Clinical trial NCT03805555: Radiofrequency vs Cryoballoon Ablation for Atrial Fibrillation Assessed by Implantable Cardiac Monitor
Official title: Radiofrequency vs Cryoballoon Catheter Ablation for Pulmonary Vein Isolation in Patients With Atrial Fibrillation - Effect on Atrial Fibrillation Burden Assessed by Implantable Cardiac Monitor (RACE-AF Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Atrial Fibrillation
Keywords: ablation
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
First posted: 2019-01-15
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Paroxysmal atrial fibrillation
* \>2 episodes in 3 months prior to enrollment
* Clinical indication for ablation

Exclusion Criteria:

* Contraindication for ablation
* Valvular heart disease
* Persistent AF only (\>7 days duration or \<7 days duration but requiring cardioversion, as persistent AF was customarily defined at the beginning of this study)
* Documented atrial flutter or other arrhythmias requiring other ablation than PVI
* Implanted pacemaker or defibrillator
* Pregnancy
* Malignant disease (non metastatic skin cancer excluded)
* Obesity (BMI \>35)
* Uncontrolled hypertension (BT \> 160/100 mmHg on repeated measurements)
* Severe sleep apnea
* Active systemic infection
* Renal insufficiency with S-creatinin \> 150 micromol/l
* Psychiatric illness or substance abuse
* Participation in other clinical studies involving medical treatment

Primary outcomes:
measure: Number of veins with durable isolation assessed by invasive follow-up 4-6 months after the index procedure.
timeFrame: 4-6 months
Secondary outcomes:
measure: Treatment failure constituted by the recurrence of atrial fibrillation (AF) after the blanking period (i.e. after the first 3 months following the index procedure).
timeFrame: 4-6 months
measure: Number of patients where procedural endpoint is met: all pulmonary veins isolated and observed isolated for 20 minutes.
timeFrame: During index procedure
measure: Duration of the index procedure
timeFrame: During index procedure
measure: X-ray exposure from the index procedure
timeFrame: During index procedure
measure: Number of patients with procedure related complications.
timeFrame: 0-3 months
measure: Number of patients with all veins isolated at follow-up invasive assessment.
timeFrame: 4-6 months
Other outcomes:
measure: Reduction in AF-burden
timeFrame: 2 years
Locations:
city: Hellerup
country: Denmark
facility: Gentofte Hospital
Study officials:
affiliation: UH Gentofte
name: Jim Hansen, MD
role: PRINCIPAL_INVESTIGATOR
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