PV-Isolation With the Cryoballoon Versus RF:a Randomized Controlled Prospective Non-inferiority Trial (FreezeAF)
Condition: Atrial Fibrillation
MeSH terms: Atrial Fibrillation
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is designed as a randomized, controlled, prospective, non-inferiority clinical
      trial, where the efficacy and safety of the cryoballoon ablation system (CE certificated)
      will be compared to the standard ablation technique (segmental isolation of the pulmonary
      veins) with radiofrequency energy. The primary study aim is to investigate whether the new
      cryoballoon ablation catheter system (Arctic Front CryoAblation Catheters, FlexCath Steerable
      Sheath, CryoCath Technologies Inc., Montreal, Canada) is at least as effective as
      radiofrequency (RF) segmental isolation in electrically disconnecting the pulmonary veins
      (PV) for the treatment of paroxysmal atrial fibrillation (AF) with respect to the absence of
      atrial arrhythmias without persistent complications after six and twelve months. Furthermore,
      the differences in terms of procedural complications such as pulmonary vein stenosis, phrenic
      nerve injuries, cerebrovascular accidents (CVA), pericardial tamponade, pain scores during
      the procedure, levels of cardiac inflammatory markers are compared between the treatment
      groups. The short and long-term clinical success as well as the costs of both systems will
      also be evaluated.
    

Detailed description: 
      Study objectives:

      This study is designed as a randomized, controlled, prospective, non-inferiority clinical
      trial, where the efficacy and safety of the cryoballoon ablation system (CE certificated)
      will be compared to the standard ablation technique (segmental isolation of the pulmonary
      veins) with radiofrequency energy. The primary study aim is to investigate whether the new
      cryoballoon ablation catheter system (Arctic Front CryoAblation Catheters, FlexCath Steerable
      Sheath, CryoCath Technologies Inc., Montreal, Canada) is at least as effective as
      radiofrequency (RF) segmental isolation in electrically disconnecting the pulmonary veins
      (PV) for the treatment of paroxysmal atrial fibrillation (AF) with respect to the absence of
      atrial arrhythmias without persistent complications after six and twelve months. Furthermore,
      the differences in terms of procedural complications such as pulmonary vein stenosis, phrenic
      nerve injuries, cerebrovascular accidents (CVA), pericardial tamponade, pain scores during
      the procedure, levels of cardiac inflammatory markers are compared between the treatment
      groups. The short and long-term clinical success as well as the costs of both systems will
      also be evaluated.

      Brief description of the cryoablation:

      This catheter system uses nitrous oxide as refrigerant to cool the inside of the catheter tip
      or the balloon down to -30 to -70 degree in a closed system. Delivering the freezing energy
      on human cells for several minutes leads to their destruction. The destructed cells cannot
      conduct anymore. For PV isolation the cryoballoon can be placed at the orifice of the
      pulmonary veins to ablate the muscle connections between the PV- and left atrium (LA).

      Study background:

      AF is a common and disabling cardiac arrhythmia, affecting 600.000-700.000 persons in
      Germany. In addition to hemodynamic compromise and higher mortality rates, AF causes an
      increased risk of systemic emboli arising from the LA. The risk of stroke inpatients with
      nonvalvular AF is 5 to 7 times greater than in comparable patients without AF; overall, 20 -
      25% of ischemic strokes are due to cardiac emboli, of which half arise in patients with
      nonvalvular AF. In addition to such proven mortality and morbidity risks, AF is associated
      with a substantial burden of symptoms, stemming from the arrhythmia itself, exacerbation of
      comorbid conditions such as congestive heart failure, associated anxiety over possible
      sequelae as well as the substantial burden of side effects from antiarrhythmic drugs (AAD).
      Currently available treatments are unsatisfactory for many reasons. AAD treatment has a
      relatively low efficacy even in patients suffering from paroxysmal AF, with frequent
      recurrences and a high incidence of intolerable drug side effects. Isolation of PVs using RF
      energy has shown considerable clinical success in the treatment of paroxysmal AF, but has
      been associated with serious complications, including PV stenosis, thromboembolic
      complications, cardiac perforation, phrenic nerve palsies, esophageal fistulae and
      pericardial tamponade. Furthermore, RF can be painful where as freezing with cryotherapy may
      be pain free.

      CryoCath Technologies has developed and tested the Arctic Front™ Cardiac CryoAblation
      Catheter System (with the FlexCath™ Steerable Sheath) to allow the rapid formation of
      continuous cryoablation lesions at the PV ostia. Pre-clinical data have demonstrated
      long-term effectiveness of balloon cryoablation for permanent electrical isolation of the PVs
      with no risk of PV stenosis. Results from these pre-clinical studies suggest that no
      pulmonary venous stenosis and no thromboembolic incidents have occurred even with multiple 4
      or 8-minute cryoenergy deliveries. However, achieving an adequate therapeutic effect using
      focal or linear cryolesions often required multiple applications and lengthy procedure times.
      Balloon cryoablation of subjects with PAF has been studied in PS-011, a feasibility study of
      the Arctic Front™ Balloon Cardiac CryoAblation Catheter System, in conjunction with the
      Freezor® MAX and Xtra and the Arctic Circler Linear™ Cardiac CryoAblation Catheter. Twenty
      (20) subjects were enrolled at two European centers using the 23 mm Arctic Front™ Balloon,
      and an additional 7 subjects were enrolled using 28 mm Arctic Front™ Balloon. Acute
      procedural success was 100%, and long term follow-up reveals a high rate of freedom from
      recurrent AF. A low incidence of adverse events was noted, with two patients experiencing
      reversible loss of phrenic nerve capture during the procedure. Both patients recovered fully.
      Of the original 20 subjects treated with the 23 mm balloon, 16 / 20 (80%) were AF-free
      between the 6 and 12 month follow-up visits. Of the additional 7 subjects treated with the 28
      mm balloon, 5 / 6 (83%) were AF free through 6 months. Another non-randomized feasibility
      study of the Arctic Front™ 23 mm Balloon Cardiac CryoAblation Catheter System under protocol
      PS-012 has completed enrollment at four centers in the United States. Based on incompletely
      monitored data, as of July 12th, 2006, 31 patients have undergone a successful cryoablation
      procedure with Acute Procedural Success (isolation of ≥ 3 PVs) in 100% (31 / 31 subjects).
      Electrical isolation was achieved in 129 / 130 PVs (99.3%). A total of 67 adverse events (AE)
      have been reported, and no deaths. Nine (9) serious AEs have been reported. Four device
      related serious AEs involved changes in phrenic nerve conduction: 3 patients had cryoablation
      discontinued immediately and nerve function recovered completely by 1 month, and the fourth
      subject had transient loss of capture during the procedure, followed at the 1 month visit by
      shortness of breath, a viral infection and slight paralysis of a hemidiaphragm. Two other
      device related serious AEs were a pericardial tamponade requiring pericardiocentesis and
      hospitalization, and a right groin hematoma. Three additional non-device related serious AEs
      included one episode of chest pain, one instance of right neck bleeding after vascular access
      and one instance of left groin site bleeding after vascular access. Long term follow-up for
      PS-012 is incomplete, but 17 subjects have reached 3 months, and 14 / 17 (82%) are free from
      recurrent AF. Only one of these 14 subjects was on a previously failed AF drug, giving a 76%
      (13 / 17) rate of freedom from recurrent AF off drugs.

      Additional data from another non-randomized clinical study are now available (Neumann et al.
      Circumferential pulmonary vein isolation with the cryoballoon technique. JACC 2008, Vol
      52(4); 273-8). 346 patients consecutive patients in three German centers have undergone a
      successful cryoablation therapy. The study population consisted of 293 patients with
      paroxysmal and 53 patients with persistent atrial fibrillation. Isolation of the pulmonary
      veins was achieved in 97% where as freedom from documented paroxysmal atrial fibrillation was
      achieved in 74% after a median follow-up of 12 month. No death and no PV narrowing occurred.
      In 26 patients (7,5%) a phrenic nerve palsy could be observed. The majority of the patients
      recovered within 6 month, all patients recovered within 12 month.

      Based on these encouraging results this randomized clinical study has been designed to
      provide valid scientific evidence of the safety and effectiveness of the Arctic Front™
      Cardiac CryoAblation Catheter System (with a FlexCath™ Steerable Sheath) to electrically
      isolate PVs in patients with PAF by comparing it with segmental isolation with RF-energy,
      which represents the most widely accepted and used energy form in AF-ablation procedures.
      Compared to the RF ablation procedures PV isolation with the Cryo Balloon technique is easier
      and faster to perform and there is no need for expensive additional mapping systems to avoid
      current dreaded complications such as PV-stenosis or esophageal fistula.

      Eligibility criteria:

      Inclusion criteria:

        -  Documented paroxysmal PAF: PAF diagnosis, 2 episodes of PAF within the last 3 months, at
           least 1 episode of PAF must be documented.

        -  Age 18-75

        -  Documented effectiveness failure of at least 1 AAD including beta-blockers

      Exclusion criteria:

        -  AAD usage < 3 half life periods (except beta-blocker)

        -  LA size > 55 mm

        -  LA thrombus

        -  Previous LA ablation/surgery, structural heart disease, heart failure class III-IV

        -  Hypertrophic cardiomyopathy

        -  Mitral prosthesis

        -  Unstable angina

        -  Uncontrolled hyperthyroidism

        -  Stroke or TIA within 6 months

        -  Myocardial infarction within 2 months

        -  Cardiac surgery within 3 months

        -  Thrombocytosis, thrombocytopenia

        -  Any condition contraindicating chronic anticoagulation

        -  EF <40%

        -  Pregnancy

        -  Life expectancy <1year

      Preprocedural investigations:

        -  Transesophageal echocardiography to exclude LA thrombus in each patient before each
           ablation

        -  CT or MRT of the LA (optional)

      Ablation procedure:

      After venous and arterial access a single or double transseptal puncture is performed. In
      both groups a pulmonary vein angiography must be performed before and after PV - isolation
      for all of the PVs. PV - potentials must be recorded before and after PV - isolation with a
      circular mapping catheter. In group 1, the RF - ablation procedure is performed using an open
      4 mm irrigated tip catheter in combination with a 3D - navigation system. It is recommended,
      that the 3D - navigation system should be able to display all mapping and ablation catheters.
      An antral PV - isolation will be performed. In group 2 a cryoablation of the PV - ostia using
      either the 28 mm or the 23 mm cryo-balloon will be attempted. At least two cryoenergy
      applications of 300 - 360 sec must be performed in each PV. Additional cryoenergy
      applications can be delivered if necessary to achieve complete isolation. The 28 mm
      cryoballoon should be used preferentially for all veins. If a complete isolation could not be
      achieved with the 28 mm cryoballoon ablation, a switch over to the 23 mm balloon is possible;
      otherwise touch-ups with a conventional cryocatheter (Freezor® Max, CryoCath) will be
      performed.

      In both groups the aim is to completely isolate the PVs. The upper limit of RF - or cryo -
      applications is dependent on the procedure duration and the clinical condition at the time of
      the procedure and left to the physician´s decision. After the ablation all the pulmonary
      veins should be assessed with angiography to detect an ablation mediated PV - stenosis.

      Anticoagulation: All patients should be anticoagulated four weeks before and at least six
      months after the index procedure. During the procedure the activated clotting time (ACT) must
      be kept between 250-350 sec by i.v. heparin administration.

      AAD: All AAD should be discontinued 4 to 5 half-life periods before the procedure. No AAD
      will be prescribed (except betablocker) after the procedure.

      Follow-up:

      All patients will be monitored during the hospital stay after the procedure (the first
      24-48h). Additional clinical visits will be performed at three, six, nine and twelve months
      after the last procedure. Another MRI or CT scan should be performed at the third month to
      re-evaluate the PVs and at least one 24h holter ECG recording to screen for symptomatic or
      asymptomatic atrial arrhythmias (AF, AT) has to be done. An event recorder or holter ECG to
      reveal the long-term recurrences will be given at the six and twelve month follow-up (for
      minimum of seven days, preferably 14 days) 22. In case of a recurrence a second procedure can
      be performed six months after the index procedure. The procedure of choice for the
      recurrences will be the same modality to which the patient originally had been randomized

      Endpoints:

      Primary endpoints:

      Combined endpoint out of:

      Absence of atrial arrhythmias and absence of persistent complications six and twelve months
      after the procedure .

      Secondary endpoints:

      Short- and mid-term clinical success Long-term clinical success Total radiation exposure
      Total procedure duration Pain sensation during the procedure Quality of life Changes in
      cardiac markers (CK, troponin, CRP) Bleedings Costs

      Biometrical concept:

      Randomization The randomization numbers will be allocated to the two groups in balanced
      permuted blocks using the random number generator of the validated software SAS®. To avoid
      any potential of predicting the group allocation of future patients, the block length is
      fixed in a separate document that is withheld from the study site. Sealed envelopes are
      produced labeled with the randomization number. Inside of the sealed envelope, a data sheet
      defines the group allocation of the patient with the respective randomization number. On
      enrollment in the study, each patient receives the randomization envelope in consecutive
      order of inclusion in the study. Basic characteristics of the patient and day of
      randomization are documented on the data sheet in order to allow a check whether the
      randomization scheme was observed strictly.

      Statistical considerations:

      Test problem and analysis of primary endpoint The primary objective of this trial is to
      demonstrate non-inferiority of isolating PVs procedure with the cryoballoon catheter (CC) as
      compared to radiofrequency isolation (RF) with respect to the primary endpoints "absence of
      atrial arrhythmias and absence of persistent complications six and twelve months after the
      procedure", respectively. For this purpose, the following test problems will be assessed:
      Null hypothesis H0: pCC (rate of absence of atrial arrhythmias and absence of persistent
      complications twelve months after the procedure with CC) - pRF (rate of absence of atrial
      arrhythmias and absence of persistent complications twelve months after the procedure with
      RF) -d versus alternative hypothesis H1: pCC - pRF > -d, where d = 0.15 defines the
      non-inferiority margin that is deemed to be acceptable in view of the advantages of CC with
      respect to aspects other than the primary endpoint. The analogous test problem is formulated
      for the endpoint after six months follow up. These test problems will be analyzed applying
      the non-inferiority test for rates according to Farrington and Manning17 at a one-sided
      significance level of a = 2.5%. The following multiple test procedure for hierarchically
      ordered hypotheses is applied to account for the multiplicity in primary endpoints: The null
      hypothesis formulated for the six months outcome is only tested if the null hypothesis for
      the twelve months outcome can be rejected; otherwise both null hypotheses are accepted. If
      both null hypotheses can be rejected, the null hypotheses H0g are tested at one-sided level a
      = 2.5% for margins g < d as long as H0g has to be accepted for a value gSTOP. Then,
      non-inferiority of CC as compared to RF has been shown for all non-inferiority margins g <
      gSTOP. This multiple test procedure controls the overall type I error rate a18, 19.

      Confirmatory analysis will be primarily based on the FAS which is consistent with the
      intention-to-treat (ITT) principle by including all patients who were randomized to the two
      groups. This approach reflects the idea that the study should match as close as possible to
      the conditions in clinical practice. However, the PP analysis plays an important role
      particularly in non-inferiority studies, and therefore the results of the PP analysis set are
      to be interpreted and discussed with special attention in parallel to the ITT analysis.

      Determination of the sample size Sample size calculation is based on the following
      considerations. In view of the advantages of CC as compared to RF in dimensions other than
      the primary endpoints, an inferiority by a difference in rates of 0.15 for CC as compared to
      RF with respect to the two primary outcomes is deemed to be acceptable. Therefore, the
      non-inferiority range was set equal to d = 0.15. On the basis of previous studies and
      experiences with the procedures16, equal rates of pCC = pRF = 0.78 are assumed for sample
      size calculation. Under these assumptions, the sample size required to achieve a power of 1 -
      b = 80% for the one-sided Farrington-Manning test at level a = 2.5% amounts to 2 x 122 = 244
      patients17. In order to cope with the uncertainty about the assumed overall rate of 0.78, a
      sample size review is performed after 150 patients are randomized or the outcome of the
      primary variable is available for 100 patients, respectively, depending on which of the
      events occurs first. No significance test is performed then and hence there is no option for
      early stopping with rejection of the null hypothesis. Instead, the overall rate for the
      primary variable is estimated based on the available data and the sample size is recalculated
      employing the obtained value in the sample size formula (i.e. pCC = pRF = estimated overall
      rate) and leaving the values for a, 1-b, and d as above. It was shown that this procedure
      does not affect the type I error rate of the analysis20.

      Each patient's allocation to the different analysis populations (full analysis set (FAS)
      according to the intention-to-treat (ITT) principle, per protocol (PP) analysis set, safety
      analysis set) will be defined prior to the analysis. The allocation will be documented in the
      statistical analysis plan.

      During the data review before start of any analysis, deviations from the protocol will be
      assessed as "minor" or "major". Major deviations from the protocol will lead to the exclusion
      of a patient from the PP analysis set. If a patient discontinues from the study prematurely,
      missing data with respect to the primary outcome variable will be replaced by ICA-r method19.

      Analysis of secondary endpoints The secondary variables will be analyzed descriptively by
      tabulation of the measures of the empirical distributions. According to the scale level of
      the variables, means, standard deviations, median, 1st and 3rd quartiles as well as minimum
      and maximum or absolute and relative frequencies, respectively, will be reported. Logistic
      regression models will be applied to assess the effects of potential risk factors on primary
      and secondary efficacy variables. Additionally, for variables with longitudinal measurements
      the time courses of individual patients and summarized by treatment groups will be compared.
      Descriptive p-values of the corresponding statistical tests comparing the treatment groups
      and associated 95% confidence intervals will be given.

      The safety analysis will be based on the set of all patients for which one of the procedures
      was applied. Adverse and serious adverse events as well as complications will be tabulated,
      absolute and relative frequencies; the severity and the relationship to the procedure will be
      given and compared between the groups. Cardiac markers will be described and interpreted with
      respect to the reference values, and the measures describing the empirical distributions of
      the changes are calculated. Additionally, for each cardiac marker, shift tables presenting
      changes between the categories "normal" and "abnormal" will be given per treatment group.

      Definitions:

      Acute procedural success: Successfully isolation of all the pulmonary veins

      Clinical success:

      Absence of any atrial arrhythmias sustaining longer than 30 seconds evaluated either by
      telemetric monitoring, 24 hour ECG recordings or event recorder Short-term clinical success:
      from the procedure until hospital discharge Mid term clinical success: up to three months
      after the procedure Long-term clinical success: up to six months after the procedure

      Procedure related complications: Any new PV-stenosis, phrenic nerve palsy, CVA, bleedings or
      vascular complications which occurs during and/or within 48 hours after the procedure.

      Persistent complications:

      Any procedure related complication lasting longer than 6 months after the procedure and
      either classified as major complication or still symptomatic.

      PV-stenosis:

      Angiographic late lumen loss of any PV in comparison to the pre-procedural data Minor:
      asymptomatic or stenosis less than 50%; Major: symptomatic or stenosis greater than 50%. 3
      months after the procedure either a computer tomography, magnet resonance tomography or a
      echocardiography will be performed to re-evaluate the severity grade of the stenosis. If a
      stenosis is detected a repeat diagnosis will be performed at 6 month.

      Phrenic nerve palsy:

      Radiological restricted movement of the diaphragm Minor: asymptomatic or less than 50%
      restriction Major: symptomatic or more than 50% restriction In cases of persistent symptoms
      due to phrenic nerve palsy at least one fluoroscopy will be performed up to the 6 months
      follow-up to verify the restriction of the diaphragm.

      Bleedings and vascular complications:

      Minor: Any bleeding or vascular complication (hematoma, pseudoaneurysm, atriovenous fistula)
      requiring prolonged hospitalization but could be managed conservatively Major: Any bleeding
      or vascular complication requiring additional therapy (i.e. surgery, transfusion therapy)

      CVA: Every new TIA or stroke after the procedure.

      Quality of life:

      Before and at every clinical visit patients will be ask to complete a standardized
      questionnaire to evaluate the symptomatic and life restrictiveness originating from the
      arrhythmia.

      Pain After venous and arterial puncture and after the complete procedure the patients will be
      asked to grade their sensation of pain (range 1-10)

      Costs Standard prices for consumable material such as catheters, electrodes, refrigerant per
      EP study will be evaluated. Purchase or leasing prices i.e. for a mapping system or the cryo
      console will not be considered.

      Abbreviations:

      AAD: Antiarrhythmic drugs AE: Adverse events AF: Atrial fibrillation AT: Atrial tachycardia
      CVA: Cerebrovascular accident EF: Ejection fraction LA: Left atrium PAF: Paroxysmal atrial
      fibrillation PNP: Phrenic nerve palsy PV: Pulmonary vein RF: Radiofrequency energy TIA:
      Transient ischemic attack
    

Intervention name(s): PV-Isolation RF; PV-Isolation Cryo
Intervention type(s): Procedure; Procedure
Intervention description(s): Radiofrequency; Cryo-Balloon
Other intervention name(s): RF; Cryo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: catheter ablation; randomized; cryo; radiofrequency; atrial fibrillation; cryo-balloon; PV-Isolation