/ Kardiologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Symptomatic PAF with at least two episodes and at least one episode documented (30 seconds episode length, documented by ECG within last 12 months).
• Documented treatment failure for effectiveness of at least one anti-arrhythmic drug(AAD Type I or III, including β-blocker and AAD intolerance).
• ≥ 18 and ≤ 75 years of age.
• Patients who are mentally and linguistically able to understand the aim of the trial and to show sufficient compliance in following the trial protocol.
• Patient is able to verbally acknowledge and understand the associated risks, benefits, and treatment alternatives to therapeutic options of this trial: cryoballoon ablation system or standard RF ablation technique. The patients, by providing informed consent, agree to these risks and benefits as stated in the patient informed consent document. All the details have been presented to him and he has signed the informed consent form for the trial.

Exclusion Criteria:

General exclusion criteria

• Any disease that limits life expectancy to less than one year.
• Participation in another clinical trial (of a drug, device or biologic), either within the past two months or ongoing.
• Pregnant women or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception [oral contraception or intrauterine device (IUD)] or sterile women can be randomized.
• Breastfeeding women.
• Substance misuse.
• Active systemic infection.
• Cryoglobulinaemia.
• Previous participation in this clinical trial.
• Employment by the sponsor or by the department of any of the investigators.
• Close relatives of any of the investigators.

Exclusion criteria related to a cardiac condition

• Patients with prosthetic valves.
• Any previous LA ablation or surgery.
• Any cardiac surgery or percutaneous coronary intervention (PCI) within three months prior to enrollment.
• Unstable angina pectoris.
• Myocardial infarction within three months prior to enrollment.
• Symptomatic carotid stenosis.
• Chronic obstructive pulmonary disease with detected pulmonary hypertension.
• Any condition contraindicating chronic anticoagulation.
• Stroke or transient ischemic attack within six months prior to enrollment.
• Any significant congenital heart defect corrected or not (including atrial septal defects or PV abnormalities) but not including patent foramen ovale.
• New York Heart Association (NYHA) class III or IV congestive heart failure.
• EF < 35 % (determined by echocardiography within 60 days of enrollment as documented in patient medical history).
• Anteroposterior LA diameter > 55 mm (by trans-thoracic echocardiography (TTE or TEE) within three months to prior enrollment).
• LA thrombus (TEE diagnostic performed on admission).
• Intracardiac thrombus.
• PV diameter > 26 mm in right sided PVs.
• Mitral prosthesis.
• Hypertrophic cardiomyopathy (see Appendix IX)
• 2° (Type II) or 3° atrioventricular block.
• Brugada syndrome or long QT syndrome.
• Arrhythmogenic right ventricular dysplasia.
• Sarcoidosis.
• PV stent.
• Myxoma.

Exclusion criteria based on laboratory abnormalities

• Thrombocytosis (platelet count > 600,000 / µl), thrombocytopenia (platelet count < 100,000 / µl).
• Any untreated or uncontrolled hyperthyroidism or hypothyroidism.
• Severe renal dysfunction (stage V, requiring or almost requiring dialysis, glomerular filtration rate (GFR) < 15 ml / min).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Cryoballoon ablation	Procedure: Electrical isolation of the pulmonary veins; Device: ArcticFront® Cardiac CryoAblation Catheter System with the FlexCath Steerable Sheath or ArcticFront® Advance Cardiac CryoAblation Catheter System with the FlexCath Steerable Sheath or any future development generations of this product line, provided they are CE marked and the centre has the experience of at least 10 procedures before including a patient into the study.
ACTIVE_COMPARATOR: Radiofrequency ablation	Procedure: Electrical isolation of pulmonary veins; Device:NaviStar® ThermoCool® Irrigated Tip Ablation Catheter in combination with 3D mapping system CARTO or any future development generations of this product line, provided they are CE marked and the centre has the experience of at least 10 procedures before including a patient into the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Recurrence of Atrial Arrhythmias or Prescription of Anti-arrhythmic Drug or Re-ablation After a Blanking Period of Three Months After the Initial Ablation Procedure	Number of subjects reporting a primary efficacy endpoint	33 months
Number of Subjects With a Primary Safety Event. A Primary Safety Event Includes a Composite of Death (Including Cardiovascular Death), All-cause Stroke/Transient Ischemic Attack (TIA) and Serious Adverse Events of Special Interest.		33 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Death		33 months
Arrhythmia-related Death		33 months
Total Procedure Duration		Through the initial ablation procedure
Total Time of Fluoroscopy		Fluoroscopy meter time through the initial ablation procedure
Number of Subjects Reporting a Cardiovascular Hospitalization Over the Duration of the Study.		33 months
Number of Cardiovascular Hospitalizations	The total number of cardiovascular hospitalizations reported over the duration of the study.	33 months

Collaborators and Investigators

• Sponsor: Medtronic Atrial Fibrillation Solutions
• Collaborators: Medtronic
• Investigators: Principal Investigator: Karl-Heinz Kuck, Prof. Dr., Asklepios Klinikum St. Georg

Publications and helpful links

General Publications

• Kuck KH, Brugada J, Furnkranz A, Metzner A, Ouyang F, Chun KR, Elvan A, Arentz T, Bestehorn K, Pocock SJ, Albenque JP, Tondo C; FIRE AND ICE Investigators. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016 Jun 9;374(23):2235-45. doi: 10.1056/NEJMoa1602014. Epub 2016 Apr 4.
• Furnkranz A, Brugada J, Albenque JP, Tondo C, Bestehorn K, Wegscheider K, Ouyang F, Kuck KH. Rationale and Design of FIRE AND ICE: A multicenter randomized trial comparing efficacy and safety of pulmonary vein isolation using a cryoballoon versus radiofrequency ablation with 3D-reconstruction. J Cardiovasc Electrophysiol. 2014 Dec;25(12):1314-20. doi: 10.1111/jce.12529. Epub 2014 Nov 12.
• Kuck KH, Brugada J, Furnkranz A, Chun KRJ, Metzner A, Ouyang F, Schluter M, Elvan A, Braegelmann KM, Kueffer FJ, Arentz T, Albenque JP, Kuhne M, Sticherling C, Tondo C; FIRE AND ICE Investigators. Impact of Female Sex on Clinical Outcomes in the FIRE AND ICE Trial of Catheter Ablation for Atrial Fibrillation. Circ Arrhythm Electrophysiol. 2018 May;11(5):e006204. doi: 10.1161/CIRCEP.118.006204.
• Chun KRJ, Brugada J, Elvan A, Geller L, Busch M, Barrera A, Schilling RJ, Reynolds MR, Hokanson RB, Holbrook R, Brown B, Schluter M, Kuck KH; FIRE AND ICE Investigators. The Impact of Cryoballoon Versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation on Healthcare Utilization and Costs: An Economic Analysis From the FIRE AND ICE Trial. J Am Heart Assoc. 2017 Jul 27;6(8):e006043. doi: 10.1161/JAHA.117.006043. Erratum In: J Am Heart Assoc. 2017 Sep 15;6(9):
• Kuck KH, Furnkranz A, Chun KR, Metzner A, Ouyang F, Schluter M, Elvan A, Lim HW, Kueffer FJ, Arentz T, Albenque JP, Tondo C, Kuhne M, Sticherling C, Brugada J; FIRE AND ICE Investigators. Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of-life outcomes in the FIRE AND ICE trial. Eur Heart J. 2016 Oct 7;37(38):2858-2865. doi: 10.1093/eurheartj/ehw285. Epub 2016 Jul 5.
• Luik A, Radzewitz A, Kieser M, Walter M, Bramlage P, Hormann P, Schmidt K, Horn N, Brinkmeier-Theofanopoulou M, Kunzmann K, Riexinger T, Schymik G, Merkel M, Schmitt C. Cryoballoon Versus Open Irrigated Radiofrequency Ablation in Patients With Paroxysmal Atrial Fibrillation: The Prospective, Randomized, Controlled, Noninferiority FreezeAF Study. Circulation. 2015 Oct 6;132(14):1311-9. doi: 10.1161/CIRCULATIONAHA.115.016871. Epub 2015 Aug 17.

Helpful Links

• Rationale and Design of FIRE AND ICE: A Multicenter Randomized Trial Comparing Efficacy and Safety of Pulmonary Vein Isolation using a Cryoballoon Versus Radiofrequency Ablation with 3D-reconstruction.
• Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation.
• FIRE AND ICE: LBCT ACC

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: December 6, 2011
• First Submitted That Met QC Criteria: December 9, 2011
• First Posted (ESTIMATE): December 13, 2011

Study Record Updates

• Last Update Posted (ACTUAL): November 2, 2018
• Last Update Submitted That Met QC Criteria: March 2, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: PAF; two episodes within the last twelve months one episode documented; Documented treatment failure of at least one antiarrhythmic; drug AAD Type I or III including β-blocker and AAD intolerance
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: FI-123