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  •    Cryoballoon Versus Radiofrequency Ablation For Paroxysmal Atrial Fibrillation: Review Of Current Literature
    Syed Rafay Ali Sabzwari, MD;1 Dhanunjaya Lakkireddy, MD, FACC, FHRS2

    1PGY-2 Internal Medicine Resident Florida Hospital Medical Center 2501 N. Orange Ave. Suite 235 Orlando, FL 32804. 2Professor of Medicine Governor-Kansas ACC Chapter Associate Editor - JAFIB Mid America Cardiology University of Kansas Hospital Kansas City, KS 66160.


    Atrial fibrillation is the most common arrhythmia affecting an estimated 3 million people in US and 20 million around the world. In the realm of rhythm control antiarrhythmic drugs (AAD) were utilized until transcatheter ablation techniques emerged. Circumferential pulmonary vein isolation (PVI) is the standard and recommended approach for catheter ablation of paroxysmal atrial fibrillation refractory to medical therapy. The first introduced and most commonly used method is radiofrequency (RF) ablation and the second most common and more recent is cryoballoon (CB) ablation. To benefit from their efficacies and optimize their usage, in the past there have been many mostly nonrandamoised single center prospective registries showing equivocal efficacy of the two techniques with slightly lower complications such as cardiac tamponade and perforation with cryoballoon technique. However in addition to the three prior randomized controlled trials, the recently published FIRE and ICE Trial by Kuck et al1 which is a large, multicenter, randomized trial compared radiofrequency and cryoballoon techniques used for ablation of paroxysmal atrial fibrillation. 

    Radiofrequency Ablation

    Mechanism Of Ablation

    Both the mechanisms share the standard approach of obtaining a cardiac computed tomography or magnetic resonance imaging to identify left atrial and pulmonary vein anatomy in detail. Venous access is obtained to reach right atrium and thereafter by using intracardiac echo trans-septal puncture is done to reach the left atrium and pulmonary veins. An electromagnetic anatomical map is created by combining data from cardiac CT scan and the electromagnetic mapping catheter. Radiofrequency involves low voltage, high frequency electrical energy [30 KHz to 1.5 MHz] delivered with a catheter to the endocardial surface in the form of focal points around a circular mapping catheter with the aim of electrically isolating the pulmonary veins which are the site for propagation of impulses that trigger atrial fibrillation

    Evolution Of Radiofrequency Ablation

    The first and the most commonly used modality for AF ablation is radiofrequency. Multiple trials have shown RF catheter ablation to be superior to AAD therapy in maintenance of sinus rhythm.2-6 Even in heart failure, a recent study has shown superiority of RF over AAD.7 Initially, the formation of denatured tissue protein coagulum at the catheter tip caused insulation and limited the efficacy of RF ablation. However in 1995, the addition of saline irrigation to cool the catheter tip8 augmented the efficacy of RF in subsequent studies.9-12 The incidence of failure of RF ablation due to PV reconnections further reduced since the introduction of contact force sensing technology.13 This lead to more durable PVI guided by a monitored contact force while performing ablation.14 

    Cryoballoon Ablation

    Mechanism Of Ablation

    After reaching the left atrium through transseptal approach similar to RF, cryothermal ablation utilizes a balloon that occludes the pulmonary vein ostia and then by filling the balloon with a liquid refrigerant causes permanent tissue damage circumferentially around the balloon. The latter technique when designed was thought to reduce procedure times, reduce risk of complications especially cardiac perforation and thrombus formation.  

    Evolution of Cryoballoon Ablation

    CB technology, a more recent modality introduced for AF ablation has been steadily growing in usage after its efficacy over AAD was shown in STOP-AF15 trial specially at the hand of less experienced hands in the field of ablation. With the newer generation CB the incidence of pulmonary vein reconnection after ablation has also decreased however still high in cases of common pulmonary vein ostia.16 Further studies to evaluate CB in non-paroxysmal AF are underway. 


    General Complications

    Overall the incidence of complications is approximately 4 percent amongst which vascular complications are the most common. These include hematoma, psuedoaneurysm, arteriovenous fistula or retroperitoneal bleed. A death rate of about 1 to 1.5 in every 1000 patients has been reported in early case series.17-18 The most serious complication and most common cause of death is cardiac tamponade occurring in around 1 percent procedures.17,19,20 Catheter entrapment in mitral valve can also occur happen but is easily managed without the need for surgery. The incidence of pulmonary vein stenosis has also decreased to 1-3 percent with better techniques causing ablation near the atrial side of the pulmonary veins. Periprocedural embolic events causing stroke are also complications for which anticoagulation needs to be maintained meticulously. However in almost all patients this complication had resolved by 3 months and in >90 percent within one year. Other even rarer complications include atrioesophageal fistula, periesophageal vagal injury and acute coronary artery occlusion. Occurrence of iatrogenic atrial septal defect and atypical flutter have also been documented. 

    Risk Of Phrenic Nerve Injury With CB

    Phrenic nerve injury has been persistently more with CB than RF with the most recent report of 2.7 percent incidence at discharge for CB compared to 0 percent for RF by Kuck et al. The close proximity of the phrenic nerve to right superior pulmonary vein is the reason behind it. Monitoring phrenic nerve activity by continuous pacing,21 recording diaphragmatic electromyograms22 during CB specially while isolating right superior pulmonary vein have been shown to more accurately predict the risk of phrenic nerve injury. Also the use of larger balloons may also lower this risk. 

    Advantages Of RF And Cb Ablation Techniques

    Current Literature

    There has been four randomized clinical trials published so far with the most recent one being The Fire and Ice Trial.1 In addition to these being discussed, some of the notable nonrandomized studies will be discussed here.  Table 2 summarizes the current literature available. 

    Table 1: Advantages of RF and CB for atrial fibrillation ablation
    Advantages of Radiofrequency Ablation Advantages of Cryoballoon Ablation
    Shorter fluoroscopic time1 Shorter procedure duration and left atrial dwell time1
    Lesser risk of pulmonary vein reconnections Circumferential lesions with a single ablation application
    Lesser incidence of phrenic nerve injury1 Lower incidence of tamponade and atrioesophageal fistula

    The Fire and Ice trial1 is a well-designed, randomized, multicenter, open-label, parallel-group trial with blinded end-point assessment supervised by a steering committee. However the data had to be transferred between two contract research organizations due to one becoming insolvent. It was a noninferiority study design not determining if one was better compared to the other. The study had a good sample size of 762 patients, refractory to class I, III antiarrhythmic drugs or beta blockers. The patient sample was comparable with respect to baseline characteristics however the cryoballoon group had a greater percentage of patients with higher CHADS-VASC score >3 (14.2 % vs 11%), type II diabetes (9.9% vs 5.9%), chronic kidney disease (13% vs 4%); however a p-value was not provided to see if these differences were significant or not. The procedures were however performed in different centers with varying level of expertise and experience which could introduce some degree of operator bias. 

    The efficacy end point was the first evidence of clinical failure happening 90 days after the procedure where the 90 day period was taken as the ‘blanking period’. Failure could be in the form of recurrence of atrial fibrillation of more than 30 seconds, atrial flutter or atrial tachycardia, repeat ablation procedure or prescription of antiarrhythmic agents. Similarly, safety end point was death from any cause, stroke or serious adverse occurrence. 

    Table 2: Comparison of studies done on CB vs RF ablation for atrial fibrillation
    Study Design Sample size (n) Efficacy Safety
    Fire and Ice Trial1 Randomized Controlled Trial 750 CB non inferior to RF Increased transient phrenic nerve injury in CB
    Freeze AF Trial23 Randomized Controlled Trial 315 Similar Increased transient phrenic nerve injury in CB
    Herrera Siklody et al25 Randomized Controlled Trial 60 Similar Similar
    Hunter et al24 Randomized Controlled Trial 155 CB better than RF Increased transient phrenic nerve injury in CB
    Aryana et al27 Nonrandomised retrospective study 27 CB-2 better than RF Increased transient and permanent phrenic nerve injury in CB
    Wasserlauf et al26 Nonrandomised prospective study 201 Similar More cardiac perforation with RF
    Jourda et al28 Nonrandomised prospective study 150 Similar Similar
    Squara et al29 Nonrandomised prospective study 376 Similar Increased transient phrenic nerve injury in CB; increased severe non-lethal complications in RF

    PVI was successful in around 98% patients in both groups and patients were successfully followed with clinic visits and through transtelephonic ECGs for a mean of 1.5 years. Results showed that there was no statistically significant difference in the primary efficacy end point for the two groups thereby cryoballoon was noninferior to radiofrequency. Some differences were higher total procedure duration and left atrial dwell time for radiofrequency group and higher total fluoroscopy time in cryoballoon group. The complications also proved to be similar between the two groups with no statistically significant difference, the most common being groin site complications and phrenic nerve injury however phrenic nerve injuries due to cryoballoon persisted at discharge compared to radiofrequency group. Although the trial did not prove superiority of the first generation or second generation catheters nor the details associated with each catheter during the procedure, it did show no difference in the efficacy and safety end points associated with the four catheters (two each for radiofrequency and cryoballoon). 

    In October, 2015 the FreezaAF trial by Luik et al23 was the second largest trial to prove noninferiority between CB and RF techniques. The primary end point was freedom from atrial arrhythmia with absence of persistent complications. Patient population was largely comparable between groups. The primary end point at 6 months was achieved by  63.1% and 64.1% for the RF and CB groups respectively, subsequently at 12 months was achieved by 70.7% with RF and 73.6% with CB (due to redo procedures). The null hypothesis could be rejected at 12 months (risk difference, 0.014; 95% CI, −0.089 to 0.117; P<0.001) and at 6 months (risk difference 0.010; 95% CI, −0.096 to 0.117; P=0.002). Periprocedural complications for the index procedure were more frequent in the CB group (5.0% RF, 12.2% CB; P=0.022) with the most significant difference being for phrenic nerve paralysis (0% RF, 5.8% CB; P=0.002).

    Hunter et al24 in December, 2015 randomized 237 patients undergoing first time paroxysmal AF ablation to RF, CB, or combined. Freedom from arrhythmia after the procedure at 1 year was achieved in 47% in the RF group, 67% in the CB group, and 76% in the combined group (P < 0.001 for RF vs CB, P<0.001 for RF vs combined, and P = 0.220 for CB vs combined). The rate of major complications between the three groups was similar except transient phrenic nerve paralysis with CB. 

    In another smaller randomized control trial with sixty patients having symptomatic drug resistant AF, by Herrera et al,25 were randomly divided into two groups undergoing RF or CB ablation. Markers of inflammation and cell damage including high-sensitive troponin T (hs-TnT), platelet aggregometry, expression of platelet surface proteins (P-selectin and glycoprotein IIb/IIIa and high-sensitive C-reactive protein (hs-CRP) were measured before and 48 hours from the procedure. No significant difference was found between patients treated with CB or RF for the above parameters, success rates, fluoroscopic time and procedural complications. The total procedural time was however shorter with CB than RF ablation.  

    Wasserlauf et al26 in April 2015 did a single-center prospective cohort study with evaluating a total of 201 patients who underwent catheter ablation for paroxysmal atrial fibrillation using CB or RF methods. The primary end point was freedom from AF, atrial flutter, and atrial tachycardia after a 3-month blanking period without requirement for antiarrhythmic drugs. Primary end point at 1-year was 60.3% for CB and 61.1% for RF (P = 0.93). Procedure times were shorter with CB (192.9 ± 44.0 minutes vs 283.7 ± 78.0 minutes, P < 0.001) as well as total fluoroscopy times (46.0 ± 22.4 minutes vs 73.0 ± 30.1 minutes, P < 0.001). Overall complication rates were equivalent; however, fewer cardiac perforations occurred with CB (0% vs 4%, P = 0.042)

    Aryana et al27 in August 2015 in a multicenter, retrospective, nonrandomized analysis of 1196 patients compared the second-generation cryoballoon (CB-2) versus point-by-point radiofrequency. This study examines the acute/long-term CAAF outcomes using these two strategies. Freedom from AF/atrial flutter/tachycardia at 12 months following a single procedure without antiarrhythmic therapy was greater with CB-2 than RF (76.6% versus 60.4%, P< 0.001). While this difference was evident in patients with paroxysmal AF (P < 0.001), it did not reach significance in those with persistent AF (P = 0.089). In addition CB-2 was associated with shorter ablation time (P < 0.001) and procedure time (P < 0.001), but greater fluoroscopic utilization (29 ± 13 minutes vs. 23 ± 14 minutes; P < 0.001). While transient (7.6% vs. 0%; P<0.001) and persistent (1.2% vs. 0%; P=0.026) phrenic nerve palsy occurred exclusively with CB-2 than RF respectively, other adverse event rates were similar between CB-2 and RF (P=0.207).

    Jourda et al28 (2015) did a smaller study with 150 consecutive patients enrolled (75 in each group). The characteristics of patients of both the groups were similar. At 12 months, AF recurrence occurred in 11 patients (14.7%) in the CB group and in 9 patients (12.0%) in the RF group (HR 1.20 95% CI 0.50–2.90, P= 0.682). Duration of the procedure was significantly lower in the RF group (P= 0.001), with a lower duration of fluoroscopy (P= 0.017) and X-ray exposure (P=0.001). In contrast, no significant difference was found regarding significant procedural complication (2.7% vs. 1.3% in RF and CB groups, respectively).

    Squara et al29 (2015) performed a multicenter study comprising 376 patients comparing procedural safety and arrhythmia recurrence after standardized PVI catheter ablation for PAF using contact force-guided RF ablation with second-generation CB ablation. Single-procedure freedom from any atrial arrhythmias at 18 months post-ablation was comparable in RF group and CB group (76 vs. 73.3%, respectively, P = 0.63). Procedure was shorter for CB group than for RF group (P= 0.003), but fluoroscopy duration and X-ray exposure were not statistically different (P = 0.1 and P = 0.22, respectively). Overall complication rate was similar in both groups: 7.1% in the RF group versus 7.3% in the CB group (P = 0.93). However, transient right phrenic nerve palsy occurred only in CB group (10 patients, 5.6%; P = 0.001) versus RF group and severe non-lethal complications (embolic event, tamponade or esophageal injury) occurred only in RF group (5 patients, 2.5%; P = 0.03) versus CB group. 


    The most recent Fire and Ice Trial along with two other randomized controlled trials show similar efficacy for CB and RF. Only two studies, one randomized and one nonrandomized showed CB to be better than RF. The only significant complication found across all studies was the increased incidence of transient phrenic nerve injury in CB group with almost no permanent sequelae. With continuous developments in catheters, safety techniques and growing expertise with PVIs and especially in the use of CB and overall decrease in incidence of all complications is expected. Although there is strong data to support CB having similar efficacy to RF, user expertise, left atrial anatomy and the need for concomitant ablation of other atrial arrhythmias might guide use of one over the other. 


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    2. Hakalahti A, Biancari F, Nielsen JC, Raatikainen MJ. Radiofrequency ablation vs. antiarrhythmic drug therapy as first line treatment of symptomatic atrial fibrillation: systematic review and meta-analysis. Europace Mar 2015;17:370-378.

    3. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation Dec 9 2008;118:2498-2505.

    4. Nair GM, Nery PB, Diwakaramenon S, Healey JS, Connolly SJ, Morillo CA. A systematic review of randomized trials comparing radiofrequency ablation with antiarrhythmic medications in patients with atrial fibrillation. Journal of cardiovascular electrophysiology Feb 2009;20:138-144.

    5. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol Dec 5 2006;48:2340-2347.

    6. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA : the journal of the American Medical Association Jan 27 2010;303:333-340.

    7. Di Biase L, Mohanty P, Mohanty S, et al. Ablation vs. Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation Mar 30 2016.

    8. Ruffy R, Imran MA, Santel DJ, Wharton JM. Radiofrequency delivery through a cooled catheter tip allows the creation of larger endomyocardial lesions in the ovine heart. J Cardiovasc Electrophysiol 1995; 6:1089.

    9. Jaïs P, Shah DC, Haïssaguerre M, et al. Prospective randomized comparison of irrigated-tip versus conventional-tip catheters for ablation of common flutter. Circulation 2000; 101:772.

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    11. Calkins H, Epstein A, Packer D, et al. Catheter ablation of ventricular tachycardia in patients with structural heart disease using cooled radiofrequency energy: results of a prospective multicenter study. Cooled RF Multi Center Investigators Group. J Am Coll Cardiol 2000; 35:1905.

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    15. Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG, Dubuc M, Reddy V, Nelson L, Holcomb RG, Lehmann JW, Ruskin JN. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol Apr 23 2013;61:1713-1723.

    16. Ciconte, G., et al. (2014). “Spontaneous and adenosine-induced pulmonary vein reconnection after cryoballoon ablation with the second-generation device.” J Cardiovasc Electrophysiol 25(8): 845-851.

    17. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798.

    18. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:32.

    19. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627.

    20. Maan A, Shaikh AY, Mansour M, et al. Complications from catheter ablation of atrial fibrillation: a systematic review. Crit Pathw Cardiol 2011; 10:76.

    21. Franceschi F, Koutbi L, Gitenay E, Hourdain J, Maille B, Trevisan L, Deharo JC. Electromyographic monitoring for prevention of phrenic nerve palsy in second-generation cryoballoon procedures. Circulation Arrhythmia and electrophysiology Apr 2015;8:303-307.

    22. Lakhani M, Saiful F, Parikh V, et al. Recordings of diaphragmatic electromyograms during cryoballoon ablation for atrial fibrillation accurately predict phrenic nerve injury. Heart Rhythm 2014; 11:369.

    23. Luik A, Radzewitz A, Kieser M, et al. Cryoballoon versus open irrigated radiofrequency ablation in patients with paroxysmal atrial fibrillation: the prospective, randomized, controlled, noninferiority FreezeAF Study. Circulation 2015;132:1311-1319

    24. Hunter RJ, Baker V, Finlay MC, et al. Point-by-point radiofrequency ablation versus the cryoballoon or a novel combined approach: a randomized trial comparing 3 methods of pulmonary vein isolation for paroxysmal atrial fibrillation (the Cryo Versus RF Trial). J Cardiovasc Electrophysiol 2015;26:1307-1314

    25. Herrera Siklody C, Arentz T, Minners J, Jesel L, Stratz C, Valina CM, Weber R, Kalusche D, Toti F, Morel O, Trenk D. Cellular damage, platelet activation, and inflammatory response after pulmonary vein isolation: a randomized study comparing radiofrequency ablation with cryoablation. Heart Rhythm Feb 2012;9:189-196.

    26. Wasserlauf J, Pelchovitz DJ, Rhyner J, et al. Cryoballoon versus radiofrequency catheter ablation for paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2015;38:483-489

    27. Aryana A, Singh SM, Kowalski M, et al. Acute and long-term outcomes of catheter ablation of atrial fibrillation using the second-generation cryoballoon versus open-irrigated radiofrequency: a multicenter experience. J Cardiovasc Electrophysiol 2015;26:832-839

    28. Jourda F, Providencia R, Marijon E, et al. Contact-force guided radiofrequency vs. second-generation balloon cryotherapy for pulmonary vein isolation in patients with paroxysmal atrial fibrillation-a prospective evaluation. Europace 2015;17:225-231

    29. Squara F, Zhao A, Marijon E, et al. Comparison between radiofrequency with contact force-sensing and second-generation cryoballoon for paroxysmal atrial fibrillation catheter ablation: a multicentre European evaluation. Europace 2015;17:718-724

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