TITLE:

Cryoballoon Ablation for Atrial Fibrillation

AUTHOR:

Judith Walsh, MD, MPH Professor of Medicine Division of General Internal Medicine Department of Medicine University of California San Francisco

PUBLISHER:

California Technology Assessment Forum

DATE OF PUBLICATION:

June 29, 2011

PLACE OF PUBLICATION:

San Francisco, CA

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CRYOBALLOON ABLATION FOR ATRIAL FIBRILATION A Technology Assessment INTRODUCTION The California Technology Assessment Forum (CTAF) was asked to assess the evidence for cryoballoon catheter ablation for the treatment of atrial fibrillation. This topic is being reviewed now because of its potential as a new nonpharmacologic ablative procedure for the treatment of atrial fibrillation (AF). BACKGROUND AF, the most common sustained atrial arrhythmia, is more common in men where the prevalence increases with increasing age1. AF can be paroxysmal (episodes terminate in less than seven days), persistent (more than seven days) or chronic (more than a year). AF can cause significant symptoms including palpitations, shortness of breath and fatigue. In addition, AF is associated with a fivefold increased risk of stroke as well as an increased risk of mortality. The two goals of therapy of AF are risk reduction of stroke and alleviation of symptoms. Stroke reduction requires anticoagulation with warfarin for most individuals. Treatment of the symptoms of AF include strategies to convert the patient back to normal sinus rhythm or strategies to control the rate of AF. Although there was no overall mortality difference, some randomized trials of rate versus rhythm control have suggested a trend toward reduced mortality in patients who are treated with rate control2-4. There were no differences in functional status of quality of life. Maintenance of sinus rhythm has typically been achieved with electrical cardioversion or with antiarrhythmic drugs. Antiarrhythmic drugs can sometimes have limited efficacy and can also have significant side effects which limit their long term use. Because of the limitations of antiarrhythmic drugs, nonpharmacologic approaches to the maintenance of sinus rhythm have been explored. These nonpharmacologic approaches include surgery or ablation procedures, such as radiofrequency ablation (RFA) or cryoballoon ablation. 2

The initiation of AF requires both a trigger either within or near the atria and a susceptible substrate within the atria5. Ablation procedures for preventing recurrent AF are directed towards 1) elimination of the triggers of AF which is done by disrupting the conduction of electrical activity between the tissues that contain the arrhythmogenic triggers (usually the pulmonary veins (PV)) and the atrial myocardium or 2) modifying the atrial substrate responsible for maintaining AF. The triggers in paroxysmal AF and chronic or persistent AF appear to be different, which makes paroxysmal AF a better potential target for ablation procedures. In paroxysmal AF, ectopic beats commonly come from muscle fibers that extend from the left atrium (LA) to the pulmonary veins (PV). These ectopic foci can be localized to the PV in about 90% of people with paroxysmal AF. Most patients only have one or two foci, making them easier targets for ablation. The majority of the foci are from 2-4 cm inside the PV and the remaining foci are usually in the right or LA. Ablation attempts have typically targeted the foci in the PV6-8. In contrast, in chronic AF, there tend to be multiple ectopic sites throughout the atria. Since ablation procedures often focus on isolation of the PV, these procedures are potentially less efficacious in patients with chronic AF9. The goal of most ablation procedures is to achieve complete electrical isolation of the PV from the left atrium. Many studies evaluate PV isolation as an intermediate outcome when evaluating cryoballoon ablation efficacy. Although RFA has been successful in eliminating some ectopic foci, and in reducing symptomatic AF at one year follow-up10, challenges with RFA have included difficulties in isolating the ectopic focus and PV stenosis. Isolation of the PV ectopic foci using RFA is complicated and requires complex imaging and mapping techniques. Because of difficulties in isolating the ectopic foci in the PV, some newer approaches have aimed to isolate all four PVs from the body of the atrium6. Cryoballoon ablation has the theoretical advantage of allowing PV isolation with a single application, whereas with conventional RFA technology, multiple applications around the PVs are

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required to isolate the PVs at the level of the antrum. In addition, cryoablation is potentially simpler and less dependent on the operator. In conclusion, cryoballoon ablation has been proposed as a treatment alternative for AF, and may be particularly useful in AF refractory to antiarrhythmic drug therapy (ADT). Similar to other ablation procedures, it has the potential advantage of avoiding long term drug side effects. In comparison with RFA, it has the theoretic advantage of simpler isolation of the pulmonary veins. Thus, the question is how does it compare to other treatment options for the treatment of drug refractory AF. TA Criterion 1: The technology must have final approval from the appropriate government regulatory bodies Cryoablation for atrial fibrillation is a procedure and not subject to FDA approval. However, devices used for this procedure may be subject to FDA approval. The Arctic Front® Cardiac CryoAblation Catheter system by Medtronic which received FDA PMA status in August 2007 is the only device approved for use for this procedure. Some studies have indicated the use of the CryoCor device for atrial fibrillation. However, the CryoCor device has FDA clearance for use in only atrial flutter and therefore any use for atrial fibrilation would be considered off label. TA criterion 1 is met. TA Criterion 2:

The scientific evidence must permit conclusions concerning the

effectiveness of the technology regarding health outcomes. The Medline database, Cochrane clinical trials database, Cochrane reviews database and Database of Abstracts of Reviews of Effects (DARE) were searched using the search terms atrial fibrillation or paroxysmal atrial fibrillation and also with the term cryotherapy or cryosurgery or cryoballoon or cryoablation or cryo-Maze or cryotherm and catheter ablation and argon or cool or cooled or cooling. The search was performed for the period from 1966 to April, 2011. The

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bibliographies of systematic reviews and key articles were manually searched for additional references and references were requested form the device manufacturer. The abstracts of citations were reviewed for relevance and all potentially relevant articles were reviewed in full. Inclusion criteria: 

Study had to evaluate cryoballoon ablation in patients with AF



Study had to measure clinical outcomes



Included only humans



Published in English as a peer reviewed article

Studies were excluded if they only focused on non-clinical outcomes. They were also excluded if they were retrospective. We also excluded studies that only evaluated cryoablation techniques as part of a surgical procedure. A total of 590 potentially relevant articles were identified. 535 were excluded for not addressing the research question. A total of 55 abstracts were evaluated. 43 were excluded. Reasons for exclusion included not reporting clinical outcomes, not being prospective, or evaluating cryoablation as part of a surgical procedure. Of these, twelve published prospective studies are included in this evaluation. Details of the twelve prospective studies and the outcomes measured are described in Table 1. There were ten prospective observational studies and two nonrandomized comparison studies. To date, no randomized controlled trials (RCT) evaluating clinical outcomes comparing cryoablation with other atrial fibrillation treatments have been published. Although the outcomes varied among the studies, typical outcomes included the percentage of individuals remaining free from atrial arrhythmias or the time to recurrence of atrial tachyarrhythmia. No studies have assessed the impact of cryoballoon ablation on the important outcomes of mortality, stroke, heart failure or progression of paroxysmal AF to more persistent forms, although typically the main goal of catheter ablation is to decrease the symptoms associated with AF.

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Table 1: Study Characteristics of Prospective studies of Cryoballoon Ablation for the Treatment of Atrial Fibrillation Study

N

Neumann, 200811

346

Hoyt, 200512

32

Defaye, 201113

117

Moreira, 200814

70

Klein, 200815

21

Chun, 200916

27

Chierchia, 201017

21

Mansour, 201018

22

Tang, 201019

23

Kuhne, 201020

14

Inclusion Criteria Symptomatic and drug refractory paroxysmal or persistent AF Drug refractory paroxysmal AF Paroxysmal or persistent AF resistant to or intolerant of drugs Recent onset parosysmal AF Highly symptomatic paroxysmal AF and at least one unsuccessful try of anti arrhythmic therapy Highly symptomatic AF despite drug treatment Symptomatic drug resistant paroxysmal AF Drug refractory persistent AF Symptomatic medically refractory paroxysmal AF Symptomatic

Intervention

Outcomes

Cryoablation (Arctic Front CryoCath)

First recurrence of AF

Cryoablation (CryoCor) Cryoablation (Arctic Front CryoCath)

First recurrence of AF Freedom from symptomatic or documented AF

Cryothermic ostial PV isolation (CryoCor) Cryoablation (Arctic Front CryoCath)

Complete success; recurrences Recurrence of symptomatic AF

Cryoablation (Arctic Front CryoCath)

Acute PVI Complications AF recurrence

Cryoablation (Arctic Front CryoCath) Cryoablation (Arctic Front CryoCath) and RFA Cryoablation (Arctic Front CryoCath)

Recurrence of atrial arrhythmias

Cryoablation

% free from AF

% AF free without antiarrhythmic drugs % free from AF

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persistent, paroxysmal AF

(Arctic Front CryoCath) Mesh Ablator catheter (MESH) (n=43) vs cryoballoon (n=36) (manufacturer not stated) (sequential patients) Cryoablation (Arctic Front ) (n=124)or RFA (n=53) (nonrandomized)

Clinical success freedom from AF off drugs

Nonrandomized comparisons Hofmann, 201021

79

Symptomatic drug refractory paroxysmal AF “Anatomically suitable Pulmonary Veins (PV)”

Kojodjojo, 201022

177

Symptomatic medically refractory persistent or paroxysmal AF

245

At least 2 episodes of documented AF in previous 2 months or treatment failure with at least one anti-arrhythmic drug

Cryoablation (Arctic Front CryoCath) vs antiarrhythmic drug therapy

Freedom from combined outcome of detectable AF, use of non-study drugs and other AF interventions

Goal 244

At least two episodes of PAF in past 3 months; failure of at least on ADT

RFA vs Cryoablation (Arctic Front CryoCath)

Freedom from AF without antiarrhythmic drugs and without persistent complications at 6 and 12 months

Completed, not yet published STOP-AF, 2010 abstract

Ongoing FREEZE-AF [Luik, 2010]

Table Legend: AF Atrial fibrillation MESH Mesh ablator catheter RFA Radiofrequency catheter ablation

PVI ADT

% free from AF

Pulmonary vein isolation Anti-arrhythmic drug therapy

Level of Evidence: 3,4,5

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TA Criterion 2 is met. TA Criteria 3: The technology must improve net health outcomes A total of 693 patients were included in 10 prospective studies of cryoballoon ablation. Two additional nonrandomized studies compared cryoablation with RFA. The study characteristics are described in Table 1 and the study results are described in Table 2. The majority of the noncomparative studies had less than 50 patients each; two of the studies were larger and accounted for 463 of the 693 patients. Follow-up ranged from six months to one year. Some of the studies only included patients with paroxysmal AF, but many included patients with either paroxysmal or persistent AF.

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Table 2: Results of Prospective Studies of Cryoballoon Ablation in the Treatment of Atrial Fibrillation Study

Mean age

Average length of

Results

follow-up Neumann, 200811

59

12 months

Hoyt, 200512

Not reported

6 months

Defaye, 201113

55

9.6 months

Moreira, 200814

40

33 months

Klein, 200815

56

6 month

Chun, 200916

56

271 days

Chierchia, 201017

73

11.5 months

Mansour, 201018

22

6 months

Tang, 201019

Not reported

7.4 months

Kuhne, 201020

59

1 year

Maintenance of sinus rhythm in 74% of patients with paroxysmal AF and 42% of those with persistent AF Of 29 with immediately successful ablation, 7 had recurrence within 3 months. Among 22 with single cryoablation, 18 (82%) free of symptomatic AF and 55% off antiarrhythmic drugs Paroxysmal AF: at 6 months 79% recurrence free and 69% recurrence free at 12 months 49% complete success (no AF and no drugs) 22% had no recurrence with antiarrhythmic drugs 86% of patients free of AF at 6 months 39% with AF recurrence 62% with no arrhythmia symptoms at follow up 86.4% AF free and not on ADT 74% free form AF at 7.4 months 71% free from AF at 9

one year follow up Nonrandomized comparisons Hofmann, 201021

56/59

6 months

Kojodjojo, 201022

57/61

13.1 months

57

12 months

Completed, not yet published STOP-AF 2010 abstract

Table legend: AF Atrial fibrillation MESH Mesh Ablator catheter RFA Radiofrequency catheter ablation

ADT PAF

Clinical success 44% in MESH and 69% in cryo (p,0.05) 77% of PAF treated with cryo free of AF at 12 months (vs 72% for RFA) 48% of persistent AF treated with cryo free of AF at 12 month follow-up (too few to calculate for RFA) 69.9% free of AF and did not require administration of a non-study drug or interventional procedure for treatment of AF Antiarrhythmic drug therapy Paroxysmal atrial fibrillation

In the single center French study done by Defaye et al., 117 consecutive patients with paroxysmal (n=92) or persistent (n=25) AF were followed for an average of 9.6 months after undergoing cryoablation. At nine months, 79% of patients with Paroxysmal atrial fibrillation (PAF) were AF free, whereas at nine months 59% with persistent AF were AF free. Phrenic nerve palsy was the most frequent complication. In the largest prospective study, 346 patients in three centers with drug refractory PAF (n=293) or persistent AF (n=53) underwent cryoablation11. Similar to the results seen in the French study, 10

more patients with PAF than with persistent AF remained in sinus rhythm at 12 month follow up (74% vs 42%). Phrenic nerve palsy was the most frequent complication. Other complications included those related to the catheter (femoral AV fistula, femoral arterial pseudoaneurysm). Two patients had transient ST elevation that resolved within two minutes. There were no cases of PV stenosis, although this complication has been reported in other studies of this procedure. Potential Benefits In all ten of the observational noncomparative studies, as well as in the two nonrandomized comparative studies, cryoballoon ablation was associated with a significant percentage of patients being free of AF and/or being off ADT at follow-up. Many of the studies included patients with both PAF and persistent AF and, in general, the benefits seemed to be greater in those with PAF, but these groups were not analyzed separately. In a recent meta-analysis of cryoballoon ablation studies, among studies reporting a three month blanking period (time frame during which transient arrhythmias were not considered recurrences) , at one year follow-up, 72.83% were free from recurrent AF23. Again, these were mostly observational studies with no comparison group. Overall, the follow-up of these observational studies were relatively short (longest was one year) and there were no comparison groups, but many patients were free of AF at follow-up. Potential Harms The most common complication of cryoballoon ablation is phrenic nerve palsy, with an incidence of 6.38% in a recent meta-analysis23. The incidence went down to 4.73% after the ablation period. The vast majority of patients recovered with time, with only 0.37% having phrenic nerve palsy that lasted more than a year. PV stenosis is a common complication of ablation procedures although it is often asymptomatic. Among studies that systematically screened for PV stenosis, the incidence of radiographic PV 11

stenosis was 0.89%23. However, in a recent study presented in abstract form (STOP-AF) , PV stenosis occurred in 3% of patients24. Overall the incidence of significant PV stenosis resulting in symptoms or requiring intervention was 0.17% in the recent meta-analysis23. The incidence of thromboembolic complications, including periprocedural stroke, transient ischemic attacks (TIA) or myocardial infarction (MI), was 0.57%, and pericardial effusion or tamponade occurred in 1.46% of cases23. Overall, when comparing the complications seen with cryoablation with those seen with RFA, the complication rates seem to be relatively similar. Summary In summary, AF cryoballoon ablation leads to a significant number of patients being free from AF at follow up and off ADT, although the longest duration of follow up for which outcomes have been measured is 12 months. Phrenic nerve palsy is the most common complication although it usually spontaneously resolves over time. PV stenosis is a potentially serious complication and its exact incidence remains controversial, in part based on differing definitions of how to define the outcome. Despite this, the incidence of symptomatic PV requiring intervention appears to be relatively low. What remains unknown are the long term effects- both positive and negative- of cryoballoon ablation.. TA Criterion 3 is met. TA Criterion 4: The technology must be as beneficial as any of the established alternatives. The main potential alternatives to cryoballoon ablation are ADT or RFA. Among patients with PAF, without prior exposure to ADT, approximately 20-40% of patients treated with either class I drugs or sotolol and 60-70% of patients treated with amiodarone will have no recurrence of AF at one year2,25,26. Many patients cannot be maintained in sinus rhythm with ADT. Amiodarone, although commonly used for the treatment of AF, is not FDA approved for this indication.

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Since ADT as the established alternative for rhythm control is not ideal, other options are needed. The main nonpharmacologic approach to AF is RFA. Several RCTs have compared RFA with ADT although the duration of follow-up was short10,27-31. In the short term, RFA has been shown to be more beneficial than ADT at preventing recurrent symptomatic AF, and for individuals for whom ADTs have failed or not tolerated, RFA has emerged as a nonpharmacologic alternative. CTAF reviewed the use of RFA as a treatment for PAF refractory to drug therapy in June, 2010, and concluded that RFA for this use met CTAF criteria 1 through 5 for safety, effectiveness and improvement in health outcomes. Thus cryoballoon ablation must be compared to either ADT or RFA. To date, two nonrandomized studies have compared cryoballoon ablation with RFA. In an Austrian study, 79 patients whose anatomy was deemed suitable underwent RFA or cryoablation. The first 43 patients received RFA and the subsequent 36 patients were treated with cryoablation. The clinical success rate was defined as absence of AF without ADT. As is typical in these studies, the first two months were a “blanking” period, and AF recurrences during this time period were not considered as failures. At six month follow-up, the clinical success rate was 69% in the cryoballoon ablation group and 44% in the RFA group (p