FIRE AND ICE

Published

Kuck K, et al. "Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation". The New England Journal of Medicine. 2016. 374(23):2235-45.
PubMed • Full text • PDF

Clinical Question

In patients with symptomatic paroxysmal atrial fibrillation (pAF) resistant to antiarrhythmic drugs referred for pulmonary vein isolation (PVI), does balloon cryoablation result in similar efficacy to traditional radiofrequency ablation in terms of long-term atrial fibrillation-free survival?

Bottom Line

In patients with symptomatic paroxysmal atrial fibrillation (pAF) resistant to antiarrhythmic drugs referred for pulmonary vein isolation (PVI), balloon cryoablation is noninferior to radiofrequency ablation in regards to a primary outcome of composite clinical failure (recurrent AF, prescription of antiarrhythmic drugs, or repeat ablation) more than 90 days after the index procedure.

Major Points

Catheter ablation for drug-refractory symptomatic paroxsymal atrial fibrillation (pAF) carries a class I indication (level of evidence A) according to the 2012 HRS/EHRA/ECAS consensus guidelines. Pulmonary vein isolation (PVI), a process by which circumferential lesions are made around each pulmonary vein, is the standard approach to pAF ablation. There are two primary technologies utilized to perform PVI - radiofrequency ablation (RFA) and balloon cryoablation. RFA achieves PVI by applying radiofrequency current in a point-by-point process around each pulmonary vein. Balloon cryoablation uses cryogenic energy to create a circular freeze around each pulmonary vein in a single step.

Both RFA and cryoablation are associated with particular advantages and disadvantages. RFA technology has been in use for longer and thus its efficacy is more established, and it requires only limited use of fluoroscopy because catheter guidance is achieved with the use of an electoanatomical mapping system. However, RFA is a complex procedure that requires extensive training and therefore is limited to a few specialized centers. Balloon cryoablation is an emerging technology that is simpler to learn and potentially easier to implement at smaller centers. However, positioning of the balloon for freezing requires more extensive fluoroscopy and its efficacy is less proven.

The 2016 FIRE and ICE trial investigated the efficacy of RFA versus cryoablation in patients with symptomatic paroxsymal AF failing appropriate antiarrhythmic therapy in regards to a primary endpoint of clinical failure including recurrent atrial fibrillation, recurrent atrial flutter or tachycardia, prescription of antiarrhythmic drugs (class I or III), or repeat ablation. Notably, the primary endpoint was defined after a 90-day "treatment period" to allow for the ablation to take effect. In FIRE and ICE, cryoablation achieved noninferiority to RFA, suggesting that these two approaches are associated with equivalent arrhythmia-free survival. At 1.5 years, both approaches led to survival free of the primary endpoint in 65%, demonstrating relatively good efficacy of either approach. Cryoablation was associated with 15 minutes less procedure time but 5 minutes more total fluoroscopy time. Adverse events were similar in both groups although cryoablation was associated with more temporary phrenic nerve injuries (with most resolving by 6 months). Overall, the results of FIRE and ICE suggest that cryoablation and RFA are both reasonable options for achievement of PVI at least in the short- to medium-term and are associated with moderate rates of arrhythmia control. Ultimately the choice of procedural approach may rest upon factors such as provider preference, local infrastructure, and operator familiarity.

Guidelines

2012 HRS/EHRA/ECAS Guidelines on Catheter and Surgical Management of Atrial Fibrillation

• Ablation is recommended for symptomatic paroxsymal AF refractory or intolerant to at least one Class 1 or 3 antiarrhythmic medication (Class 1, LOE A)

Design

• Multicenter, randomized, noninferiority, parallel-group, open-label trial
• Patients randomized 1:1 to RFA or cryoablation
  • RFA (N=376)
  • Cryoablation (N=374)
• Setting: 16 centers in 8 countries
• Enrollment: 2012-2015
• Mean follow-up: 1.5 years
• Analysis: Modified intention-to-treat (randomized and received treatment)
• Primary Outcome: Clinical failure > 90 days after index ablation (recurrent AF, documented atrial flutter or tachycardia, initiation of anti-arrhythmic, repeat ablation)

Population

Inclusion Criteria

• Symptomatic pAF with at least two episodes and at least one episode documented (30 seconds episode length, documented by ECG within last 12 months)
• Documented treatment failure of at least one anti-arrhythmic drug (AAD Type I or III, including beta blocker and AAD intolerance)
• ≥ 18 and ≤ 75 years of age
• Patients who are mentally and linguistically able to understand the aim of the trial and to show sufficient compliance in following the trial protocol
• Patient is able to provide informed consent

Exclusion Criteria

• Life expectancy < 1 year
• Participation in another trial or previous participation in the current trial
• Pregnant women or women with childbearing potential not on reliable birth control
• Breastfeeding women
• Substance abuse
• Active infection
• Cryoglobulinemia
• Employment by the sponsor or by the department of any of the investigators
• Close relatives of any of the investigators
• Patients with prosthetic valves
• Any previous LA ablation or surgery
• Any cardiac surgery or PCI within 3 months prior to enrollment
• Symptomatic carotid stenosis
• Unstable angina or MI 3 months prior to enrollment
• COPD with detected pulmonary hypertension
• Any condition contraindicating anticoagulation
• Stroke/TIA 6 months prior to enrollment
• Significant uncorrected congenital heart defect
• NYHA class III or IV CHF
• LVEF < 35%
• Anteroposterior LA diameter > 55 mm
• LA thrombus
• Intracardiac thrombus
• PV diameter > 26mm in right sided PVs
• Mitral prosthesis
• Hypertrophic cardiomyopathy
• 2nd degree Type II AVB or 3rd degree AVB
• Brugada syndrome or long QT syndrome
• Arrhythmogenic right ventricular dysplasia
• Sarcoidosis
• PV stent
• Myxoma
• Thrombocytosis or thrombocytopenia
• Uncontrolled thyroid disease
• Severe renal dysfunction (GFR < 15ml/min)

Baseline Characteristics

From the RFA group.

• Demographics: age 60 years, male 63%, BMI 27.8
• AF: Time since pAF diagnosis 4.7yrs, LA diameter 40.6mm, CHADS2-Vasc Score 1.8, Hx DCCV 23.4%
• CHF: LVH 0.5%, No CHF 73.9%, NYHA I 10.7%, NYHA II 15.5%
• Comorbidities: CAD 8.5%, CKD 1.1%, HTN 58.8%, HLD 28.3%, T2DM 5.9%, Stroke 1.1%, TIA 2.7%, MI 2.4%, CABG 1.1%, PCI 4.3%
• Medications: AAD 59.8%, ACE inhibitor 23.7%, beta blocker 67.3%, anticoagulant 72.9%

Interventions

• Randomization 1:1 to RFA vs. cryoablation, stratified by center and age (≤ 65 vs. > 65)
• Cryoablation: PVI accomplished by placing the device at each PV antrum, advancing it toward the PV to achieve occlusion, then cooling the tissue by filling the balloon with a liquid refrigerant
• RFA: PVI accomplished by continuous circular burn around each PV antrum with point-by-point applications of radiofrequency energy using electroanatomical navigation
• After the index ablation procedure, in-office visits were scheduled at 3, 6, and 12 months, and every 6 months thereafter
• Review of arrhythmia symptoms done by telephone interview at 9 months and every 6 months thereafter
• Weekly transtelephonic ECG recording during the study and whenever arrhythmias felt
• An end-point review committee, the members of which were unaware of the treatment-group assignments, adjudicated primary safety and efficacy events

Outcomes

Comparisons are RFA vs. cryoablation

Primary Outcomes

Treatment Failure (Recurrent atrial arrhythmia, need for AAD, need for repeat ablation > 90 days after index procedure)

143 (35.9%) vs. 138 (34.6%); HR 0.96 [95% CI 0.76-1.22]; p < 0.001 (noninferiority)

Secondary Outcomes

Recurrent atrial arrhythmia

87 vs. 80

Antiarrhythmic drug treatment

49 vs. 51

Repeat ablation

7 vs. 7

Death

0 vs. 2; p = 0.25

Total procedure duration (min)

140.9 vs. 124.4; p < 0.001

Left atrial dwell time (min)

108.6 vs. 92.3; p < 0.001

Total fluoroscopy time (min)

16.6 vs. 21.7; p < 0.001

Rehospitalization for cardiovascular causes

55 (13.5%) vs. 44 (9.4%); HR 0.78 [95% CI 0.53-1.16]; p = 0.28

Subgroup Analyses

Prespecified subgroup analyses of the primary efficacy endpoint revealed no significant interactions. A prespecified comparison of the primary efficacy endpoint among the four separate types of catheters revealed no significant heterogeneity.

Adverse Events

Primary safety endpoint (death, stoke/TIA, serious adverse event)

51 (12.8%) vs. 40 (10.2%)

Atrial arrhythmia

13 (3.5%) vs. 8 (2.1%); p = 0.38

Non-arrhythmic adverse event

36 (9.6%) vs. 28 (7.5%); p = 0.36

Groin site complication

16 (4.3%) vs. 7 (1.9%); p = 0.09

Unresolved phrenic nerve injury (at discharge)

0 (0%) vs. 10 (2.7%); p = 0.001

Unresolved phrenic nerve injury (at 12 months)

0 (0%) vs. 1 (0.3%); p = 0.50

Criticisms

• Primary efficacy events were adjudicated after a 90-day post-ablation "treatment period" to allow for ablation to take effect. As a result, the effect of early treatment failures is underestimated. A differential effect of ablation approach on early treatment failure cannot be ruled out (and may be clinically relevant)
• Relatively short duration of follow-up (mean 1.5 years) cannot rule out a difference in long-term arrhythmia control between RFA and cryoablation
• Open-label nature of the intervention introduces potential bias. This is mitigated somewhat by blinded independent outcomes adjudication
• Study was not powered to rule out mortality difference to ensure safety
  • Of note, cryoablation had a non-significant trend towards a higher mortality

Funding

• Trial funded by Medtronic
• Trial oversight by FGK Representative Service as legal sponsor
• Legal sponsorship and trial oversight was transferred to Medtronic for completion of the trial after the initial contract research organization became insolvent