National Medical Policy

Transcription

1 National Medical Policy Subject: Policy Number: Catheter Ablation for Atrial Fibrillation NMP175 Effective Date*: May 2010 Update: July 2016 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 16 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. Health Net, Inc. considers pulmonary vein isolation (PVI) using cryoablation (CA), as an alternative to radiofrequency ablation (RFA), for treatment of electrocardiographic (ECG)-documented persistent atrial fibrillation (AF) in adult patients who are resistant to or cannot tolerate medical therapy. There is limited peer-reviewed literature to support the comparative efficacy of CA versus RFA for this indication. Cryoablation for Atrial Fibrillation Jul 16 2

3 Health Net, Inc. considers redo-pulmonary vein isolation (PVI) using cryoablation (CA) for treatment of ECG-documented paroxysmal atrial fibrillation (PAF) in adult patients with previously failed pulmonary vein isolation (PVI) by RFA. There is a paucity of peer-reviewed literature to support the comparative efficacy of CA versus RFA for this indication. 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. 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 16 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 July 2016 Achieving long-term successful outcomes with ablation of persistent atrial fibrillation (AF) remains a clinical and procedural challenge. The authors goals were to assess 2 ablation strategies for persistent AF: pulmonary vein antral isolation (PVAI) in sinus rhythm after direct current cardioversion versus PVAI and ablation targeting complex-fractionated atrial electrograms while in AF. Bassiouny et al. (2016) completed a randomized study to either direct current cardioversion before PVAI and posterior wall/septum ablation while in sinus rhythm (group 1), versus same ablation in group 1 in addition to complex-fractionated atrial electrogram ablation while in AF (group 2). The procedural profiles and clinical outcomes of the 2 strategies were compared. Ninety patients were randomized to group 1 (n=46) or group 2 (n=44). There were no differences in baseline characteristics between groups. Over 365 days of follow-up after the index procedure, 16 patients (35%) in group 1 and 13 patients (30%) in group 2 remained arrhythmia-free off antiarrhythmic medications. Over long-term follow-up (median, 867 days), arrhythmia-free survival off antiarrhythmic medications was more likely in group 1 than in group 2 in Kaplan-Meier analysis (Log Rank P=0.04). Group 1 ablation was associated with significantly shorter procedural duration and fluoroscopy time (231±72 versus 273±76 min; P=0.008 and 54 [Q1-Q3: 46-67] versus 66 (Q1-Q3: 53-83] min; P=0.018, respectively). In patients with persistent AF, PVAI in sinus rhythm after direct current cardioversion is associated with higher success and shorter procedural and fluoroscopy times compared with PVAI in AF with additional complex-fractionated atrial electrogram ablation. 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. Cryoablation for Atrial Fibrillation Jul 16 4

5 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. 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 Cryoablation for Atrial Fibrillation Jul 16 5

6 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 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 Cryoablation for Atrial Fibrillation Jul 16 6

7 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 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 Cryoablation for Atrial Fibrillation Jul 16 7

8 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 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 Cryoablation for Atrial Fibrillation Jul 16 8

9 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. 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 Cryoablation for Atrial Fibrillation Jul 16 9

10 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 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 Cryoablation for Atrial Fibrillation Jul 16 10

11 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) 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 Cryoablation for Atrial Fibrillation Jul 16 11

12 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 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. Cryoablation for Atrial Fibrillation Jul 16 12

13 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 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 Cryoablation for Atrial Fibrillation Jul 16 13

14 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 (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. Cryoablation for Atrial Fibrillation Jul 16 14