Radiofrequency vs Cryoballoon Ablation for Atrial Fibrillation Assessed by Implantable Cardiac Monitor
Condition: Atrial Fibrillation
MeSH terms: Atrial Fibrillation
Study type: Interventional

Summary: 
      The study is a prospective randomized comparison of two methods of catheter ablation of
      atrial fibrillation: Radiofrequency ablation which is the standard of care will be compared
      to Cryoballoon ablation to perform pulmonary vein isolation. Primary endpoint for the
      randomized comparison is the number of pulmonary veins that remain isolated on follow up
      investigation. All patients will receive an implantable loop recorder to monitor clinical
      response and identify patients who benefit the most from durable pulmonary vein isolation.
      All patients will undergo a follow-up invasive assessment of pulmonary vein isolation, and
      veins with reconnection will be re-isolated to determine if this strategy alters clinical
      long-term outcome of ablation.
    

Detailed description: 
      Atrial fibrillation (AF) is the most common heart rhythm disorder and carries considerable
      mortality, morbidity and socio-economic costs in western societies. Treatment options include
      anticoagulation to prevent thromboembolisms, antiarrhythmic or heart rate limiting drugs to
      control symptoms, and catheter or surgical ablation to potentially eliminate sources of
      atrial fibrillation. Curative treatment is difficult, but ablation has been shown to be
      superior to anti-arrhythmic drug treatment in the prevention of recurrent symptomatic atrial
      fibrillation in selected patients. The highest success rates are achieved in patients with
      self-limiting episodes (paroxysmal atrial fibrillation, PAF), where data from randomized
      controlled trials such as the recent MANTRA-PAF trial suggests ablation as a reasonable first
      line treatment option. Almost anticipatory to these recent studies, there has been an
      exponential growth in ablation procedures, which over the past decade has been offered
      increasingly to patients without prior antiarrhythmic drug treatment. The therapeutic concept
      for ablation is elimination of triggers of PAF by pulmonary vein isolation (PVI): Focal
      triggers of atrial fibrillation are primarily located around the ostia of the pulmonary veins
      draining into the left atrium, and the cornerstone of standard ablation strategies is to form
      an encircling lesion around the pulmonary vein to isolate the trigger areas, thereby
      preventing triggering of atrial fibrillation. However, success rates remain far below those
      achieved with ablation of other types of arrhythmias, and results of long-term follow up has
      shown annual rates of recurrence in the order of 5-10% even in patients with initially
      successful ablation, leading to long term cure rates at or well below 50%. This highlights
      the need for more effective ablation strategies to achieve better long-term cure rates for
      atrial fibrillation.

      To meet this need, there has been a continuing development of ablation strategies and methods
      of ablation, including technologies for robotic steering of catheters and technologies to
      sense contact force between the ablation catheters and the heart to improve lesion formation.
      Cryoballoon ablation is emerging as a safe, efficacious and simple method to isolate
      pulmonary veins by a freeze-thaw lesion around the ostia, and seems to be the most promising
      alternative to radiofrequency (RF) ablation for atrial fibrillation. The latter is a complex
      procedure involving the use of electroanatomical computer mapping systems to generate
      three-dimensional models of the left atrium in each patient, and has a very long learning
      curve for operators. In contrast, cryoballoon ablation is achieved with a compliant balloon
      placed over a guiding catheter in the pulmonary vein ostia and designed for single shot
      isolation of each vein, without the use of a mapping system and with relatively short
      learning curves. However, there has been no direct comparison of the two methods in a
      randomized study, such as the one we are now proposing.

      The underlying cause for recurrences of atrial fibrillation after ablation is presumed to be
      recovery of electrical connection to the pulmonary veins. This presumption is based on the
      finding of a high rate of reconnected pulmonary veins in patients with clinical recurrence
      undergoing a second ablation procedure, but whether it exceeds that found in patients without
      recurrence has not been systematically investigated in order to provide proof of concept. One
      problem in this regard, is the difficulty in assessing the true occurrence of atrial
      fibrillation since many episodes, particularly after ablation, are known to be asymptomatic
      and self limiting. This problem can now be overcome by continuous monitoring of the heart
      rhythm with a small subcutaneously implantable cardiac monitor which has been shown to
      reliably detect episodes of atrial fibrillation and determine the time spent in atrial
      fibrillation ("AF burden") This also raises the possibility that pre-ablation monitoring in
      the individual patient can identify specific patterns of atrial fibrillation that is either
      amenable or resistant to curative ablation, thereby improving patient selection for catheter
      ablation.

      A considerable proportion of patients have to undergo more than one ablation procedure within
      the first year to achieve freedom from atrial fibrillation (30-50% depending on a number of
      clinical factors). Re-isolation of the pulmonary veins will eliminate atrial fibrillation in
      about 50-60% of these patients, but even so, as with initially successfully ablated patients
      there is a long-term recurrence rate. Whether this pattern of short and long-term
      recurrences, that carries considerable morbidity, socioeconomic costs and loss of quality of
      life, could be avoided by a routine strategy with a second ablation procedure with
      consolidating pulmonary vein isolation has not been investigated. Our study will provide
      hypothesis-generating data on this issue.

      Thus, several key questions regarding ablation for atrial fibrillation lack definitive
      answers, including the following:

        1. What is the best method for achieving durable pulmonary vein isolation?

        2. Is durable isolation of all pulmonary veins necessary and sufficient to eliminate atrial
           fibrillation in all patients?

        3. How do we select the patients that will benefit most from PV isolation? Specifically,
           can continuous pre-ablation monitoring identify patients that are likely to have either
           excellent or little effect of ablation?

        4. Could early re-isolation of pulmonary veins improve long-term results, even in patients
           without early recurrences of AF?

      The overall purpose of the present study proposal is to provide answers to these questions by
      using an implantable cardiac monitor implanted 1 month prior to ablation to assess the effect
      of PVI in patients with paroxysmal AF, randomized to either best radiofrequency ablation
      (using a 3D mapping system with contact force sensing technology and irrigated tip catheters)
      or Cryoballoon ablation using a new generation of the cryoballoon catheter. The outcome of
      ablation will be assessed by 1) The number of completely isolated pulmonary veins at a
      planned 2nd procedure 4-6 months after the initial procedure and 2) reduction in AF burden
      pre- vs post ablation. All patients will thus undergo a second procedure (either a clinically
      indicated re-ablation procedure or a planned invasive study) no earlier than 4 months and no
      later than 6 months after the initial procedure. In agreement with current standards, the
      study will utilize a 3 month blanking period after the first ablation (during which
      recurrences can be a nonspecific consequence of ablation and are therefore not counted as
      therapy failure). Pulmonary veins that are found to be re-connected during the 2nd procedure
      will be isolated irrespective of symptom status and arrhythmia occurrence.

      Because this study design is tightly controlled and patients burdened with direct, invasive
      outcome measures, we have the opportunity and the obligation to maximize the scientific
      benefit of the study by analyzing data in several strata by pre-specified subprotocols in an
      embedded 2-in-1 study design.

      Data will be analyzed according to randomization status of the patient (i.e.
      intention-to-treat), to achieve the primary study objective of comparing the two methods of
      ablation; and subsequently according to pulmonary vein isolation status (irrespective of
      randomization) to achieve the study objectives of determining the effect of durable pulmonary
      vein isolation on the occurrence of atrial fibrillation. Finally, the whole cohort will be
      followed for two years to determine mid- to long-term effects of repeated PV isolation on AF
      burden.
    

Intervention name(s): Radiofrequency ablation; Cryoballoon ablation
Intervention type(s): Procedure; Procedure
Intervention description(s): Pulmonary vein isolation by radiofrequency ablation; Pulmonary vein isolation by cryoballoon ablation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ablation