Background The volume of atrial fibrillation (AF) catheter ablation procedures has increased to address the growing patient population with AF; however, the impact of cryoballoon ablation on electrophysiology (EP) lab throughput is under-studied when treating patients with persistent AF (PsAF). Objective To assess EP lab utilization associated with cryoballoon ablation for the treatment of patients with PsAF and to evaluate mechanisms that optimize hospital resources. Methods Procedural data derived from the STOP Persistent AF trial were input into a discrete event simulation to assess EP lab utilization during AF ablation procedures. Patient and physician delays and lab occupancy times were modeled in a nominal and efficient EP lab setting over 1000 days. Accounting for variation in procedural times, we evaluated the number of days in which preplanned pulmonary vein isolation (PVI) cases resulted in overtime or excess time for non-ablation EP cases within a given lab day. A sensitivity analysis determined the parameters that most strongly influenced EP lab throughput. Results Lab occupancy times for the Nominal Use (NU) case included 165 procedures, and the High-Efficiency Use (HEU) case was derived from 69 procedures conducted at sites with faster procedure times than average. The HEU case had shorter lab occupancy times than the NU case (158 ± 32 minutes vs 188 ± 51 minutes, respectively). In the NU case, a total of 2000 procedures were conducted, with 28 lab days (2.8%) extending into overtime and 900 lab days (90%) exhibiting excess time for a non-ablation EP case. In the HEU case, a total of 3000 procedures were conducted, with 87 lab days (8.7%) extending into overtime and 635 lab days (63.5%) exhibiting excess time for a non-ablation EP case. The model was most sensitive to lab occupancy duration and the time of day that overtime started. Conclusions Cryoballoon ablation for the treatment of patients with PsAF confers EP lab efficiencies that can support 3 PVI cases in a lab day.

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic, Inc. OnBehalf Cryo AF Global Registry Investigators Background Heart failure (HF) concomitant to atrial fibrillation (AF) can exacerbate the risk of hospitalization, morbidity, mortality, and impairment in quality of life posed by each condition alone. While the reciprocal relationship between HF and AF challenges effective treatment for these patients, catheter ablation for treatment of AF is reasonable for select patients with AF and HF according to guidelines. Purpose: Assess real-world usage and healthcare utilization outcomes of cryoablation for patients with AF and HF. Methods: The Cryo AF Global Registry (NCT02752737) is an ongoing, prospective, multicenter registry. Patients with AF were enrolled and treated with cryoballoon ablation (Arctic Front Advance, Medtronic) according to clinical practice at 56 sites in 26 countries world-wide. Subjects with NYHA class I-III at baseline comprised the HF cohort and were compared to patients without HF (No-HF). Freedom from atrial arrhythmia recurrence ≥30 sec, adverse events associated with the AF ablation procedure, repeat ablations, AAD usage, and cardiovascular rehospitalization over a 12-month follow-up were compared between cohorts. Results: A total of 1,303 patients (318 HF, 985 No-HF) were included. The HF cohort included patients with NYHA Class I (56.3%) and II/III (43.7%) with either preserved (81.6%) or mid/reduced (18.4%) left ventricular ejection fraction. HF patients were more often female (45.6% vs 33.6%) with persistent AF (25.8% vs 14.3%), larger left atrial diameter (4.4 ± 0.9 vs 4.0 ± 0.7 cm), and higher rates of hypertension (67.9% vs 49.1%) and prior myocardial infarction (3.8% vs 1.7%; all, P < 0.05). The rate of serious procedure-related complications was 5.3% in HF and 3.0% in No-HF (P = 0.08). Freedom from atrial arrhythmia recurrence at 12-months was not different between HF and No-HF patients with either paroxysmal (84.2% (95% CI:78.6-88.4) vs 86.8% (95% CI: 84.2 – 89.0)) or persistent AF (69.6% (95% CI: 58.1 – 78.5) vs 71.8% (95% CI: 63.2-78.7)), respectively (p = 0.32, HF vs No-HF). AF-related symptoms and antiarrhythmic drug use were significantly reduced after cryoablation in the HF and No-HF cohorts (P < 0.05). Freedom from repeat ablation at 12-months was similar between HF and No-HF patients. Of patients who had a cardiovascular rehospitalization after cryoablation, 78% presented with a supraventricular tachyarrhythmia. Persistent AF and HF at baseline both increased the risk of cardiovascular rehospitalization after cryoballoon ablation (P < 0.05). Conclusion: Cryoablation is used to treat patients with AF and concomitant HF in real-world practice and is similarly safe and effective at 12-months in patients with and without HF.

Abstract Background Recent trials demonstrated the safety and efficacy of cryoballoon ablation prior to antiarrhythmic drug (AAD) usage in patients with paroxysmal atrial fibrillation (AF); however, global utilization and outcomes of first-line cryoablation in real-world AF patient management are unknown. Purpose To evaluate baseline characteristics and outcomes in patients selected for first-line cryoablation for treatment of AF. Methods The Cryo Global Registry (NCT02752737) is an ongoing, prospective, multicenter registry. In this analysis, AF patients with an index cryoballoon ablation performed according to local standards of care at 58 centers in 26 global countries were included. Subjects with no prior failed antiarrhythmic drug (AAD) usage and not taking an AAD at baseline were considered first-line and compared to drug-refractory patients who had failed an AAD prior to enrollment in the study and/or were taking an AAD at baseline. Baseline characteristics, serious procedure-related complication rates, and 12-month freedom from a ≥30sec AF/atrial flutter (AFL)/atrial tachycardia (AT) recurrence after a 90-day blanking period were compared between the groups. Results In total, 31% of the 1,394 patients (433 first-line, 961 drug-refractory) received a first-line cryoablation. The proportion of first-line enrollments by world region (3.7%-53.5%) and countries within region (i.e. EU: 0–59%) varied widely. Drug-refractory patients failed a mean of 1.2±0.5 AADs prior to cryoablation. First-line and drug-refractory patients were similar in age (60±13 vs 61±11), sex (35.1% vs 36.8% female), and CHA2DS2-VASC (2.0±1.6 vs 2.1±1.6). First-line was more often paroxysmal AF (87.3% vs 80.2%), with lower BMI (27±5 vs 28±5), diagnosed with AF fewer years (2.1±3.9 vs 3.7±5.0), and had smaller left atrial diameters (39±7 vs 42±8 mm; all p<0.05). Hypertension and history of congestive heart failure were less common in first-line (p<0.05), but similar rates of prior myocardial infarction, stroke, coronary artery disease, diabetes, and sleep apnea were reported. Procedure, left atrial dwell, and cryoapplication times were similar between cohorts (all p>0.05). Serious adverse event rates were not statistically different between first-line and drug-refractory patients (2.3% vs 3.4%, respectively; p=0.32). Freedom from AF/AFL/AT after cryoablation in first-line vs drug-refractory PAF was 90.0% (95% CI: 86.4–92.7%) and 84.4% (95% CI: 81.5–86.8%) and in first-line vs drug-refractory persistent AF was 72.9% (95% CI: 58.6–83.0%) vs 70.2% (95% CI: 62.9–76.4%), respectively. First-line ablation resulted in higher rates of freedom from arrhythmia recurrence (p=0.02). Conclusion First-line cryoablation in a real-world setting resulted in improved efficacy without increasing the risk of a safety event. These data support cryoablation as an early intervention strategy for treatment of AF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Medtronic, Inc.

Background Cryoballoon ablation for the treatment of patients with atrial fibrillation (AF) has been utilized in Europe for >15 years. Objectives Report patient and procedural characteristics that influence the safety of cryoablation for the treatment of AF. Methods Patients enrolled in the prospective, multicenter Cryo AF Global Registry were treated at 38 European centers. Freedom from a >= 30s episode of AF/atrial flutter (AFL)/atrial tachycardia (AT) at 12-months and serious complications were analyzed. Univariate and multivariable models identified baseline patient and procedural characteristics that predicted a procedure-related complication. Results Of the 1418 subjects who completed an index procedure, the cohort was 62 +/- 11 years of age, 37.7% female, and 72.2% paroxysmal AF (PAF). The mean procedure, left atrial dwell, and fluoroscopy times were 81 +/- 34, 54 +/- 25, and 14 +/- 13 min, respectively. Among the 766 patients with 12-month follow-up, freedom from a >= 30 s AF/AFL/AT recurrence was 83.3% (95% CI: 79.8%-86.3%) and 71.6% (95% CI: 64.6%-77.4%) in patients with PAF and persistent AF. The serious procedure- and device-related adverse event rates were 4.7% and 2.0%. No baseline patient characteristic independently predicted a procedure-related adverse event; however, prolonged procedure duration (OR = 1.01 [95% CI: 1.00-1.01]), use of general anesthesia (OR = 1.71 [95% CI: 1.01-2.92]), and delivery of a cavotricuspid isthmus line (OR = 3.04 [95% CI: 1.01-9.20]) were each independently associated with the occurrence of a serious procedural safety event (all p < .05). Conclusions Cryoballoon ablation is safe and effective in real-world use across a broad cohort of patients with AF.

The STOP Persistent AF trial demonstrated that pulmonary vein isolation (PVI) by cryoablation was safe and effective for the treatment of patients with persistent atrial fibrillation (PsAF). To evaluate freedom from symptomatic atrial arrhythmia recurrence and corresponding patient quality of life after cryoablation for PsAF. The STOP Persistent AF trial was a prospective study that evaluated the safety and efficacy of PVI via cryoballoon ablation (Arctic Front Advance, Medtronic, Inc.) for the treatment of patients with PsAF (<6 mo episode duration) enrolled at 25 sites in the US, Canada, and Japan. The primary efficacy endpoint was freedom from ≥30 sec AF/AFL/AT recurrence, reablation, AAD increase or initiation at 12-mo excluding a 3-mo blanking period. Symptoms were documented at the time of 24 h Holters at 6 and 12 mo and weekly/symptomatic transtelephonic monitoring. Freedom from ≥30 sec symptomatic AF/AFL/AT recurrence after the blanking period was evaluated. Quality of life (AFEQT) was compared between patients with and without a symptomatic recurrence at 12 mo. A total of 165 patients (65±9 years, 70.3% male, LAD 4.2±0.6 mm, AF onset 2.5±4.8 years) were included. Freedom from all primary efficacy failures was 54.8% (95% CI: 46.7-62.1%), and freedom from symptomatic AF/AFL/AT recurrence was 71.1% (95% CI: 63.4 - 77.5%) at 12-months. Asymptomatic recurrence accounted for 36.1% of efficacy failures in the trial. Overall, the mean AFEQT score increased from 63.7 at baseline to 89.5 at 12 mo (25.8 point increase; p<0.001). The AFEQT score improved more in patients without an efficacy failure vs subjects with symptomatic arrhythmia recurrence (31.2% vs 17.1%, p<0.001). The 12 mo improvement in AFEQT for subjects with asymptomatic recurrence (25.0%) was not significantly different from either the symptomatic recurrence or treatment success group (17.1% and 31.2%, respectively; p>0.05). A high rate of freedom from symptomatic arrhythmia recurrence evaluated with weekly monitoring and significant improvements in quality of life were observed after cryoablation for PsAF.

The risk of hospitalization and symptoms that reduce quality of life are exacerbated in patients with heart failure (HF) concomitant to atrial fibrillation (AF). Guidelines indicate that catheter ablation for the treatment of AF is reasonable in select patients with AF and HF.

Abstract Background Cryoballoon ablation is a commonly used approach to treat patients with atrial fibrillation (AF). Objectives Report on the safety and efficacy of cryoballoon ablation for the treatment of AF in the largest global cohort of cryoablated patients prospectively studied within a single registry. Methods The Cryo AF Global Registry is a prospective, multi‐center registry. Patients with paroxysmal AF (PAF) or persistent AF (PsAF) were treated with the cryoballoon catheter according to routine practices at 93 sites across 36 countries. Primary efficacy endpoints included freedom from AF and freedom from AF/atrial flutter (AFL)/atrial tachycardia (AT) ≥30 seconds. The primary safety endpoint was serious device‐ or procedure‐related adverse events over 12 month follow‐up. Results During this evaluation window, 2922 subjects completed an index cryoballoon procedure, and 1440 completed 12 month follow‐up. The cohort was 61 ± 12 years of age, 36.3% female, and 78.7% PAF. Serious device‐ and procedure‐related adverse event rates were 1.5% and 3.4%, respectively. Freedom from AF/AFL/AT after the 90 day blanking period was 86.4% (95% CI: 84.3%‐88.3%) in patients with PAF and 70.9% (95% CI: 64.6%‐76.4%) in patients with PsAF. Freedom from AF/AFL/AT in first‐line PAF and PsAF was 90.0% (95% CI: 86.4%‐92.7%) and 72.9% (95% CI: 58.6%‐83.0%) at 12 months, respectively. Conclusions The Cryo Global AF Registry is the largest evaluation to demonstrate cryoablation is an efficient, safe, and effective treatment for patients with AF worldwide. Cryoablation was commonly used to treat patients prior to an AAD failure and may facilitate earlier therapy for patients on the AF disease continuum.

To date, multiple modes of research have been leveraged to study the optimal cryoballoon ablation parameters to safely, effectively, and efficiently isolate the pulmonary veins for the treatment of atrial fibrillation. Basic scientific investigation, preclinical studies, clinical observations, trials, and, more recently, computational modeling have helped to generate and test new hypotheses for the advancement of cryoballoon treatment in patients with atrial fibrillation. In this review, we examine the data and evidence that have contributed to the development of patient-tailored dosing strategies that are currently used for pulmonary vein isolation by using the Arctic Front series of cryoballoon ablation catheters. (c) 2020 The Authors. Published by Elsevier Inc. on behalf of Heart Rhythm Society. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation to treat patients with symptomatic drug-refractory atrial fibrillation (AF). OBJECTIVE The purpose of this study was to assess the safety and efficacy of PVI using the cryoballoon catheter to treat patients with persistent AF. METHODS STOP Persistent AF (ClinicalTrials.gov Identifier: NCT03012841) was a prospective, multicenter, single-arm, Food and Drug Administration-regulated trial designed to evaluate the safety and efficacy of PVI-only cryoballoon ablation for drug-refractory persistent AF (continuous episodes <6 months). The primary efficacy endpoint was 12-month freedom from >= 30 seconds of AF, atrial flutter (AFL), or atrial tachycardia (AT) after a 90-day blanking period. The prespecified performance goals were set at >40% and <13% for the primary efficacy and safety endpoints, respectively. Secondary endpoints assessed quality of life using the AFEQT (Atrial Fibrillation Effect on Quality of Life) and SF (Short Form)-12 questionnaires. RESULTS Of 186 total enrollments, 165 subjects (70% male; age 65 +/- 9 years; left atrial diameter 4.2 +/- 0.6 cm; body mass index 31 +/- 6) were treated at 25 sites in the United States, Canada, and Japan. Total procedural, left atrial dwell, and fluoroscopy times were 121 +/- 46 minutes, 102 +/- 41 minutes, and 19 +/- 16 minutes, respectively. At 12 months, the primary efficacy endpoint was 54.8% (95% confidence [CI] 46.7%-62.1%) freedom from AF, AFL, or AT. There was 1 primary safety event, translating to a rate of 0.6% (95% CI 0.1%-4.4%). AFEQT and SF-12 assessments demonstrated significant improvements from baseline to 12 months postablation (P <.001). CONCLUSION The STOP Persistent AF trial demonstrated cryoballoon ablation to be safe and effective in treating patients with drug-refractory persistent AF characterized by continuous AF episodes <6 months.

BACKGROUND Although there are considerable data on the safety of cryoablation, data on the rare but severe complication of atrioesophageal fistula (AEF) following cryoballoon ablation are limited. OBJECTIVE To report the global, user-reported incidence of AEF associated with cryoballoon ablation for the treatment of atrial fibrillation using Medtronic's complaint database. METHODS User-reported cryoballoon ablation complications occurring between July 1, 2009, and March 31, 2019, were reviewed to identify cases of AEF. A global event rate of AEF was calculated by dividing the event count by total catheter utilization over the same period. Data on symptoms and patient sequalae were reported as available. RESULTS More than 500,000 Arctic Front cryoballoon catheters (Arctic Front, Arctic Front Advance, Arctic Front Advance ST, and Arctic Front Advance Pro; Medtronic, Inc) were distributed globally during the 9.75-year study period. During this time, 18 confirmed AEF, 1 suspected AEF, and 1 pericardial esophageal fistula were identified; therefore, global incidence of AEF associated with the Arctic Front family of ablation catheters was 0.00396%. Patients most commonly presented with fever (88.2%), and initial symptoms were reported a median of 21 (interquartile range: 4-30) days after the ablation. Although rare, the development of an AEF resulted in death in 68.8% (11/16) of patients with known outcomes. CONCLUSIONS AEF is a possible but rare complication of cryoballoon ablation with a reported frequency of 1 in every 25,000 patients treated. Awareness of the prevalence and manifestation of AEF associated with cryoballoon ablation is critical for early identification and treatment of this complication.

It is common practice to observe patients during an overnight stay (ONS) following a catheter ablation procedure for the treatment of atrial fibrillation (AF).

Background:The FIRE AND ICE trial assessed efficacy and safety of pulmonary vein (PV) isolation using cryoballoon versus radiofrequency current (RFC) ablation in patients with drug refractory, symptomatic, paroxysmal atrial fibrillation (AF). The purpose of the current study was to assess index lesion durability as well as reablation strategy and outcomes in trial patients undergoing a reablation procedure. Methods:Patients with reablation procedures during FIRE AND ICEwere retrospectively consented and enrolled at 13 trial centers. The first reablation for each patient was included in the analysis. Documented arrhythmias before reablation, number and location of reconnected PVs, lesions created during reablations, procedural characteristics, and acute as well as long-term outcomes were assessed. Results:Eighty-nine (36 cryoballoon and 53 RFC) patients were included in this study. Paroxysmal atrial fibrillation was the predominant recurrent arrhythmia (69%) before reablation. Reablations occurred at a median of 173 and 182 days (P=0.54) in the cryoballoon and RFC cohorts, respectively. The number of reconnected PVs was significantly higher in the RFC than the cryoballoon group (2.1±1.4 versus 1.4±1.1; P=0.010), which was driven by significantly more reconnected left superior PVs and markedly more reconnected right superior PVs. The number of (predominantly RFC) lesions applied during reablation was significantly greater in patients originally treated with RFC (3.3±1.3 versus 2.5±1.5; P=0.015) with no difference in overall acute success (P=0.70). After reablation, no differences in procedure-related rehospitalization or antiarrhythmic drug utilization were observed between cohorts. Conclusions:At reablation, patients originally treated with the cryoballoon had significantly fewer reconnected PVs, which may reflect RFC catheter instability in certain left atrial regions, and thus required fewer lesions for reablation success. Repeat ablations were predominantly performed with RFC and resulted in similar acute success, duration of hospitalization, and antiarrhythmic drug prescription between the study cohorts.

HomeJournal of the American Heart AssociationVol. 7, No. 24The FIRE AND ICE Trial: What We Know, What We Can Still Learn, and What We Need to Address in the Future Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBThe FIRE AND ICE Trial: What We Know, What We Can Still Learn, and What We Need to Address in the Future Karl‐Heinz Kuck, MD, Josep Brugada, MD, Michael Schlüter, PhD, Kendra M. Braegelmann, PhD, Fred J. Kueffer, MS, K. R. Julian Chun, MD, Jean‐Paul Albenque, MD, PhD, Claudio Tondo, MD, PhD, Hugh Calkins, MD, on behalf of the FIRE AND ICE Trial Investigators Andreas Metzner, Feifan Ouyang, Julian Chun, Alexander Fürnkranz, Arif Elvan, Thomas Arentz, Michael Kühne, Christian Sticherling, Laszlo Gellér, Matthias Busch, Lluis Mont, Alberto Barrera, Thomas Deneke, Volker Kühlkamp, Ricardo Ruiz‐Granell, Peter Neuzil and Nicasio Pérez‐Castellano Karl‐Heinz KuckKarl‐Heinz Kuck Department of Cardiology, Asklepios Klinik St Georg, Hamburg, Germany Search for more papers by this author , Josep BrugadaJosep Brugada Hospital Clinic, University of Barcelona, Spain Search for more papers by this author , Michael SchlüterMichael Schlüter Department of Cardiology, Asklepios Klinik St Georg, Hamburg, Germany Search for more papers by this author , Kendra M. BraegelmannKendra M. Braegelmann Medtronic, Inc, Minneapolis, MN Search for more papers by this author , Fred J. KuefferFred J. Kueffer Medtronic, Inc, Minneapolis, MN Search for more papers by this author , K. R. Julian ChunK. R. Julian Chun Cardioangiologisches Centrum Bethanien, Frankfurt, Germany Search for more papers by this author , Jean‐Paul AlbenqueJean‐Paul Albenque Cardiologie Générale, Interventionnelle – Rhythmologie, Clinique Pasteur, Toulouse, France Search for more papers by this author , Claudio TondoClaudio Tondo Heart Rhythm Center, Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Search for more papers by this author , Hugh CalkinsHugh Calkins Department of Arrhythmia Services, Johns Hopkins Medical Institutions, Baltimore, MD Search for more papers by this author , on behalf of the FIRE AND ICE Trial Investigators Search for more papers by this author , Andreas MetznerAndreas Metzner Search for more papers by this author , Feifan OuyangFeifan Ouyang Search for more papers by this author , Julian ChunJulian Chun Search for more papers by this author , Alexander FürnkranzAlexander Fürnkranz Search for more papers by this author , Arif ElvanArif Elvan Search for more papers by this author , Thomas ArentzThomas Arentz Search for more papers by this author , Michael KühneMichael Kühne Search for more papers by this author , Christian SticherlingChristian Sticherling Search for more papers by this author , Laszlo GellérLaszlo Gellér Search for more papers by this author , Matthias BuschMatthias Busch Search for more papers by this author , Lluis MontLluis Mont Search for more papers by this author , Alberto BarreraAlberto Barrera Search for more papers by this author , Thomas DenekeThomas Deneke Search for more papers by this author , Volker KühlkampVolker Kühlkamp Search for more papers by this author , Ricardo Ruiz‐GranellRicardo Ruiz‐Granell Search for more papers by this author , Peter NeuzilPeter Neuzil Search for more papers by this author and Nicasio Pérez‐CastellanoNicasio Pérez‐Castellano Search for more papers by this author Originally published10 Dec 2018https://doi.org/10.1161/JAHA.118.010777Journal of the American Heart Association. 2018;7:e010777The FIRE AND ICE Trial (ClinicalTrials.gov, identifier NCT01490814) was initiated in 2012 as a multicenter, randomized, head‐to‐head comparison of radiofrequency current (RFC) and cryoballoon catheter ablation for the treatment of patients with drug‐refractory symptomatic paroxysmal atrial fibrillation (AF). Six years on, it remains the largest, randomized comparison of safety and efficacy between 2 catheter ablation modalities used in the treatment of patients with AF. This landmark trial not only established noninferiority between cryoballoon and RFC ablation for pulmonary vein isolation (PVI) with regard to the study's efficacy and safety primary end points,1 but also, it evaluated secondary end points that were critical for a representative study interpretation.In congruence with our trial data presentations, Pocock and Stone discussed characteristics of a clinical trial that should be evaluated to ascertain clinically meaningful outcomes from statistically positive trials.2 Specifically, their review focused on the balanced interpretation of clinical evidence. In addition to the magnitude of benefit, the size of the trial, the balance between safety and efficacy, and the specificity of the results to a select patient population, the authors discuss careful interpretation of composite primary outcomes and the important role secondary outcomes can play in interpreting results.2 Because thoughtful assessment of secondary end points can reveal treatment implications that may otherwise be hidden within the primary (often composite) trial end points, the FIRE AND ICE Trial was predefined to evaluate secondary measures of clinical success. These secondary end points were designed to capture insight into the patient‐felt burden of AF after cryoballoon or RFC ablation and identified significant differences between treatment cohorts in measures of clinical success for both patients and healthcare systems.3The secondary outcomes advanced our understanding of the patient‐felt impact of AF recurrence after ablation, but important outstanding questions remain. To identify critical evidence gaps that need to be addressed, this review first comprehensively summarizes the published data from the FIRE AND ICE Trial. It then provides additional analyses to evaluate the influence of events that occurred during the blanking period on the overall patient burden of AF recurrence and the impact of newly introduced technology on the trial results. Finally, we discuss outstanding questions and anticipated upcoming trials aimed at closing knowledge gaps to ultimately guide and optimize treatment strategies across the AF disease continuum.What We Know From the FIRE AND ICE TrialPrimary Efficacy and SafetyThe FIRE AND ICE Trial tested noninferiority between cryoballoon (Arctic Front or Arctic Front Advance; Medtronic, Inc) and RFC (ThermoCool, ThermoCool SF, or ThermoCool SmartTouch; Biosense Webster, Inc) ablation for PVI in a large, randomized cohort of patients with drug‐refractory paroxysmal AF.1 The primary efficacy end point was assessed by way of a time‐to‐first‐event analysis, outside the landmark 90‐day blanking period (during which, recurrence[s] of atrial arrhythmias were not counted against the primary end point), of the following prespecified failure events: (1) documented recurrence of AF >30 seconds, atrial tachycardia, or atrial flutter; (2) prescription of antiarrhythmic drugs; and (3) repeat catheter ablation. The Kaplan‐Meier primary efficacy event‐rate estimates at 12 months after the index procedure were 34.6% in the cryoballoon cohort and 35.9% in the RFC cohort, confirming noninferiority between the ablation modalities (P<0.001).1This trial also identified no difference in the primary safety end point between treatment cohorts (P=0.24).1 Although there was no statistical difference in the absolute number of patients who reached the primary safety end point, there were differences in the type of safety events that occurred in cryoballoon‐ versus RFC‐treated patients. Specifically, phrenic nerve injury at discharge was reported more often in the cryoballoon (2.7%) than in the RFC treatment cohort (0%; P=0.001), and there was a trend for more groin site complications in the RFC cohort than in the cryoballoon cohort (4.3% versus 1.9%; P=0.09).1 The occurrence of atrial flutter or atrial tachycardia after catheter ablation of AF is well documented, and although debated, it is thought to be created (in part) by incomplete lesions or gaps in AF ablation lines that develop into a new substrate for a reentry circuit.5 For this reason, occurrences of atrial flutter and atrial tachycardia were also included as a serious adverse event. It was reported that atrial flutter and atrial tachycardia tended to be more prevalent in the RFC cohort versus the cryoballoon cohort (10/376 [2.7%] versus 3/374 [0.8%]; P=0.09).1 This observation may suggest that newly arrhythmogenic tissue, potentially driven by incomplete PVI or tissue heterogeneity, tends to be created more frequently after an index RFC ablation than an index cryoablation.Secondary OutcomesBecause the FIRE AND ICE Trial was a large trial and the primary end point hypothesis was met, it was both appropriate and important to evaluate this data set further with respect to secondary outcomes.2 Predefined secondary end points in the trial were designed to compare procedure and fluoroscopy times between the 2 cohorts as well as the patient‐felt disease burden of AF through quality of life, cardiovascular rehospitalizations, and repeat ablations. Mean total procedure and left atrial dwell durations were significantly shorter in the cryoballoon cohort, whereas mean fluoroscopy time was significantly shorter in the RFC cohort.1 As per the Short Form 12 and the EuroQol 5‐dimension form, the treatment groups experienced similar improvements in mental and physical measures of quality of life by 6 months, which were maintained in both groups throughout follow‐up.3 Secondary analyses also revealed that the cryoballoon cohort (versus RFC) had significantly fewer all‐cause rehospitalizations (32.6% versus 41.5%; P=0.01), cardiovascular rehospitalizations (23.8% versus 35.9%; P<0.01), repeat ablations (11.8% versus 17.6%; P=0.03), and direct current cardioversion after the index procedure (3.2% versus 6.4%; P=0.04).3The reduced need for subsequent medical treatment after the index ablation procedure in the cryoballoon cohort was a clinical result illustrating the generalized impact that AF disease burden imposes on current healthcare systems. A trial‐period economic analysis revealed lower resource use in the cryoballoon treatment group (205 healthcare uses in 122 of 374 patients) compared with the RFC treatment group (268 healthcare uses in 154 of 376 patients).4 This reduction in resource use was modeled to translate into significantly reduced patient and overall healthcare expenditures across 3 distinct healthcare systems (ie, Germany, United Kingdom, and United States).4For Which Patients Is Catheter Ablation Challenging?Regardless of the catheter ablation modality, 37% (281/750) of patients treated in the trial reached the primary efficacy end point.1 The reasons for individual patient failure and the optimal strategy to treat patients for whom PVI is inadequate remain largely unknown. To inform treatment strategy, a multivariable regression analysis was performed to identify baseline characteristics that predict poor outcomes after catheter ablation of paroxysmal AF, regardless of the treatment modality. Of 22 baseline patient characteristics, female sex was a strong, independent predictor of the primary end point and of cardiovascular rehospitalization.6 Baseline characteristics that were indicative of a longer cardiac disease progress (previous direct current cardioversion, hypertension, and longer duration of AF) were also independently associated with poorer clinical outcomes,6 but it is unclear how these baseline characteristics impede clinical success. To better understand the impact of treatment paradigms on patient outcomes, we returned to the study data set to assess the influence of the 90‐day blanking period on patient burden of arrhythmia recurrence and to assess the effect of technological advancement on trial results.What We Can Still Learn: Patient‐Felt Burden of AF Disease and the Blanking PeriodTime‐to‐first event analyses can be critical to a robust clinical study because they are designed to restrict the influence of oversampling bias by a few highly symptomatic subjects in a larger patient cohort; however, the major limitation of this clinical study design in real‐world patient application is that it fails to reveal the sequalae a patient experiences after the clinical trial end point. The “patient burden” of AF recurrence after an index ablation is not limited to the first event, but rather is defined by the summation of the number, type, and severity of events that follow. As illustrated, a patient without any AF recurrence after an index procedure is deemed a clinical trial success (Figure 1) and likely lives a lifestyle reflective of that freedom from atrial arrhythmia. By comparison, both a patient with an isolated recurrence and a patient with frequent recurrences are equally deemed clinical trial failures by time‐to‐first event analysis (Figure 1). However, in the real world, the patient with frequent recurrences is burdened by more episodes of atrial arrhythmias than the patient with an isolated recurrence, and, therefore, the former patient is more likely to undergo a future cardioversion, rehospitalization, and/or repeat ablation. Arrhythmias that lead to emergency department triage and rehospitalization should not be ignored (or remain uncounted) because of a time‐to‐first‐event clinical study design.Download figureDownload PowerPointFigure 1 Clinical trial success and failure vs patient burden of atrial fibrillation (AF) recurrence. Clinical trial success is illustrated in the top panel by the absence of AF recurrence events from the time of the index ablation through the end of the study period indicated by the vertical, dashed line. The middle panel demonstrates a patient who reached the clinical trial end point via an isolated AF recurrence, indicated by the single, vertical solid line within the study period. The bottom panel represents a patient who reached the clinical trial end point and subsequently experienced multiple AF recurrence events after the initial recurrence, which is demonstrated by the collection of vertical, solid lines over time. Critically, both patients in the middle and bottom panel initially recurred at the same time point during the clinical trial; therefore, these 2 patients are counted equally in the primary efficacy end point, although the burden of AF that followed the initial recurrence drastically differs between the 2 patients.The distinction between “clinically free of AF” and “meaningfully free of AF” is increasingly recognized,7 and future studies will define patient disease burden and healthcare burden while still collecting traditional clinical study measurements of AF burden. In the FIRE AND ICE Trial, predefined secondary outcome measurements were rigorously collected and analyzed with the intention to explore patient and healthcare arrhythmia burden. Although the trial was not designed to assess AF burden (ie, the percentage of time a patient was in AF), the predefined secondary outcomes elucidated the impact of 2 different catheter ablation treatments on patient‐felt AF disease burden via measures of quality of life, repeat ablations, and cardiovascular rehospitalizations, which one may infer are the outcome measures of AF disease burden.The secondary analysis was predefined to include events that occurred during the blanking period to capture the total patient and healthcare burden of AF recurrence between the 2 cohorts. However, for this current review of study data, cardiovascular rehospitalization and repeat ablations that occurred during the 90‐day blanking period were excluded to reveal the impact of these early events on the overall conclusions (Figure 2). This additional analysis demonstrated that there were significantly fewer cardiovascular rehospitalizations in the cryoballoon cohort whether or not events in the 90‐day blanking period were included in the analysis (P<0.01 and P=0.02, respectively; Figure 2A). RFC catheter ablation was associated with a significantly higher risk of cardiovascular rehospitalization regardless of the events that occurred within the first 90 days after the index procedure. The number of total hospitalizations and the number of subjects hospitalized in each cohort are detailed in Table 1. By contrast, freedom from repeat ablation was no longer statistically significant when repeat ablations that occurred within the 90‐day blanking period were removed from the analysis (P=0.03 versus P=0.10; Figure 2B). The numbers of repeat ablations in the cryoballoon and RFC cohorts are presented in Table 2.Download figureDownload PowerPointFigure 2 Survival free from predefined secondary end points, including and excluding events that occurred during the 90‐day blanking period (modified intention‐to‐treat cohort). A, Freedom from cardiovascular rehospitalization with and without a 90‐day blanking period in cryoballoon‐ vs radiofrequency current (RFC)–treated cohorts is presented. Freedom from cardiovascular rehospitalization was significantly higher in the cryoballoon cohort both when events in the blanking period were included in the analysis (log‐rank test, P<0.01) and when they were not used (log‐rank test, P=0.02). B, Freedom from repeat ablation in the cryoballoon vs RFC cohort with and without the blanking period is compared. Freedom from repeat ablation was significantly higher in the cryoballoon cohort when events in the blanking period were included in the analysis (log‐rank test, P=0.03), but the cohorts were no longer statistically different when events in the blanking period were excluded (log‐rank test, P=0.10).Table 1 Cardiovascular Rehospitalizations Within and Beyond the Blanking Period by CohortRandomization ArmTime of Cardiovascular RehospitalizationNo. of Rehospitalizations (No. of Subjects; % of Subjects)CryoballoonTotal139 (89; 23.8)Within blanking period48 (42; 11.2)Beyond blanking period91 (59; 15.8)Radiofrequency currentTotal203 (135; 35.9)Within blanking period83 (71; 18.9)Beyond blanking period120 (86; 22.9)Table 2 Repeat Ablations Within and Beyond the Blanking Period by CohortRandomization ArmTime of the Repeat AblationNo. of Repeat Ablations (No. of Subjects; % of Subjects)CryoballoonTotal49 (44; 11.8)Within blanking period12 (12; 3.2)Beyond blanking period37 (34; 9.1)Radiofrequency currentTotal70 (66; 17.6)Within blanking period19 (19; 5.1)Beyond blanking period51 (49; 13.0)With or without the blanking period, the observed difference in freedom from cardiovascular rehospitalization and repeat ablation between cohorts continues to diverge beyond the first year of follow‐up (Figure 2). These data may suggest that, although the timing of initial recurrence was equivalent between cohorts, the symptoms and severity of recurrence felt by patients treated with RFC necessitated increased intervention over time.What We Can Still Learn: Impact of New TechnologyOver the course of the trial, technological advancements in both cryoballoon and RFC ablation catheters were introduced into the commercial market and incorporated into the study at the discretion of the investigators. In the cryoballoon arm, Arctic Front ablation catheters were denoted as the first‐generation cryoballoon, and Arctic Front Advance catheters were labelled as the second‐generation cryoballoon. Similarly, in the RFC arm, ThermoCool and ThermoCool SF were categorized as the first‐generation RFC catheters, whereas the contact‐force sensing ThermoCool SmartTouch catheters were denoted as the advanced‐generation RFC ablation catheters. New catheter technology was not equally adopted into the trial; the second‐generation cryoballoon was used in 75.6% of patients in the cryoballoon arm, whereas advanced‐generation RFC catheters were used in only 24.7% of patients in the RFC group.1 The disproportionate use of second‐generation cryoballoon versus advanced‐generation RFC catheters may have obscured the efficacy of the advanced‐generation RFC contact‐force sensing technology. Although there was no difference in the primary efficacy outcome between catheter generations,1 it is imperative to understand the influence of newly introduced technology on the comprehensive clinical outcomes as new technologies inundate the field of AF ablation.Safety and Procedural Outcomes by Catheter GenerationAdditional analyses according to catheter subtype using an as‐treated cohort consistent with prior publications were performed (Figure 3). Importantly, this revealed no difference in the primary safety end point between catheter subtypes (P=0.44; Figure 4). Analyses of procedural data indicated that total procedure and left atrial dwell times were significantly shorter for second‐generation cryoballoon‐treated patients compared with the first‐generation cryoballoon‐ or any‐generation RFC ablation catheter‐treated cohort (P<0.01), whereas the mean procedure and left atrial dwell times were unchanged between first‐ and advanced‐generation RFC procedures (Table 3). Use of the second‐generation cryoballoon reduced the fluoroscopy exposure time compared with patients treated with the first‐generation cryoballoon (20±13 versus 27±15 minutes). However, the fluoroscopy time for the second‐generation cryoballoon remained higher than for the first‐generation RFC (17±19 minutes) or the advanced‐generation RFC (17±12 minutes) treated cohorts (Table 3).Download figureDownload PowerPointFigure 3 Flowchart of patient cohort assignment in the FIRE AND ICE Trial. This figure depicts the total number of patients randomized, the total number of patients in the modified intention‐to‐treat (ITT) cohort, and the patients who composed the as‐treated cohorts used for analyses of subcatheter differences. Cryo indicates cryoballoon; RFC, radiofrequency current.Download figureDownload PowerPointFigure 4 Survival free from a primary safety event by catheter subtype. An across‐group analysis of the as‐treated cohort revealed there was no statistical difference in the risk of a primary safety event across catheter subtypes (log‐rank test, P=0.44). RFC indicates radiofrequency current.Table 3 Procedural Data by Catheter TypeParameterFirst‐Generation Cryoballoon (N=90)Second‐Generation Cryoballoon (N=279)First‐Generation RFC (N=284)Advanced‐Generation RFC (N=93)P ValueAcute PVIa99.2 (351/354)98.7 (1107/1122)98.2 (1134/1155)97.1 (362/373)0.13bAcute left common PVIa100 (10/10)100 (16/16)74.2 (23/31)c90.0 (9/10)0.04bProcedure time, min140±32118±38141±57143±50<0.01dLeft atrial dwell time, min101±3289±29109±47109±41<0.01dFluoroscopy time, min27±1520±1317±1917±12<0.01dData are given as mean±SD unless otherwise indicated. PVI indicates pulmonary vein isolation; RFC, radiofrequency current.aData are given as percentage (number/total). These were treated/targeted pulmonary veins.bP value from exact test.cRF randomization arm treated with ThermoCool: 21/29; cryoballoon randomization arm treated with ThermoCool: 2/2.dP value from ANOVA.The overall rate of acute PVI approached 100% regardless of the ablation modality used (P=0.13; Table 3). However, there were catheter‐dependent differences in the rate of acute PVI during treatment of left common pulmonary veins (LCPVs; P=0.04; Table 3). Specifically, 100% of LCPVs were isolated with the first‐generation (10/10) and second‐generation (16/16) cryoballoon. By contrast, 74.2% (23/31) of LCPVs were isolated with the first‐generation RFC ablation catheter, which improved to an acute isolation rate of 90.0% (9/10) with use of the advanced‐generation RFC ablation catheter. Of the 31 LCPVs ultimately treated with RFC, 2 were from patients initially randomized to cryoballoon ablation (both of whom experienced successful acute isolation with the first‐generation RFC ablation catheter). Together, these data suggest that LCPVs are frequently isolated regardless of the catheter ablation technology. While RFC ablation catheters are inherently flexible during lesion application in uncommon anatomical features, high rates of LCPV isolation via the cryoballoon are likely enabled by a segmental approach to circumferential isolation of the LCPV ostium.9Predefined Secondary Outcomes by Catheter SubtypeTo better understand the influence of the ablation catheter generation on predefined secondary outcomes, freedom from cardiovascular rehospitalization and repeat ablation was analyzed by ablation catheter subtype (Figure 5). This analysis revealed a significant difference in freedom from cardiovascular rehospitalization between catheter types (P<0.01). Both first‐ and second‐generation cryoballoon cohorts were associated with higher rates of freedom from cardiovascular rehospitalization compared with either the first‐ or advanced‐generation RFC cohorts (Figure 5A). Notably, patients treated with the second‐generation cryoballoon experienced a higher rate of freedom from cardiovascular rehospitalization than those treated with the first‐generation cryoballoon. By contrast, freedom from cardiovascular rehospitalization was similar for the first‐ and advanced‐generation RFC catheters (Figure 5A). Although there was a difference in freedom from cardiovascular rehospitalization between catheter subtypes, there was no significant difference in the rates of repeat ablation between the 4 catheters (Figure 5B).Download figureDownload PowerPointFigure 5 Freedom from predefined secondary end points by catheter subtype in the as‐treated cohort. A, Freedom from cardiovascular rehospitalization by catheter subtype is displayed; there was a significant difference between catheter types (log‐rank test, P<0.01). B, The freedom from repeat ablation across catheter subtypes in the as‐treated cohort. There was no difference in the rate of repeat ablation when examined by catheter type (log‐rank test, P=0.12). RFC indicates radiofrequency current.What We Need to Address in the FutureAs with all successful trials, the FIRE AND ICE Trial generated many questions and future directions for potential clinical research. Specifically, pressing questions persist in the categories of repeat ablations, persistent AF, and newer ablation catheter technologies.The FIRE AND ICE Redo StudyA substantial proportion of patients experienced recurrence of AF (37% primary efficacy failure in the FIRE AND ICE Trial) after an initially successful PVI. In these patients, re‐isolation of the PVs may be warranted. Little is known about redo ablation after PVI, particularly in regard to electrophysiological differences after an initial cryoballoon or RFC procedure. During a follow‐up of maximally 33 months, repeat ablations were performed in 12% (n=44) of patients who had undergone an index PVI with the cryoballoon and 18% (n=66) of patients after an index PVI using RFC.Recently, 89 of the 110 FIRE AND ICE Trial patients with repeat ablations were retrospectively consented and enrolled in a redo study (ClinicalTrials.gov, identifier NCT03314753) with the intention to evaluate lesion durability, repeat ablation strategy, and procedural characteristics in those trial patients. There were 36 patients originally randomized to cryoballoon ablation and 53 patients randomized to RFC ablation. These repeat ablation data are currently being analyzed and will be published shortly.The FIRE AND ICE II Randomized TrialAF is progressive in nature, and paroxysmal AF evolves into persistent AF with an overall rate of 5.5% per year.10 AF can initiate irreversible fibrosis at many cardiac sites.11 With more atrial fibrosis, subjects with AF are increasingly likely to experience less favorable outcomes.12 The clinical implications of this association warrant further investigation.There is a need for adequately powered randomized trials evaluating catheter ablation in subjects with persistent, as opposed to paroxysmal, AF. The FIRE AND ICE II randomized outcome trial has been designed to compare the efficacy and safety of PVI using cryoballoon versus RFC ablation with a contact‐force sensing catheter in subjects with persistent AF. The primary objective of the trial is to demonstrate that cryoballoon ablation is noninferior to RFC ablation with respect to the time‐to‐first clinical failure, defined as recurrence of atrial arrhythmias or intervention for AF (a blanking period of 90 days will be maintained after the index procedure), which maintains study design congruence with historical trials so that the data can be compared. Intervention for AF will include hospitalizations, cardioversions, repeat ablations, and new antiarrhythmic subscriptions given for the treatment of AF. Furthermore, on the basis of magnetic resonance imaging, the trial will investigate the impact of left atrial volume and left atrial fibrosis on clinical outcome and assess lesion formation 3 months after ablation. In addition, the impact of PVI on electrical sources identified by body surface mapping will be investigated.The Potentially Revolutionary Ablation Modality: Pulsed Electrical Field AblationIn the next decade, this cryoballoon versus RFC series of trials may only serve to be a historical reference point as newer or newly redesigned ablation energies and catheters enter the commercial market space. The “novel” pulsed electrical field (PEF) ablation technology13 is (in fact) a revival of an old technology (namely, electroporation) that was used in the early days of catheter ablation at different energy settings, largely with high voltages delivered in a single pulse. PEF ablation uses similarly high voltages (ie, 900–2500 V), but they are de

Background: Data on predictors of long-term clinical outcomes after catheter ablation of atrial fibrillation (AF) are limited. We sought to assess the association of baseline covariates with clinical outcomes in the 750 patients with drug-refractory paroxysmal AF enrolled in FIRE AND ICE. Methods: In a 2-part analysis, univariate and multivariable Cox regression models were first used to identify baseline patient characteristics predictive of catheter ablation efficacy determined by the clinical end points of (1) atrial arrhythmia recurrence (primary efficacy failure), (2) cardiovascular rehospitalization, and (3) repeat ablation. Propensity score stratification methods were then used to account for differences in baseline characteristics between sexes. Results: Female sex (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.08–1.73; P=0.010) and prior direct current cardioversion (HR, 1.40; 95% CI, 1.07–1.82; P=0.013) were independently associated with atrial arrhythmia recurrence. Female sex (HR, 1.36; 95% CI, 1.02–1.80; P=0.035) and hypertension (HR, 1.48; 95% CI, 1.09–2.00; P=0.013) independently predicted cardiovascular rehospitalization. A longer history of AF (HR, 1.03; 95% CI, 1.00–1.06; P=0.039) increased the rate of repeat ablation. Women continued to have higher rates of primary efficacy failure and cardiovascular rehospitalization after propensity score adjustment, with adjusted HRs of 1.51 (95% CI, 1.16–2.18; P<0.05) and 1.40 (95% CI, 1.15–2.17; P<0.05), respectively. Conclusions: After catheter ablation of paroxysmal AF, female sex was associated with an almost 40% increase in the risks of primary efficacy failure and cardiovascular rehospitalization. Primary efficacy failure was also adversely impacted by a history of direct current cardioversion, whereas hypertension had a negative impact on cardiovascular rehospitalization. History of AF was the only predictor of repeat ablation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01490814.