National Medical Policy

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1 National Medical Policy Subject: Policy Number: Catheter Ablation for Atrial Fibrillation NMP175 Effective Date*: May 2010 Update: July 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Cryoablation for Atrial Fibrillation Jul 15 1

2 Current Policy Statement Health Net, Inc. considers catheter ablation for the treatment of atrial fibrillation medically necessary for any of the following: 1. Individuals with symptomatic paroxysmal AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication when a rhythm control strategy is desired. Prior to consideration of AF catheter ablation, assessment of the procedural risks and outcomes relevant to the individual patient is recommended. 2. Selected individuals with symptomatic persistent AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication 3. Individuals with recurrent symptomatic paroxysmal AF, as an initial rhythm control strategy prior to therapeutic trials of antiarrhythmic drug therapy, after weighing risks and outcomes of drug and ablation therapy. Health Net, Inc. may consider catheter ablation for the treatment of atrial fibrillation medically necessary in certain select patients, upon review, for either of the following: 1. Selected individuals with symptomatic long-standing (>12 months) persistent AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication, when a rhythm control strategy is desired. 2. Prior to initiation of antiarrhythmic drug therapy with a class I or III antiarrhythmic medication for symptomatic persistent AF, when a rhythm control strategy is desired. Important Notes: Radiofrequency catheter ablation using a percutaneous catheter-based approach is an effective method for treating drug-refractory symptomatic atrial fibrillation. Cryoballoon ablation is an alternative to point-by-point radiofrequency ablation to achieve pulmonary vein isolation. The evidence supporting the efficacy of catheter ablation is strongest for paroxysmal AF in younger patients with little to no structural heart disease and in procedures performed in highly experienced centers. AF catheter ablation should not be performed in patients who cannot be treated with anticoagulant therapy during and following the procedure. Not Medically Necessary Health Net, Inc. considers catheter ablation for the treatment of atrial fibrillation to restore sinus rhythm with the sole intent of obviating the need for anticoagulation as not medically necessary. Investigational Health Net, Inc. considers Topera 3D Rotor Mapping Solution, comprising the RhythmView Workstation and the FIRMap catheter, investigational because of a paucity of peer-reviewed literature to support it. Definitions Paroxysmal AF AF that terminates spontaneously or with intervention within 7 d of onset. Episodes may recur with variable frequency Cryoablation for Atrial Fibrillation Jul 15 2

3 Persistent AF Continuous AF that is sustained >7 d. Longstanding persistent AF Continuous AF of >12 mo duration. Permanent AF There has been a joint decision by the patient and clinician to cease further attempts to restore and/or maintain sinus rhythm. Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of the AF. Acceptance of AF may change as symptoms, the efficacy of therapeutic interventions, and patient and clinician preferences evolve. Definitions AF Atrial fibrillation DC Direct current MVS Mitral valve surgery LA Left atrium AAD Antiarrhythmic Drug WPW Wolff-Parkinson-White STOP-AF Sustained Treatment of Paroxysmal Atrial Fibrillation RFA Radiofrequency Ablation AVRT Atrioventricular reentrant tachycardia AVNRT Atrioventricular nodal reentry tachycardia SVT Supraventricular tachycardia PVI Pulmonary vein isolation CPVA Circumferential pulmonary vein ablation Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes Atrial Fibrillation ICD-10 Codes I48- Atrial fibrillation and flutter I48.92 Cryoablation for Atrial Fibrillation Jul 15 3

4 CPT Codes Comprehensive electrophysiologic evaluation including transseptal catheterizations, insertion and repositioning of multiple electrode catheters with induction or attempted induction of an arrhythmia with atrial recording and pacing, when possible, right ventricular pacing and recording, His bundle recording with intracardiac catheter ablation of arrhythmogenic focus, with treatment of atrial fibrillation by ablation by pulmonary vein isolation Additional linear or focal intracardiac catheter ablation of the left or right atrium for treatment of atrial fibrillation remaining after completion of pulmonary vein isolation (List separately in addition to code for primary procedure) (New ) Unlisted cardiovascular service or procedure HCPCS Codes N/A Scientific Rationale Update February 2016 The Topera 3D Rotor Mapping Solution, comprising the RhythmView Workstation and the FIRMap catheter, allows physicians to perform intraprocedural mapping of individualized rotors and other electrical sources of atrial fibrillation (AF), and guide ablation of these sources. The FIRMap Catheter first received 510(k) clearance (K130827) on October 31, Per the manufacturer, the Topera 3D Rotor Mapping Solution may be used in patients with cardiac arrhythmias such as AF, atrial flutter, atrial tachycardia, and ventricular tachycardia. In the studies analyzed for this report, the mean age of included patients ranged from 61 to 63 years, and the patients had paroxysmal, persistent, or long-standing persistent AF, or recurring AF after prior ablation. Sommer et al. (2015) completed a single-center case study of rotor elimination during AF ablation using Focal Impulse and Rotor Mapping (FIRM), describing 20 consecutive patients with case descriptions of 3 patients with recurrent longstanding persistent AF after prior ablation. In all cases, endocardial mapping using a 64- electrode basket catheter was performed to identify rotors, which were eliminated using radiofrequency catheter ablation. After it was verified that all identified rotors were eliminated, standard ablation consisting of PV isolation was performed. Notably, persistent AF terminated in only 1/20 (5%) patients. However, after a follow-up of 6 months, single-procedure freedom from AF was 80% (16/20 patients) with only 1 patient on antiarrhythmic drugs. All three patients in the highlighted series are AF free despite the lack of acute procedural AF termination. Patients with persistent AF including those with unsuccessful prior ablation can be treated successfully by rotor targeted ablation, using the elimination of all rotors rather than acute AF termination as the procedural endpoint. However, there is no description to date of the clinical outcomes using rotor elimination during ablation as the procedural endpoint. In addition, a series of studies question whether procedural AF termination is a desirable endpoint for ablation after many forms of AF ablation. This is the only study that used the FIRMap catheter and met the inclusion criteria for this report. After FIRM-guided ablation followed by conventional ablation, persistent AF terminated in 5% of patients; within 1 week of the procedure, half of the patients experienced recurring and required cardioversion, and 6 months following ablation, 80% of patients were free from arrhythmia (AF or atrial tachycardia). Therefore, the results are inconclusive regarding the clinical utility of FIRM-guided ablation. No safety issues were reported. Limitations of this study include the observational descriptive design, small sample size, no control group, and short follow-up. Cryoablation for Atrial Fibrillation Jul 15 4

5 There is a Phase 3 Clinical Trial on Outcome of Different Ablation Strategies In Persistent and Long-Standing Persistent Atrial Fibrillation (OASIS) that is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT , and it was last updated on November 18, This prospective randomized study aims to compare the impact of three different catheter ablation approaches on long-term procedure outcome in terms of arrhythmia recurrence in persistent (PeAF) and longstanding persistent atrial fibrillation (LSPAF) patients. The three strategies to be evaluated are 1) ablation at sources guided by FIRMap (using RhythmView Workstation from TOPERA), 2) ablation at sources guided by FIRMap + conventional pulmonary vein antrum isolation (PVAI) and 3) Extended PVAI plus ablation of non- PV triggers and complex fractionated atrial electrograms (CFAE). The estimated primary completion date is December Position Statements The 2014 ACC/AHA/HRS guidelines (developed in conjunction with the Society of Thoracic Surgeons) do not specifically refer to the Topera system and recommend the consideration of ablation for AF for rate or rhythm control in specific circumstances. The European Society of Cardiology (ESC, 2012) updated guidelines on AF (developed with the European Heart Rhythm Association) do not specifically refer to the Topera system. They support the use of left atrial catheter ablation under specific circumstances. Overall, there is a paucity of peer-reviewed literature along with a low-quality body of evidence that is insufficient to evaluate the net health outcomes of FIRM-guided ablation with the Topera 3D Rotor Mapping Solution as a treatment for patients with AF. The limitations of individual studies included lack of a control group in all but 1 study, which was not randomized. The majority of the studies were small with short follow-up. It was noted that the comparative study had an unequal sample size, differences in some baseline patient characteristics, and uneven follow-up. The conclusion of insufficient evidence is primarily due to the poor quality of the individual studies, and inconsistency of the evidence. Scientific Rationale Update July 2015 AHRQ (2015) completed a systematic review of databases from 2005 to 2014, on Catheter Ablation for Treatment of Atrial Fibrillation, to evaluate the current state of evidence regarding effectiveness and harms of catheter ablation for atrial fibrillation (AF) with a focus on longer-term outcomes and evidence relevant to the Medicare population. Randomized trials and observational studies comparing the efficacy, effectiveness, or safety of catheter ablation (i.e., radiofrequency or cryoballoon ablation) to medical therapy in patients with AF were included. Analyses were stratified by type of AF and length of followup (>12 months vs. 12 months). The quality of included studies was assessed, data were extracted, results were summarized qualitatively and using meta-analysis, and the strength of the evidence was graded for each primary outcome. Of 3,471 citations identified, 46 studies were included. In the Medicare population, evidence was insufficient for all outcomes. Regarding the longer-term effect of radiofrequency ablation (RFA) versus medical therapy in the general population, low-strength of evidence suggested no statistical differences between groups in all-cause mortality for people with paroxysmal AF. Long-term (>12 months) freedom from any atrial arrhythmia recurrence was greater following RFA versus medical therapy (pooled relative risk [RR] 1.24, 95% confidence interval [CI] 1.11 to 1.47) in paroxysmal AF patients (moderate-strength evidence). There was insufficient evidence to draw conclusions for all other long-term primary outcomes including stroke, myocardial infarction, and congestive heart Cryoablation for Atrial Fibrillation Jul 15 5

6 failure. Regarding the short-term ( 12 months) effect of RFA compared with medical therapy, low strength of evidence suggested no significant differences between groups for all-cause mortality regardless of AF type and myocardial infarction in paroxysmal AF patients. Freedom from short-term recurrence was greater following RFA based on moderate strength of evidence (pooled RR 2.62, 95% CI 1.90 to 3.90). Reablation ranged from 0 to 53.8 percent across AF types and time frames. At 6 months, RFA was associated with better health-related quality of life in those with persistent AF and heart failure (i.e., low strength of evidence); however, results were inconsistent across measures and heterogeneity precluded pooling of data or drawing firm conclusions. In terms of harms, no statistical differences in 30-day mortality or stroke or 3-month AF recurrence between groups were found, with low strength of evidence. The pooled risk of cardiac tamponade following RFA was 1.7 percent (95% CI 0.8 to 3.6) for people with paroxysmal AF based on low strength evidence, while evidence was insufficient to draw conclusions regarding persistent AF patients. There was insufficient evidence to draw conclusions regarding efficacy or safety for cryoballoon ablation, with the exception of low strength of evidence for greater freedom from protocol-defined failure, which included freedom from AF, following cryoballoon ablation versus medical therapy. There was insufficient evidence to draw conclusions regarding efficacy or safety for cryoballoon ablation versus RFA or medical therapy. There was insufficient evidence to draw conclusions regarding the efficacy, effectiveness, and safety of catheter ablation in the Medicare population. In the general population, there was moderate evidence that RFA is superior to medical therapy for enhancing patient freedom from recurrence of atrial arrhythmias in both the short and long term regardless of AF type, but reablation was common. RFA does not appear to impact all-cause mortality in the short or long term in those with paroxysmal AF (low strength of evidence); however, there was insufficient evidence to draw conclusions regarding other primary clinical outcomes in the short or long term. Firm conclusions regarding health-related quality of life were not possible given heterogeneity across studies for instruments employed, measurement timing, and clinical characteristics. For harms, no differences between RFA and medical therapy in 30-day mortality, stroke, or 3-month risk of AF were seen, with low strength of evidence. Evidence comparing cryoballoon ablation with medical therapy or with RFA was insufficient to draw conclusions regarding efficacy or safety, with the exception of low strength of evidence for greater freedom from protocol-defined failure following cryoballoon ablation versus medical therapy. To better understand the impact of catheter ablation on key outcomes (stroke, mortality, health-related quality of life, and symptom improvement) compared to other treatment strategies, large methodologically sound studies are needed, particularly on persistent AF patients. Studies with sufficient sample sizes are needed to effectively determine whether catheter ablation versus other treatments will benefit certain patient subgroups more than others, and whether there are subgroups in which catheter ablation might best used as a first- versus second-line treatment. Pappone et al. (2014) completed an 8-year prospective study, known as the Wolff- Parkinson-White registry, of either symptomatic or asymptomatic Wolff-Parkinson- White patients referred to the authors Arrhythmology Department for evaluation or ablation. Inclusion criteria were a baseline electrophysiological testing with or without radiofrequency catheter ablation (RFA). Primary end points were the percentage of patients who experienced ventricular fibrillation (VF) or potentially malignant arrhythmias and risk factors. Among 2169 enrolled patients, 1001 (550 asymptomatic) did not undergo RFA (no-rfa group) and 1168 (206 asymptomatic) underwent ablation (RFA group). There were no differences in clinical and electrophysiological characteristics between the 2 groups except for symptoms. In the no-rfa group, VF occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period (P<0.001) and atrioventricular reentrant tachycardia Cryoablation for Atrial Fibrillation Jul 15 6

7 initiating atrial fibrillation (P<0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank P<0.001). Time-dependent receiver-operating characteristic curves for predicting VF identified an optimal anterograde effective refractory period of the accessory pathway cutoff of 240 milliseconds. The prognosis of the Wolff-Parkinson-White syndrome essentially depends on intrinsic electrophysiological properties of AP rather than on symptoms. RFA performed during the same procedure after electrophysiological testing is of benefit in improving the long-term outcomes. Mont et al. (2014) completed a randomized trial with the goal of comparing the effectiveness of catheter ablation (CA) vs. antiarrhythmic drug therapy (ADT) in treating persistent AF. Patients with long-standing persistent AF were excluded. Primary endpoint at 12-month follow-up was defined as any episode of AF or atrial flutter lasting >24 h that occurred after a 3-month blanking period. Secondary endpoints were any atrial tachyarrhythmia lasting >30 s, hospitalization, and electrical cardioversion. In total, 146 patients were included (aged 55 ± 9 years, 77% male). The ADT group received class Ic (43.8%) or class III drugs (56.3%). In an intention-to-treat analysis, 69 of 98 patients (70.4%) in the CA group and 21 of 48 patients (43.7%) in the ADT group were free of the primary endpoint (P = 0.002), implying an absolute risk difference of 26.6% (95% CI ) in favour of CA. The proportion of patients free of any recurrence (>30 s) was higher in the CA group than in the ADT group (60.2 vs. 29.2%; P < 0.001) and cardioversion was less frequent (34.7 vs. 50%, respectively; P = 0.018). Catheter ablation is superior to medical therapy for the maintenance of sinus rhythm in patients with persistent AF at 12-month follow-up. The present study applied a common approach of wide pulmonary vein encirclement and additional substrate modification was left to the operator's criteria. The present study was not designed to compare techniques. Further randomized trials are needed to establish the best approach in this particular population. The study was terminated before reaching the planned sample size due to a lower than expected recruitment rate. The main limitation for recruitment was related to conducting the study in ablation centres, where patients were specifically referred for AF ablation. This could have established a bias against participation among the centre's more symptomatic patients, who might well prefer prompt ablation to the possibility of being randomized to a drug therapy. However, the difference between groups in the primary endpoint was higher than assumed in the sample size calculation, which likely compensated for the loss of statistical power in the sample size. The evaluation of primary and secondary endpoints was performed by an external committee, blinded to treatment allocation. The superiority of CA over ADT is evaluated at relatively short term of 12 months, however, whether these results would persist after the first year is unknown. The cardiac rhythm monitoring during follow-up was performed with the current standard of care in our environment: 12-lead ECG at 1-, 3-, 6-, and 12-month follow-up and whenever patients reported symptoms, and 24-h Holter at 6 and 12 months. The purpose of the study was not to establish the absolute effectiveness of CA, but to compare it with ADT. Therefore, more intense monitoring could perhaps have identified a higher rate of recurrences; in any case, it would have equally affected both arms and would not have had a substantial impact on the difference between them. It is unlikely that sustained episodes (>24 h) remained undetected because the primary endpoint required episodes lasting at least 24 h. The primary endpoint was chosen by the steering committee as more appropriate in the context of patients with persistent AF than the recommended >30 s of AF, given the cardiac monitoring strategy applied during the follow-up. We recognize the novelty of the concept, but it was considered more robust given limited monitoring. This endpoint could lead to an overestimation of the positive results; however, we aimed to evaluate differences between groups Cryoablation for Atrial Fibrillation Jul 15 7

8 instead of assessing the absolute efficacy of the treatment. Additionally, significant differences were found between treatments in the secondary endpoint (>30 s), validating to some extent the selection of the primary endpoint. Morrillo et al. (2014) completed a randomized trial to compare radiofrequency ablation with antiarrhythmic drugs (i.e., standard therapy) in treating patients with paroxysmal AF as a first-line therapy. 127 treatment-naive patients with paroxysmal AF were randomized at 16 centers in Europe and North America to received either antiarrhythmic therapy or ablation. The first patient was enrolled July 27, 2006; the last patient, January 29, The last follow-up was February 16, Sixty-one patients in the antiarrhythmic drug group and 66 in the radiofrequency ablation group were followed up for 24 months. The time to the first documented atrial tachyarrhythmia of more than 30 seconds, symptomatic or asymptomatic AF, atrial flutter, or atrial tachycardia, detected by either scheduled or unscheduled electrocardiogram, Holter, transtelephonic monitor, or rhythm strip, was the primary outcome. Secondary outcomes included symptomatic recurrences of atrial tachyarrhythmias and quality of life measures assessed by the EQ-5D tool. Forty-four patients (72.1%) in the antiarrhythmic group and in 36 patients (54.5%) in the ablation group experienced the primary efficacy outcome (hazard ratio [HR], 0.56 [95% CI, ]; P=.02). For the secondary outcomes, 59% in the drug group and 47% in the ablation group experienced the first recurrence of symptomatic AF, atrial flutter, atrial tachycardia (HR, 0.56 [95% CI, ]; P=.03). No deaths or strokes were reported in either group; 4 cases of cardiac tamponade were reported in the ablation group. In the standard treatment group, 26 patients (43%) underwent ablation after 1-year. Quality of life was moderately impaired at baseline in both groups and improved at the 1 year follow-up. However, improvement was not significantly different among groups. Among patients with paroxysmal AF without previous antiarrhythmic drug treatment, radiofrequency ablation compared with antiarrhythmic drugs resulted in a lower rate of recurrent atrial tachyarrhythmias at 2 years. However, recurrence was frequent in both groups. Trial Registration clinicaltrials.gov Identifier: NCT Xu et al. (2014) Currently radiofrequency and cryoballoon ablations are the two standard ablation systems used for catheter ablation of atrial fibrillation; however, there is no universal consensus on which ablation is the optimal choice. The authors completed a meta-analysis with special emphases on comparing the efficacy and safety between cryoballoon and radiofrequency ablations by synthesizing published clinical trials. Articles were identified by searching the MEDLINE and EMBASE databases before September 2013, by reviewing the bibliographies of eligible reports, and by consulting with experts in this field. There were respectively 469 and 635 patients referred for cryoballoon and radiofrequency ablations from 14 qualified clinical trials. Overall analyses indicated that cryoballoon ablation significantly reduced fluoroscopic time and total procedure time by a weighted mean of (95% confidence interval [95% CI]: 2.82 to 25.45; P = 0.014) minutes and (95% CI: 8.54 to 50.77; P = 0.006) minutes compared with radiofrequency ablation, respectively, whereas ablation time in cryoballoon ablation was nonsignificantly elongated by a weighted mean of (95% CI: to 34.04; P = 0.307) minutes. Patients referred for cryoballoon ablation had a high yet not significant success rate of catheter ablation compared with cryoballoon ablation (odds ratio; 95% CI; P: 1.34; 0.53 to 3.36; 0.538), and cryoballoon ablation was also found to be associated with the relatively low risk of having recurrent atrial fibrillation (0.75; 0.3 to 1.88; 0.538) and major complications (0.46; 0.11 to 1.83; 0.269). There was strong evidence of heterogeneity and low probability of publication bias. The authors findings demonstrate greater improvement in fluoroscopic time and total procedure duration for atrial fibrillation patients referred for cryoballoon ablation than those for radiofrequency ablation. Cryoablation for Atrial Fibrillation Jul 15 8

9 Jourda et al. (2014) completed a prospective single centre evaluation with the goal to develop data comparing the mid-term outcome of patients undergoing pulmonary vein isolation (PVI) catheter ablation using contact-force (CF)-guided radiofrequency (RF) vs. second-generation balloon cryotherapy. The study was done from March 2011 to February 2013, comparing CF radiofrequency (i.e., Thermocool, SmartTouchTM, Biosense Webster, Inc.) (CF group) with cryoballoon ablation (I,e,. Arctic Front AdvanceTM 28 mm cryoballoon, Medtronic, Inc.) (CB group), in regards to procedural safety and efficacy, as well as recurrence at 12 months. Overall, 150 consecutive patients were enrolled (75 in each group). The characteristics of patients of both the groups were similar (61.2 ± 9.9 years, women 25.3%, mean AF duration 4.1 ± 4.0 years, mean CHA2DS2-VASc score 1.4 ± 1.3, mean HAS-BLED 1.4 ± 0.6). Duration of the procedure was significantly lower in the CF group (110.7 ± 32.5 vs ± 48.3 min, P = 0.001), with a lower duration of fluoroscopy (21.5 ± 8.5 vs ± 9.9 min, P = 0.017) and X-ray exposure (4748 ± 2411 cgy cm² vs ± 5361 cgy cm², P = 0.001). In contrast, no significant difference was found regarding significant procedural complication (2.7 vs. 1.3% in CF and CB groups, respectively; P = 0.56), and PVI was eventually achieved in all cases. At 12 months, AF recurrence occurred in 11 patients (14.7%) in the CB group and in 9 patients (12.0%) in the CF group (HR = % CI ; log rank P = 0.682). The authors preliminary findings suggest that CF-guided radiofrequency and cryotherapy present very similar performances in the setting of paroxysmal AF catheter ablation AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: CHA2DS2-VASc score (Birmingham 2009) was developed and is used for risk stratification of ischemic stroke in patients with nonvalvular atrial fibrillation. The CHA2DS2-VASc score has been recommended in 2014, by the AHA, the American College of Cardiology, and the Heart Rhythm Society, in collaboration with the Society of Thoracic Surgeons, as the only score to apply when assessing stroke risk in nonvalvular AF. The CHADS2 score is no longer recommended by these professional societies. However, CHADS2 is still preferred by the American College of Chest Physicians (ACCP), while the European Society of Cardiology (ESC) guideline update recommends the use of either score. For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include warfarin (INR 2.0 to 3.0) ( )(Level of Evidence: A) Scientific Rationale Update July 2014 Research efforts have focused on ablation techniques that can be performed via percutaneous transcatheter approaches and that can create atrial lesions, and subsequent scar tissue using radiofrequency (RF), cryothermal, microwave, laser, or high-frequency ultrasound (HFUS) energy. These ablation techniques completely or partially replicate the Cox-Maze III lesion set, which includes lesions around the pulmonary Veins (PVs) for PV isolation (PVI), and lesions extending from the left PVs to right PVs, from one PV to the left atrial (LA) appendage, and from one PV to the mitral annulus. The choice of lesions may be universal at the treating center or may be based on electrophysiological mapping, which is used during ablation procedures to identify erratic conduction pathways and to ensure complete disruption of such pathways. Studies using microwave, laser, and HFUS ablation techniques have been scarce but have reported disappointing results with respect to efficacy (microwave) or safety (laser, HFUS). RF ablation is widely used, has provided an effective method for treating drug-refractory symptomatic atrial fibrillation and is considered the gold standard in ablation of paroxysmal atrial fibrillation (PAF). RF ablation of the pulmonary veins entails the delivery of radiofrequency energy to multiple, closely spaced points at or near the atrium-vein junctions. The resulting localized tissue Cryoablation for Atrial Fibrillation Jul 15 9

10 damage blocks abnormal electrical signals that arise in the pulmonary veins and trigger atrial fibrillation (AF). The chief goal of ablation in patients with AF is to improve their quality of life by eliminating or reducing symptoms and avoiding the adverse effects of medication. However, RFA poses a risk for PV stenosis, intercavitary thrombi, and esophageal and circumflex artery injury and multiple procedures are often required. Cryoablation creates lesions by delivering temperatures of 30 to 90 centigrade (C) via a cryoballoon (for PVI only) or a focal cryoprobe (for PVI and all other lesions) and, theoretically, has advantages over RF ablation, including reversible lesions and reduced risk for myocardial injury, PV stenosis, and thrombi versus RF ablation. Per the 2014 AHA/ACC/HRS guideline on Atrial Fibrillation, The role of catheter ablation in the management of AF continues to evolve rapidly, with improvements in the efficacy and safety of the procedure. The efficacy of radiofrequency catheter ablation for maintaining sinus rhythm is superior to current antiarrhythmic drug therapy for maintenance of sinus rhythm in selected patient populations. A number of systematic reviews of the efficacy of AF catheter ablation versus antiarrhythmic drug therapy have been performed. Cryoballoon ablation is an alternative to pointby-point radiofrequency ablation to achieve pulmonary vein isolation. The evidence supporting the efficacy of catheter ablation is strongest for paroxysmal AF in younger patients with little to no structural heart disease and in procedures performed in highly experienced centers. Studies have demonstrated a reduction of AF related symptoms in these contexts. Evidence is insufficient to determine whether AF catheter ablation reduces all-cause mortality, stroke, and HF. Ongoing clinical trials (CABANA [Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation] and EAST [Early Therapy of Atrial Fibrillation for Stroke Prevention Trial]) should provide new information for assessing whether AF catheter ablation is superior to standard therapy with either rate- or rhythm-control drugs for reducing total mortality and other secondary outcome measures, and whether early application of a rhythm-control therapy involving ablation, antiarrhythmic drugs, or both, can impact endpoints of stroke, cardiovascular death, or HF compared with usual care. These important trials will help to address whether catheter ablation provides benefit beyond improvements in quality of life. The decision whether to pursue catheter ablation depends on a large number of variables, including the type of AF (paroxysmal versus persistent verses longstanding persistent), degree of symptoms, presence of structural heart disease, candidacy for alternative options such as rate control or antiarrhythmic drug therapy, likelihood of complications, and patient preference. The majority of patients that are enrolled in in trials of catheter ablation have been younger healthy individuals with symptomatic paroxysmal AF refractory to 1 antiarrhythmic medication. The safety and efficacy of catheter ablation are less well established for other populations of patients, especially patients with longstanding persistent AF, very elderly patients, and patients with significant HF including tachycardia-induced cardiomyopathy. The 2014 AHA/ACC/HRS Atrial Fibrillation Guidelines make the following recommendations regarding catheter ablation to maintain sinus rhythm: Class I (Procedure/Treatment should be performed/administered) 1. AF catheter ablation is useful for symptomatic paroxysmal AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication when a rhythm control strategy is desired. (Level of Evidence: A) Cryoablation for Atrial Fibrillation Jul 15 10

11 2. Prior to consideration of AF catheter ablation, assessment of the procedural risks and outcomes relevant to the individual patient is recommended. (Level of Evidence: C) Class IIa (It is reasonable to perform procedure/administer treatment) 1. AF catheter ablation is reasonable for selected patients with symptomatic persistent AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication. (Level of Evidence: A) 2. In patients with recurrent symptomatic paroxysmal AF, catheter ablation is a reasonable initial rhythm control strategy prior to therapeutic trials of antiarrhythmic drug therapy, after weighing risks and outcomes of drug and ablation therapy. (Level of Evidence: B) Class IIb (Procedure/treatment may be considered) 1. AF catheter ablation may be considered for symptomatic long-standing (>12 months) persistent AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication, when a rhythm control strategy is desired. (Level of Evidence: B) 2. AF catheter ablation may be considered prior to initiation of antiarrhythmic drug therapy with a class I or III antiarrhythmic medication for symptomatic persistent AF, when a rhythm control strategy is desired. (Level of Evidence: C) Class III: Harm 1. AF catheter ablation should not be performed in patients who cannot be treated with anticoagulant therapy during and following the procedure. (Level of Evidence: C) 2. AF catheter ablation to restore sinus rhythm should not be performed with the sole intent of obviating the need for anticoagulation. (Level of Evidence: C) Definitions Paroxysmal AF AF that terminates spontaneously or with intervention within 7 d of onset. Episodes may recur with variable frequency Persistent AF Continuous AF that is sustained >7 d. Longstanding persistent AF Continuous AF of >12 mo duration. There has been a joint decision by the patient and Permanent AF clinician to cease further attempts to restore and/or maintain sinus rhythm. Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of the AF. Acceptance of AF may change as symptoms, the efficacy of therapeutic interventions, and patient and clinician preferences evolve. Mugnai et al (2014) compared the results of pulmonary vein isolation using conventional irrigated radiofrequency (RF) approach versus the cryoballoon (CB) ablation. From January 2008 to December 2011, a total of 426 patients with drugresistant symptomatic paroxysmal atrial fibrillation underwent pulmonary vein isolation as the index procedure by conventional manual RF or CB ablation at a single center. A final population of 396 patients was considered for analysis and divided into 2 groups: conventional RF ablation (n = 260) and CB ablation (n = 136). At a mean follow-up of 23 ± 13 months (median 27, range 4 to 68), the success rate for RF ablation group was 57.3% (149 patients) and was 63.2% (86 patients) for cryoablation group (p = 0.25). Procedural times were significantly shorter in the cryoablation group (192 ± 49 vs 112 ± 58 minutes, p < ) but not Cryoablation for Atrial Fibrillation Jul 15 11

12 fluoroscopy times (36 ± 14 vs 31 ± 17 minutes, p = 0.45). No clinical predictors were found to predict atrial fibrillation recurrences. Complication rates were similar in both groups except for phrenic nerve palsy that was uniquely observed in the CB group (8.1%, p < ). All phrenic nerve palsies resolved during follow-up. The investigators concluded, on a medium-term follow-up, conventional point-by-point RF ablation and CB ablation showed similar success rates. Procedural times were significantly shorter in the CB approach. The most frequent complication during CB procedures was phrenic nerve palsy, which occurred in 8.1% of patients and resolved in all during the follow-up period. Packer et al (2013) assessed the safety and effectiveness of a cryoballoon ablation technology designed to achieve single-delivery pulmonary vein (PV) isolation. Patients with documented symptomatic paroxysmal AF and previously failed therapy with 1 membrane active antiarrhythmic drug underwent 2:1 randomization to either cryoballoon ablation (n = 163) or drug therapy (n = 82). A 90-day blanking period allowed for optimization of antiarrhythmic drug therapy and reablation if necessary. Effectiveness of the cryoablation procedure versus drug therapy was determined at 12 months. Patients had highly symptomatic AF (78% paroxysmal, 22% early persistent) and experienced failure of at least one antiarrhythmic drug. Cryoablation produced acute isolation of three or more PVs in 98.2% and all four PVs in 97.6% of patients. PVs isolation was achieved with the balloon catheter alone in 83%. At 12 months, treatment success was 69.9% (114 of 163) of cryoblation patients compared with 7.3% of antiarrhythmic drug patients (absolute difference, 62.6% [p < 0.001]). Sixty-five (79%) drug-treated patients crossed over to cryoablation during 12 months of study follow-up due to recurrent, symptomatic AF, constituting drug treatment failure. There were 7 of the resulting 228 cryoablated patients (3.1%) with a >75% reduction in PV area during 12 months of follow-up. Twenty-nine of 259 procedures (11.2%) were associated with phrenic nerve palsy as determined by radiographic screening; 25 of these had resolved by 12 months. Cryoablation patients had significantly improved symptoms at 12 months. Investigators concluded the STOP AF trial demonstrated that cryoballoon ablation is a safe and effective alternative to antiarrhythmic medication for the treatment of patients with symptomatic paroxysmal AF, for whom at least one antiarrhythmic drug has failed, with risks within accepted standards for ablation therapy. (A Clinical Study of the Arctic Front Cryoablation Balloon for the Treatment of Paroxysmal Atrial Fibrillation [Stop AF]; NCT ). Straube et al (2014) reported CB ablation results in >70% freedom from atrial fibrillation at 1 year. The authors compared safety and efficacy from single-center data of the first (CBG1) and second (CBG2) cryoballoon. From March 2011 to December 2012, CB ablation with spiral mapping was performed consecutively in 484 patients with symptomatic atrial fibrillation. CBG1 was used in 364 of 484 (75%) and CBG2 in 120 of 484 (25%) patients. Periprocedural data were analyzed. Acute pulmonary vein (PV) isolation with CB only was achieved in 99.86% and 100% of veins with CBG1 and CBG2, respectively (P=0.43). Number of applications until PV isolation decreased significantly with CBG2 (1.45±0.81 versus 1.28±0.64; P=0.001). Procedural, left atrial, and fluoroscopy time were reduced by -5%, -11%, and -15% (P<0.05), respectively. Two balloons were used less frequently. Time to isolation decreased significantly with 23-mm (48 versus 33 seconds; P<0.0001) and 28-mm CBG2 (76 versus 52 seconds; P<0.0001). Early PV reconduction rarely occurred with CBG2 (2.6% versus 0.42%; P=0.0023). In-hospital atrial fibrillation recurrence rates were similar. Balloon temperatures were significantly warmer with 23-mm CBG2 and a trend for colder balloon temperature with 28-mm CBG2 were observed compared with their predecessors. Comparable low rates of phrenic nerve palsy were recorded (1.1% versus 1.7%; P=0.64). Esophageal temperatures were similar. Major complication rates were low (3.3% versus 3.33%; P=1.0). Investigators concluded Cryoablation for Atrial Fibrillation Jul 15 12

13 CBG2 attains high rates of acute PV isolation within a significant faster and less complex procedure. Time to isolation is shorter, and PV isolation is achieved with fewer applications using CBG2. These enhancements were not at the cost of complications. Long-term success rates remain to be demonstrated. Andrade et al (2014) reported early recurrence of atrial fibrillation (ERAF) is common after radiofrequency catheter ablation for AF. The authors sought to determine the incidence and prognostic significance of ERAF after cryoballoon ablation. Moreover, the benefit of early reablation for ERAF after cryoballoon ablation is undetermined. The Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) trial randomized 245 patients with paroxysmal AF to medical therapy versus cryoballoon-based pulmonary vein ablation. Patients were followed for 12 months. ERAF was defined as any recurrence of AF >30 seconds during the first 3 months of follow-up. Late recurrence (LR) was defined as any recurrence of AF >30 seconds between 3 and 12 months. Of the 163 patients randomized to cryoablation, 84 patients experienced ERAF (51.5%). The only significant factor associated with ERAF was male sex (hazard ratio [HR], 2.18; 95% confidence interval [CI], ; P=0.041). LR was observed in 41 patients (25.1%), and was significantly related to ERAF (55.6% LR with ERAF versus 12.7% without ERAF; P<0.001). Among patients with ERAF, only current tobacco use (HR, 3.84; 95% CI, ; P<0.001) was associated with LR. Conversely, early reablation was associated with greater freedom from LR (3.3% LR with early reablation versus 55.6% without; HR, 0.04; 95% CI, ; P=0.002). Investigators concluded ERAF after cryoballoon ablation occurs in 50% of patients and is strongly associated with LR. Early reablation for ERAF is associated with excellent long-term freedom from recurrent AF. Pérez-Castellano et al (2014) compared the efficacy of a simplified strategy for PV cryoablation (group C) vs PV isolation with open-irrigated radiofrequency catheters (group R). Fifty patients with paroxysmal atrial fibrillation (AF) and 4 independent PVs received a Reveal XT implantable cardiac monitor and were randomized to group C or group R. In group C, PV ablation was done with a single Arctic Front balloon (23 or 28 mm) per patient and two 300-second applications per PV. No further applications were delivered to close residual conduction gaps. In group R, bidirectional PV conduction block was pursued with Lasso and Navistar ThermoCool catheters and the CARTO system. The primary end point was the proportion of patients remaining free from AF recurrences 2 minutes without taking antiarrhythmic drugs 12 months after ablation. The primary end point was met by 12 (48%) patients in group C and 25 (68%) patients in group R (odds ratio 0.43; P =.05). This difference disappeared after adjustment for acute procedural outcome. In patients for whom all 4 PVs were blocked at the end of the procedure, there was no difference between group C and group R in the primary end point (67% vs 68%; P =.94). Investigators concluded the efficacy of the simplified strategy for PV cryoablation tested in this study is inferior to PV isolation using open-irrigated radiofrequency catheters with electrophysiological and electroanatomical guidance. Complete PV conduction block is critical to the success of AF ablation Aytemir et al (2013) sought to identify the periprocedural complications, mid-term success rates and predictors of recurrence after AF ablation with cryoballoon. A total of 236 patients (54% male, mean age 54.6±10.45 years and 79.6% paroxysmal AF) with symptomatic AF underwent PV isolation with cryoballoon due to failure with 1 antiarrhythmic drug previously. Procedural success, complications and follow-up data were defined according to recent guidelines. Acute procedural success rate was 99.5%. Mean procedural and fluoroscopy times were 72.5±5.3 and 14±3.5 min. At a median of 18 (6-27)months follow-up, 80.8% of paroxysmal AF patients and 50.0% of persistent AF patients were free from AF recurrence. In multivariate regression analysis, body mass index (BMI) (hazard ratio (HR), 1.35; 95% confidence interval Cryoablation for Atrial Fibrillation Jul 15 13

14 (CI), , p=0.001), smoking (HR, 2.12; 95% CI, , p<0.001), nonparoxysmal AF (HR, 1.26; 95% CI, , p=0.024), duration of AF (HR, 1.42; 95% CI, , p=0.015), left atrium (LA) diameter (HR, 2.42; 95% CI, , p<0.001) and early AF recurrence (HR, 4.88; 95% CI, , p<0.001) were independent predictors of AF recurrence following cryoablation. Investigators concluded the results showed that AF ablation with cryoballoon is effective and safe. Non-paroxysmal AF, duration of AF, smoking, BMI, LA diameter and early recurrence were found to be the most powerful predictors and could be helpful to select patients for appropriate therapeutic strategy. Neumann et al (2013) described 5 years follow-up results and predictors of success of cryoballoon (CB) ablation in patients with paroxysmal atrial fibrillation (PAF). In total, 163 patients were enrolled with symptomatic, drug refractory PAF. Pulmonary vein isolation (PVI) with CB technique was performed. Primary endpoint of this consecutive single-centre study was first electrocardiogram-documented recurrence of AF, atrial tachycardia or atrial flutter (AFLAT). Five years success rate after single CB ablation was 53%. In 70% of the patients acute complete PVI was achieved with a single 28 mm balloon. The univariate predictors of AFLAT recurrence were (1) size of left atrium, with normalized left atrium (NLA) [hazard ratios (HR) of 1.81, 95% confidence interval (CI): ] when compared with NLA <10.25 (35% vs. 53%, P = ) and (2) renal function, with impaired glomerular filtration rate (GFR) <80 ml/min (HR of 1.26, 95% CI: ) when compared with GFR 80 ml/min (45% vs. 53%, P = 0.041). Normalized left atrium was the sole independent predictor for outcome (HR 2.11; 95% CI: ; P = ). Investigators concluded sinus rhythm can be maintained in a substantial proportion of patients with PAF even 5 years after circumferential PVI using CB ablation. The rate of decline in freedom from AFLAT was highest within the first 12 months after the index procedure. The patients with enlarged left atrium and/or impaired renal function have lower outcome. Numerous clinical trials evaluating cryoablation in the treatment of atrail fibrillation are ongoing. Scientific Rationale Update December 2013 Cryoablation uses freezing temperatures to create lesions in the atria that prevent electrical conduction from ectopic triggers and re-entrant circuits, thereby stopping atrial fibrillation and restoring the heart to sinus rhythm. The Heart Rhythm Society (HRS) assembled a task force to develop a consensus statement on catheter and surgical ablation of atrial fibrillation. The consensus statement was based on expert experience and a review of literature and was developed in partnership with the European Heart Rhythm Society (EHRS), a branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS), and in collaboration with the American College of Cardiology (ACC), the American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). It was endorsed by the American College of Cardiology Foundation, the AHA, the ECAS, the EHRS, the STS, the APHRS, and the HRS (Calkins et al., 2012). The consensus statement described cryoablation and summarized the study data for cryoablation. However, recommendations were for catheter ablation, concomitant surgical ablation, and stand-alone surgical ablation in general and were not differentiated among different energy sources. The consensus statement prepared by the Heart Rhythm Society (HRS, 2012) and other professional organizations reports that candidates for ablation are patients with symptomatic atrial fibrillation (AF) refractory or intolerant to at least one Class 1 or Cryoablation for Atrial Fibrillation Jul 15 14

15 Class 3 AAA, and patients with symptomatic AF who have not tried AAAs and will undergo ablation as first-line treatment. Per the Heart Rhythm Society It is also important to recognize that RF energy is by far the dominant energy source that has been used for catheter ablation of AF. Cryoablation has more recently been developed as a tool for AF ablation procedures. In summary, while surgery for AF has been performed for two decades, prospective multicenter clinical trials are needed to better define the relative safety and efficacy of various surgical tools and techniques. It is critical for future studies to better document the possible survival benefits of adjunctive AF surgery. At present, an ongoing randomized National Institutes of Health (NIH) multicenter trial is examining the efficacy of surgical ablation in patients with persistent AF and mitral valve disease. Moreover, surgeons need to adopt consistent definitions f procedural success and follow-up methodology, as defined in this and previous consensus documents, in order to compare the different surgical series and the surgical results to catheter ablation. The type and frequency of follow-up have varied widely between series. The true success rates of these procedures are likely to be lower than have been reported if more extensive monitoring is performed in the future. Even considering these shortcomings, the Cox-Maze procedure has had good long-term results when used as a stand-alone procedure or when performed as a concomitant procedure in patients undergoing other indications for cardiac surgery. The advent of ablation technology has simplified the surgical treatment of AF and expanded the indications, particularly for concomitant AF procedures in patients undergoing other cardiac surgery. Minimally invasive and hybrid approaches could expand the indications for stand-alone surgery AF in the future. However, data are insufficient to establish the efficacy of cryoablation or the comparative effectiveness and safety of cryoablation relative to other approaches and to define standardized treatment protocols and patient selection criteria. Additional peer-reviewed studies are necessary to determine the efficacy of cryoablation, whether used alone or in conjunction with cardiac surgery, to clarify the comparative effectiveness of cryoablation related to other treatment approaches for atrial fibrillation, and to and to determine the long-term outcome of cryoablation. Scientific Rationale Update December 2012 In 2011, the ACCF/AHA/HRS, updated their 2006 Guidelines. The information is titled, Focused Update on the Management of Patients With Atrial Fibrillation. Per this 2011 update, the future directions in catheter-based ablation therapy for atrial fibrillation is noted below: Catheter ablation to maintain sinus rhythm has been reported in trials and metaanalyses including data from more than 6,900 patients. Patients undergoing ablation are a selected population characterized by a predominance of those with symptomatic paroxysmal AF that have failed treatment with one or more antiarrhythmic drugs, with normal size or mildly dilated atria, normal or mildly reduced ventricular function, and absence of severe pulmonary disease. Following ablation, most patients are free of recurrent, paroxysmal AF for 1 year or more. In the ThermoCool trial, a randomized multicenter study of 167 symptomatic patients with paroxysmal AF who had not shown improvement with at least 1 antiarrhythmic drug, radiofrequency catheter ablation with pulmonary vein isolation resulted in significantly fewer episodes of recurrent AF than did treatment with additional antiarrhythmic drugs. Quality-of-life and symptom severity scores were significantly better after 3 months in the group treated with catheter ablation. Major treatment-related adverse events were similar between catheter-treated and drugtreated groups at 30 days. More than 5,000 patients were screened to recruit these 167 study subjects. Important exclusions included patients with AF >30 days' Cryoablation for Atrial Fibrillation Jul 15 15

16 duration, ejection fraction <40%, left atrial diameter >5 cm, severe pulmonary disease, recent MI, coronary artery bypass graft surgery, thromboemboli, treatment with amiodarone, or previous catheter ablations for AF. The average age of patients undergoing catheter ablation was relatively young at 55.7 years (95% CI: 54.1 to 57.4), and they had paroxysmal, symptomatic AF for a relatively long time: 5.7 years (95% CI: 4.8 to 6.6). All ablation procedures were performed by highly experienced operators in high-volume centers. Although the primary endpoint in all centers was electrical isolation of all pulmonary veins in each patient who underwent AF ablation, other aspects of the ablation procedures were not standardized, including the use of linear lesions. Repeat catheter ablation procedures were performed in 12.6% of the ablation group. Ultimately, 34% of ablation patients had recurrence of symptomatic AF during the 9-month follow-up period, compared with 84% of the drug-treated group. In this highly selected patient population, in patients for whom 1 antiarrhythmic drug has failed, subsequent antiarrhythmic drug treatment is likely to fail; such patients may benefit from catheter ablation. Despite these advances, the long-term efficacy of catheter ablation to prevent recurrent AF requires further study. Available data demonstrate 1 year or more of freedom from recurrent AF in most (carefully selected) patients. However, AF can recur without symptoms and be unrecognized by the patient or physician. There is uncertainty as to what the risk of recurrence of AF is over the long term, because AF may recur with minimal symptoms. This distinction has important implications for the duration of anticoagulation therapy in patients with risk factors for stroke associated with AF. In addition, little information is yet available about the late success of ablation in patients with heart failure and other advanced structural heart disease, who may be less likely to enjoy freedom from recurrence of AF. Bohenen et al. (2012) Updated understanding of the risks of catheter ablation is important because techniques have evolved for procedures treating non-lifethreatening as well as potentially lethal arrhythmias. This prospective study sought to assess the incidence and predictors of major complications from contemporary catheter ablation procedures at a high-volume center. Over a 2-year period, 1,676 consecutive ablation procedures were prospectively evaluated for major complications throughout 30 days post procedure. Predictors of major complications were determined in a multivariate analysis adjusted for demographics, clinical variables, ablation type, and procedural factors. Rates of major complications differed between procedure types, ranging from 0.8% for supraventricular tachycardia, 3.4% for idiopathic ventricular tachycardia (VT), 5.2% for atrial fibrillation (AF), and 6.0% for VT associated with structural heart disease (SHD). Ablation type (ablation for AF [odds ratio (OR) 5.53, 95% confidence interval (CI) 1.81 to 16.83], for VT with SHD [OR 8.61, 95% CI 2.37 to 31.31], or for idiopathic VT [OR 5.93, 95% CI 1.40 to 25.05]all referenced to supraventricular tachycardia ablation), and serum creatinine level>1.5 mg/dl (OR 2.48, 95% CI 1.07 to 5.76) were associated with increased adjusted risk of major complications, whereas age, gender, body mass index, international normalized ratio level, hypertension, coronary artery disease, diabetes, and prior cerebrovascular accident were not associated with increased risk. In a large cohort of contemporary catheter ablation, major complication rates ranged between 0.8% and 6.0% depending on the ablation procedure performed. Aside from ablation type, renal insufficiency was the only independent predictor of a major complication. Rahman et al. (2010) Surgical treatment of atrial fibrillation (AF) with heat-based therapies has been associated with a high rate of arrhythmia recurrence. The authors studied the short-term to medium-term outcomes with a unique biatrial linear ablation procedure for AF treatment using an argon-based cryoablation device during concomitant cardiac operations. Between March 2005 and July 2008, 57 patients Cryoablation for Atrial Fibrillation Jul 15 16

17 (47% men) with problematic AF underwent a linear endocardial ablation procedure (Star pattern) using the flexible argon-based cryoablation probe during concomitant cardiac operations. Procedures were performed with valve or coronary operations, including mitral valve replacement (25%), mitral valve repair (16%), coronary artery bypass grafts (21%), and congenital heart surgery (8%). Atrial fibrillation was persistent or long-standing persistent in 50.9% of patients. Kaplan-Meier survival curves (with the standard error) demonstrated 91% (3.9%) of patients were still free of their first recurrence at 6 months, 81% (5.6%) at 12 months, and 70% (6.8%) at 24 months. Time to first recurrence was not significantly associated with age (p = 0.47), gender (p = 0.52), or type of AF (p = 0.69). There were no complications attributed to the cryoablation procedure. There was one in-hospital death and one death after discharge. Twelve patients (21%) required permanent pacemaker implantation postoperatively. There were no early or late thromboembolic events. This study demonstrated the medium-term efficacy of cryoablation with a unique biatrial pattern of linear lesions for the treatment of AF during a concomitant cardiac operation. Short-term to medium-term outcomes were at least equivalent to those reported for other energy modalities, FOR. Okado et al. (2010) compared the surgical outcomes of maze procedures in patients who had undergone cryoablation and RF ablation and mitral valve surgery. METHODS: From January 2004 to August 2009, a total of 40 patients underwent the maze procedure and concomitant mitral operation as a 1st operation. Of these, the cryoablation maze procedure (n = 20) and RF ablation procedure (n = 20) were performed in the patients with similar background, although more patients in the RF group had undergone mitral valve repair (n = 15) compared to the cryoablation group (n = 8) [p = 0.025]. RESULTS: The peri-operative data, such as operative duration, cardiopulmonary bypass time, aortic cross-clamp time, postoperative ventilation time, and the duration of intensive care unit (ICU) stay did not show any significant difference between cryoablation group and RF group. Both ablation procedures were similarly effective in restoring sinus rhythm at the early postoperative period (cryoablation: 80%, RF: 70%). Nine patients in the cryoablation group and 13 patients in the RF ablation group required anti-arrhythmic medication.the authors concluded the RF ablation technique is simpler and equally effective in controlling atrial fibrillation compared to the cryoablation for the maze procedure of concomitant mitral valve surgery. There were quite a few Clinical Trials on Cryoablation for Atrial Fibrillation in various stages of development. They are noted below: There is a randomized controlled Clinical Trial on A Clinical Study of the Arctic Front Cryoablation Balloon for the Treatment of Paroxysmal Atrial Fibrillation (Stop-AF) with the ClinicalTrials.gov Identifier of NCT This study (STOP AF) is a prospective, randomized, controlled, multicenter, pivotal clinical investigation conducted at 26 sites in the U.S. and Canada. Subjects with paroxysmal atrial fibrillation (PAF) referred for ablative intervention after efficacy failure of one or more Study Atrial Fibrillation (AF) Drugs (flecainide, propafenone or sotalol) were randomized 2:1 to cryoablation intervention. The Experimental Group included 163 patients who received cryoablation, and who previously failed AF drug therapy. The cryoablation was intended to isolate the pulmonary veins and ablate arrhythmia foci. The Control Group included 82 patients receiving only an AF drug. Subjects were followed for 12 months with scheduled and symptom-driven assessments to detect recurrent atrial fibrillation by means of periodic electrocardiograms, weekly scheduled trans-telephonic monitoring, patient-initiated trans-telephonic monitoring, and 24-hour Holter monitoring at 6 and 12 months. The first 90 days after study therapy was initiated was considered a blanked period for all subjects. Limitations of the Cryoablation for Atrial Fibrillation Jul 15 17

18 study included early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data. This was last updated July 25, Final outcomes will be completed after the last patient is enrolled and the 12-month follow-up is terminated. There is another Clinical Trial on Cryoablation of Atrial Fibrillation Using a Novel Cryoablation System, which is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT , and this was last updated September 13, The primary endpoint is the safety and tolerability of ablation using the AFreeze Cryoablation System consisting of the ablation CoolLoop catheter, its steerable sheath and the cryoconsole Cryo-Caddy, that will be assessed and expressed in a number of participants with AE. Another Clinical Trail on Sustained Treatment of Paroxysmal Atrial Fibrillation Post-Approval Study (STOP AF PAS), is also recruiting participants. The ClinicalTrials.gov Identifier is NCT , and was last updated on October 24, The Post-Approval Study (PAS) is a prospective multi-center, nonrandomized, single arm, controlled, unblinded clinical study designed to provide long-term safety and effectiveness of the Arctic Front Cardiac CryoAblation System. There was a completed Clinical Trial on Safety and Efficacy of CryoCor Cryoablation for PAF, last updated on July 14, 2011, with no study results posted yet. The ClinicalTrials.gov Identifier is NCT The purpose of this prospective, randomized multi-center clinical study is to establish the benefits of the CryoCor(TM) Cardiac Cryoablation System for treating symptomatic paroxysmal atrial fibrillation (PAF) in comparison to treatment with antiarrhythmic medications alone. This study also evaluates the safety profile of the CryoCor(TM) Cardiac Cryoablation System when used in this same setting. Another Clinical Trial on Durability of Pulmonary Vein Isolation Following Cryoablation for Treatment of Paroxysmal Atrial Fibrillation (SUPIR), is not yet open for participant recruitment. The ClinicalTrials.gov Identifier is NCT The purpose of the study is to determine the permanency of PV isolation with the Arctic Front Advance cryoablation system in paroxysmal AF patients. It will also provide data on acute procedural outcomes and measures as well as clinical AF recurrence in these patients approximately 3 months postablation. This study was last verified on August 12, A Phase 3 Clinical Trial Effect of Balloon Cryoablation on Left Atrial Function (CRYO-LA) is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT , which was last updated on February 18, Based on the potentially deleterious effects of damage caused by cryoablation, to the atrial myocardium during balloon ablation, this prospective, non-randomized, singlecenter study has been designed to assess the atrial effects of balloon cryoablation. A Clinical Trial on FIRE AND ICE: Comparative Study of Two Ablation Procedures in Patients With Atrial Fibrillation is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT and was last updated July 9, The purpose of this trial is to compare the 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. The estimated study completion date is August Cryoablation for Atrial Fibrillation Jul 15 18

19 A Clinical Trial on Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA) is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT , and this was last updated on August 31, This trial has the overall goal of establishing the appropriate roles for medical and ablative intervention for atrial fibrillation (AF). The CABANA Trial is designed to test the hypothesis that the treatment strategy of left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) will be superior to current state-of-the-art therapy with either rate control or rhythm control drugs for reducing total mortality in patients with untreated or incompletely treated AF. The majority of the Clinical Trials noted above do not include the estimated study completion dates. Scientific Rational Update December 2011 Cryoablation has been used for targeted ablation of slow pathways and accessory pathways under specific circumstances. The release of a cryoablation balloon that delivers a circumferential lesion at the antrum of the pulmonary vein has made the technology available for the treatment of AF. This technology may reduce procedure times and reduce the risk of complications related to RF energy, specifically thrombus formation at the lesion site and cardiac perforation due to direct catheter related trauma or excessive heating at the catheter-tissue interface. The efficacy and adverse events associated with cryoballoon ablation for the treatment of AF have been evaluated in the following clinical study: Kojodjojo et al. (2010) completed a study with the goal of investigating the efficacy of a strategy using a large cryoablation balloon to perform antral cryoablation with 'touch-up' ostial cryoablation for pulmonary venous isolation (PVI) in patients with paroxysmal and persistent atrial fibrillation (AF). Paroxysmal and persistent AF patients undergoing their first left atrial ablation were recruited. After cryoballoon therapy, each PV was assessed for isolation and if necessary, treated with focal ostial cryoablation until PVI was achieved. Follow-up with Holter monitoring was performed. Clinical outcomes of the cryoablation protocol were compared, with consecutive patients undergoing PVI by RFA. 124 consecutive patients underwent cryoablation. 77% of paroxysmal and 48% of persistent AF subjects were free from AF at 12 months after a single procedure. Over the same time period, 53 consecutive paroxysmal AF subjects underwent PVI with RFA and at 12 months, 72% were free from AF at 12 months (p=ns). There were too few persistent AF subjects (n=8) undergoing solely PVI by RFA as a comparison group. Procedural and fluoroscopic times during cryoablation were significantly shorter than RFA. PV isolation can be achieved in less than 2 h by a simple cryoablation protocol with excellent results after a single intervention, particularly for paroxysmal AF. It appears from this study that cryoablation around the pulmonary venous (PV) ostia for AF therapy seems to be potentially safer compared to radiofrequency ablation (RFA). It appears that in this small non-randomized trial comparing cryoballoon to standard radiofrequency ablation, cryoballoon has similar efficacy rates in maintaining sinus rhythm at 6 and 12 months. However, larger peer-reviewed randomized controlled or comparative studies with long-term results are needed. Linhart et al. (2009) completed a case-control setting and compared 20 patients with paroxysmal AF who underwent their first PV ablation with the cryoballoon technique to 20 matched patients with conventional RF ablation. In the case of persistent electrical potentials after cryoballoon ablation, it was combined with ablation with a conventional cryocatheter. All patients performed daily event recording for 3 months after ablation procedure. Ablation parameters and success rate after 3 and 6 months were compared. In the cryoballoon group, the overall success rate was 55% (50% in Cryoablation for Atrial Fibrillation Jul 15 19

20 the cryoballoon only group [14 patients] and 66% in the combination group [6 patients]), as opposed to the RF group with 45%. AF episode burden was lower after cryoballoon ablation. There was no significant difference between cryoballoon and RF ablation regarding procedure parameters. In the cryoballoon group, 3 phrenic nerve palsies occurred using the 23 mm balloon that resolved spontaneously. PV ablation with the cryoballoon technique is feasible and seems to have a similar success rate in comparison to RF ablation. Procedure and fluoroscopy duration are not longer than in conventional RF ablation. Although the short-term results are promising in this study, the long-term efficacy and safety of cryoablation for the treatment of atrial fibrillation is lacking. Surgical approaches that are available for atrial fibrillation include the maze and corridor operations as well as radiofrequency or cryoablation. These procedures appear effective in a high percentage of patients. However, the follow-up for many of these studies was limited in scope and did not employ very rigorous arrhythmia surveillance. Although there is some published data suggesting transcatheter cryoablation is technically feasible and may be effective for the treatment of AF in some individuals, the studies are in general limited by small numbers of individuals studied and short follow-up periods. Clinical experience is limited and at the present time radiofrequency energy is considered the more established and widely accepted method for transcatheter ablation of AF. There is currently insufficient evidence available to draw conclusions as to whether transcatheter cryoablation is as effective as radiofrequency ablation for the abolition of AF. Prospective, randomized, comparative studies of these two energy sources are currently lacking and would be required to establish the relative long term efficacy and safety of the two techniques. Scientific Rationale Initial Cryoablation, also known as cryotherapy, cryosurgery, cryothermy, or cryoanalgesia, involves the use of extreme cold temperatures by liquid nitrogen or argon gas to destroy diseased or abnormal tissue. Atrial fibrillation (AF) is the most common sustained arrhythmia, and is present in approximately 35% of patients presenting for mitral valve surgery and in 1 to 6% of adult patients undergoing other forms of cardiac surgery. If left untreated, AF is associated with increased morbidity, and, in some subgroups, increased mortality. This arrhythmia is a supraventricular tachyarrhythmia characterized by uncoordinated atrial signals that result in mechanical heart dysfunction. Atrial mechanical dysfunction as a result of AF could largely be attributed to the structural abnormalities that could at times result from atrial arrhythmia. However, atrial fibrillation could also occur in the absence of structural heart disease. If structural heart disease is present, it is most commonly mitral stenosis. Atrial fibrillation is distinct from atrial flutter and atrial tachycardia, but individuals may have more than one of these three arrhythmias. Atrial fibrillation may be asymptomatic or may produce symptoms such as heart palpations, lethargy, dizziness, chest discomfort, shortness of breath, or a combination of these symptoms. Individuals with atrial fibrillation may also have an increased risk of stroke as a result of blood clots forming in the left atrium and then embolizing to the brain. Conservative treatments for AF include electrical cardioversion to control the heart rhythm, and anticoagulants to prevent the formation of blood clots. Cryoablation for Atrial Fibrillation Jul 15 20