Dual-energy lattice-tip ablation system for persistent atrial fibrillation: a randomized trial

Clinical outcomes of catheter ablation for atrial fibrillation (AF) are suboptimal due, in part, to challenges in achieving durable lesions. Although focal point-by-point ablation allows for the creation of any required lesion set, this strategy necessitates the generation of contiguous lesions without gaps. A large-tip catheter, capable of creating wide-footprint ablation lesions, may increase ablation effectiveness and efficiency. In a randomized, single-blind, non-inferiority trial, 420 patients with persistent AF underwent ablation using a large-tip catheter with dual pulsed field and radiofrequency energies versus ablation using a conventional radiofrequency ablation system. The primary composite effectiveness endpoint was evaluated through 1 year and included freedom from acute procedural failure and repeat ablation at any time, plus arrhythmia recurrence, drug initiation or escalation or cardioversion after a 3-month blanking period. The primary safety endpoint was freedom from a composite of serious procedure-related or device-related adverse events. The primary effectiveness endpoint was observed for 73.8% and 65.8% of patients in the investigational and control arms, respectively (P < 0.0001 for non-inferiority). Major procedural or device-related complications occurred in three patients in the investigational arm and in two patients in the control arm (P < 0.0001 for non-inferiority). In a secondary analysis, procedural times were shorter in the investigational arm as compared to the control arm (P < 0.0001). These results demonstrate non-inferior safety and effectiveness of the dual-energy catheter for the treatment of persistent AF. Future large-scale studies are needed to gather real-world evidence on the impact of the focal dual-energy lattice catheter on the broader population of patients with AF. ClinicalTrials.gov identifier: NCT05120193.

Baseline patient characteristics, including sex, are provided in the manuscript.Findings do not to one sex or gender, and sex and gender were not prespecified in the study design.Self-reporting (e.g.discussion between patient and treating physician) was used to determine patient sex.Informed consent was obtained from all patients prior to enrollment in the study.Sex-or gender-based analyses are not provided, as it was not the main purpose of the clinical study.

Reporting on race, ethnicity, or other socially relevant groupings
All baseline patient characteristics (age, sex, comorbidities, years of diagnosis of persistent AF) are provided in Table 1 of the manuscript.

Population characteristics
All baseline patient characteristics (age, sex, comorbidities, years of diagnosis of persistent AF) are provided in Table 1 of the manuscript.

Recruitment
Participants were recruited by participating institutions in the clinical study based on direct conversations between healthcare providers and patients.All participants were required to meet inclusion/exclusion criteria prior to undergoing their index procedure.Randomization between the investigational and control arms serves as a method of experimental control for human clinical trials to reduce selection bias introduced by the sampling methods.All subjects were blinded to their treatment assignment.

Ethics oversight
FDA, and all IRB's/ ethics committees assigned to local hospitals in United States, Israel and Czech Republic Note that full information on the approval of the study protocol must also be provided in the manuscript.

Field-specific reporting
Please select the one below that is the best fit for your research.If you are not sure, read the appropriate sections before making your selection.

Life sciences
Behavioural & social sciences Ecological, evolutionary & environmental sciences For a reference copy of the document with all sections, see nature.com/documents/nr-reporting-summary-flat.pdf

Life sciences study design
All studies must disclose on these points even when the disclosure is negative.

Sample size
All study measurements were taken from distinct samples, with each trial participant as an independent sample.To achieve power >80% for testing each primary endpoint using the Farrington-Manning method, a sample size of 350 evaluable subjects (175 per arm) was required for the primary analysis cohort (i.e.randomized and treated subjects), with assumed underlying rate of 8%, noninferiority margin of 8% and onesided alpha of 0.05 for the primary safety endpoint, and assumed underlying rate of 60%, noninferiority margin of 15% and one-sided alpha of 0.025 for the primary effectiveness endpoint.A total of 410 randomized subjects were planned based on a conservative 15% attrition estimate.
Data exclusions No data was excluded from the analysis.

Replication
All study data entered into the clinical study database was 100% source data verified by clinical study monitors.Study data was monitored against source documentation, and queried for accuracy of data collection.An independent statistician reproduced analyses of the primary and several secondary endpoints reported in the manuscript, and all other data points were verified by a peer reviewer.An independent core lab adjudicated all arrhythmia monitoring transmissions, and an independent clinical events committee adjudicated all reported adverse events.All study measurements were taken from distinct samples, with each trial participant as an independent sample.
Randomization Randomization was completed via an electronic data capture system, where randomization was blocked and stratified by site and by enrollment in a neurological sub-study.Randomized patients were blinded to their procedural assignment.Trial participants who met study eligibility criteria were randomized 1:1 to either the investigational arm or the control arm.

Blinding
Investigator blinding was not possible, as they were responsible for treatment of the patient with either the control or investigational device.
An autonomous board responsible for data and safety monitoring supervised the participants' safety and the execution of the trial, while an independent clinical events committee that was blinded to the randomization, evaluated all outcomes of clinical significance.An independent core lab that was blinded to randomization adjudicated all arrhythmia transmissions.Randomized subjects were blinded to their treatment assignment.
Reporting for specific materials, systems and methods Clinical trial registration NCT05120193

Study protocol
The full trial protocol is available in the Supplementary Material.

Data collection
Patients were treated between December 2021-December 2022, and followed for one year at their respective hospital institutions until December 2023.

Outcomes
The primary effectiveness endpoint was freedom from a composite of multiple failure modes, including: failure to acutely isolate all targeted PVs and complete all left atrial ablation with the assigned study device during the index procedure; repeat ablation at any time after the index procedure; and after a 3-month blanking period, documented occurrence of atrial tachyarrhythmia, escalation or initiation of Class I or III antiarrhythmic drugs, or cardioversion.Documented recurrence of atrial fibrillation, atrial tachycardia, or atrial flutter was based on either: (a) an episode ≥ thirty seconds in duration documented by ECG, TTM, or Holter monitor or (b) an episode covering an entire twelve-lead electrocardiogram recording lasting at least ten seconds.The study protocol included additional superiority testing contingent upon noninferiority of the primary endpoints.Energy application time, elapsed treatment time, total procedure time, and primary effectiveness were sequentially tested for superiority of the investigational device compared to the control device.
The primary safety endpoint was a composite of prespecified device-or procedure-related serious adverse events including death, atrio-esophageal fistula, stroke, myocardial infarction, cardiac tamponade/perforation, PV stenosis, phrenic nerve paralysis, transient ischemic attack, thromboembolism, major vascular access complications/bleeding, heart block, gastroparesis, severe pericarditis, or new or extended hospitalization for a cardiovascular or pulmonary adverse event.Adverse events were determined as serious if they (1) lead to death, (2) lead to serious deterioration in the health of the subject (including life-threatening illness or injury, permanent impairment of a body structure or function, >24-hour hospitalization, chronic disease, or medical or surgical intervention to prevent injury or permanent impairment of a body structure or function), (3) lead to fetal distress/ death, or a congenital abnormality or birth defect.Hospitalizations for pre-existing conditions or procedures without serious deterioration in health were not defined as serious.All primary adverse events were prespecified and their severity and association with the device or procedure were adjudicated by an independent clinical events committee.
Energy application time, elapsed treatment time, total procedure time, and primary effectiveness were sequentially tested for superiority of the investigational device compared to the control device as a prespecified secondary outcome.Pre-specified secondary effectiveness and performance endpoints included assessment of changes in quality of life, use of anti-arrhythmic drugs during the effectiveness evaluation period, procedure times, fluoroscopy time, and ablation lesion sets delivered.All other endpoints were based on post-hoc analyses.

Novel plant genotypes
Describe the methods by which all novel plant genotypes were produced.This includes those generated by transgenic approaches, gene editing, chemical/radiation-based mutagenesis and hybridization.For transgenic lines, describe the transformation method, the number of independent lines analyzed and the generation upon which experiments were performed.For gene-edited lines, describe the editor used, the endogenous sequence targeted for editing, the targeting guide RNA sequence (if applicable) and how the editor was applied.

Seed stocks
Report on the source of all seed stocks or other plant material used.If applicable, state the seed stock centre and catalogue number.If plant specimens were collected from the field, describe the collection location, date and sampling procedures.

Authentication
Describe any authentication procedures for each seed stock used or novel genotype generated.Describe any experiments used to assess the effect of a mutation and, where applicable, how potential secondary effects (e.g.second site T-DNA insertions, mosiacism, off-target gene editing) were examined.

Design specifications
An initial cohort of at least 60 randomized subjects (at least 30 from the investigational or the control arm) underwent the cerebral MRI after the ablation procedure.MRI was performed within 72 hours after their index ablation procedure.
Randomization was blocked and stratified by site and by enrollment in the neurological assessment sub-study.
Behavioral performance measures Behavioral performance during the MRI was not monitored.

Area of acquisition
A whole brain scan was used.

Diffusion MRI Used Not used
Parameters Two distinct b values, 0 and 1000s/mm2, in three diffusion directions.

Preprocessing Preprocessing software
Standard of care MRI pre-processing software was used in 12 different centers for 37 investigational patients, and 10 different centers for 35 control patients.

Normalization
Standard of care MRI pre-processing software was used in 12 different centers for 37 investigational patients, and 10 different centers for 35 control patients.

Normalization template
Standard of care MRI pre-processing software was used in 12 different centers for 37 investigational patients, and 10 different centers for 35 control patients.

Noise and artifact removal
Standard of care MRI pre-processing software was used in 12 different centers for 37 investigational patients, and 10 different centers for 35 control patients.

Volume censoring
Standard of care MRI pre-processing software was used in 12 different centers for 37 investigational patients, and 10 different centers for 35 control patients.

Statistical modeling & inference
Model type and settings All manuscripts should comply with the ICMJE guidelines for of clinical research and a completed CONSORT checklist must be included with all submissions.
We require information from authors about some types of materials, experimental systems and methods used in many studies.Here, indicate whether each material, system or method listed is relevant to your study.If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.
For each DWI sequence, an apparent diffusion coefficient (ADC) map was obtained.The slices and orientation of the DWI and FLAIR sequences were matched.
Statistical modeling was not performed for this analysis.