Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation (ADVENT)

Authors, Journal, Affiliations, Type, DOI

• Authors: Vivek Y. Reddy, Edward P. Gerstenfeld, Andrea Natale, William Whang, Frank A. Cuoco, Chinmay Patel, Stavros E. Mountantonakis, Douglas N. Gibson, John D. Harding, Christopher R. Ellis, Kenneth A. Ellenbogen, David B. DeLurgio, Jose Osorio, Anitha B. Achyutha, Christopher W. Schneider, Andrew S. Mugglin, Elizabeth M. Albrecht, Kenneth M. Stein, John W. Lehmann, Moussa Mansour, for the ADVENT Investigators
• Journal: New England Journal of Medicine, 2023; 389:1660–71
• Affiliations: Helmsley Electrophysiology Center, Icahn School of Medicine at Mount Sinai (lead); 30 US centers, 65 operators
• Type: Multicenter, randomized, single-blind, noninferiority pivotal trial; Bayesian adaptive Goldilocks design
• DOI: https://doi.org/10.1056/NEJMoa2307291
• Funding: Farapulse–Boston Scientific (manufacturer of PFA system); first author had final manuscript authority

Overview

The ADVENT trial was the first randomized controlled trial to compare pulsed field ablation (PFA) to conventional thermal ablation (radiofrequency or cryoballoon) for drug-refractory paroxysmal AF. Among 607 patients at 30 US centers, PFA met noninferiority for both primary efficacy (freedom from treatment failure: 73.3% vs 71.3%; posterior probability of NI >0.999) and primary safety (serious adverse events: 2.1% vs 1.5%; posterior probability of NI >0.999) at 1 year. On the key secondary safety endpoint, PFA produced significantly less pulmonary vein narrowing (0.9% vs 12.0% cross-sectional area reduction; posterior superiority >0.999), confirming its tissue-selectivity advantage. One procedure-related death occurred in the PFA arm from catheter manipulation (not energy delivery), and 3 asymptomatic MRI-detected cerebral lesions were identified in the PFA arm versus 0 in the thermal arm — a signal requiring monitoring.

Keywords

Pulsed field ablation, paroxysmal atrial fibrillation, pulmonary vein isolation, radiofrequency ablation, cryoballoon ablation, irreversible electroporation, noninferiority trial, catheter ablation, electroporation

Key Takeaways

Trial Design

• Multicenter, randomized, single-blind, noninferiority pivotal trial; 30 US centers, 65 operators; enrollment March 2021–June 2022
• 706 patients enrolled; 80 roll-in patients excluded; 607 in modified ITT population (305 PFA, 302 thermal — 167 RF, 135 cryo)
• Bayesian adaptive design (Goldilocks sampling): enrollment stopped at 550 patients per prespecified stopping criteria; 607 had already been enrolled at that point
• Noninferiority margins: safety 8 percentage points; efficacy 15 percentage points
• Trial success required: posterior probability of NI >0.966 (safety) and >0.956 (efficacy); both exceeded 0.999

Patients

• Adults ≤75 years with symptomatic PAF refractory to ≥1 antiarrhythmic drug (Class I, II, III, or IV)
• Randomized 1:1; stratified by site; patients blinded to assignment (82.6% PFA and 83.4% thermal unaware of assignment at discharge)
• Baseline characteristics balanced between groups

Interventions

• PFA arm: Multielectrode pentaspline PFA catheter (Farapulse); high-voltage microsecond electrical pulses delivered to each PV via deflectable sheath; no esophageal management strategies used
• Thermal arm: RF with saline-irrigated contact force–sensing catheter; or cryoballoon catheter advanced to each vein; esophageal temperature monitoring/cooling/deviation permitted
• Procedural endpoint (all arms): entrance conduction block of all treated PVs after 20-minute observation period

Follow-up

• 1 year; telephone calls at 7, 30, 60 days; office visits at 3, 6, 12 months
• Arrhythmia monitoring: 72-hour Holter at 6 and 12 months; trans-telephonic ECG weekly post-blanking and for symptoms
• Cardiac CT or MRI at 3 months for PV anatomy assessment
• Brain MRI substudy within 48h post-procedure (subgroup)
• Adherence to follow-up visits >99%; 92.8% with known 12-month outcomes

Primary Efficacy Endpoint

• Freedom from composite: initial procedural failure to achieve PVI with assigned method; documented atrial tachyarrhythmia ≥30s after 3-month blanking; AAD (Class I/III) or cardioversion post-blanking; amiodarone at any time; repeat ablation at any time
• PFA: 204/305 success, 80 failure, 21 censored → estimated probability 73.3%
• Thermal: 194/302 success, 85 failure, 23 censored → estimated probability 71.3%
• Between-group difference 2.0 pp (95% BCI −5.2 to 9.2); posterior probability of NI >0.999 — NONINFERIORITY MET

Primary Safety Endpoint

• Composite of device/procedure-related serious adverse events within 7 days (plus atrioesophageal fistula and PV stenosis regardless of timing)
• PFA: 6 patients; estimated incidence 2.1%
• Thermal: 4 patients; estimated incidence 1.5%
• Between-group difference 0.6 pp (95% BCI −1.5 to 2.8); posterior probability of NI >0.999 — NONINFERIORITY MET

Secondary Safety: Pulmonary Vein Cross-Sectional Area

• PFA: −0.18 cm² (−0.9%) change from baseline to 3 months
• Thermal: −1.18 cm² (−12.0%) — RF subgroup −1.86 cm² (−19.5%); cryo subgroup −0.39 cm² (−3.3%)
• Posterior probability of PFA superiority >0.999 — PFA SUPERIOR
• No patient in either group had clinical symptoms of pulmonary vein stenosis

Secondary Efficacy (Superiority Test)

• Posterior probability of PFA superiority over thermal = 0.708 — NOT superior

Procedural Characteristics

• PVI success at index procedure: 99.6% (PFA) vs 99.8% (thermal)
• PV reconnection during 20-min wait: 4.4% PFA (53/1208 veins) vs 5.5% thermal (65/1182 veins)
• Total procedure time: 105.8 ± 29.4 min (PFA) vs 123.1 ± 42.1 min (thermal) — PFA shorter by ~17 min
• Fluoroscopy time: 21.1 ± 11.0 min (PFA) vs 13.9 ± 12.8 min (thermal) — PFA requires more fluoroscopy
• CTI ablation for atrial flutter: 70 patients (23.0%) PFA vs 86 patients (28.5%) thermal
• Extra-PV ablation: 5 patients (1.6%) PFA vs 16 patients (5.3%) thermal

Safety Events of Note

• Death (1): PFA arm — pericardial tamponade → emergency sternotomy → multiorgan failure → death on day 10; attributed to catheter manipulation, not PFA energy delivery; incidence consistent with MANIFEST-PF (0.06%)
• Pericardial tamponade (2): Both PFA arm (one fatal, one non-fatal); 0 thermal
• Phrenic nerve paralysis (persistent, 2): Both in cryoballoon arm; 0 in PFA arm
• Asymptomatic cerebral lesions on MRI substudy: 3/33 (9.1%) PFA vs 0/37 (0%) thermal — signal without clinical stroke events
• Clinical stroke (1): Occurred in RF arm; 0 in PFA arm
• Atrioesophageal fistula: 0 in either arm
• PV stenosis symptoms: 0 in either arm

Durability of PVI at Repeat Ablation

• Repeat ablation performed: 14 patients (4.6%) PFA vs 20 patients (6.6%) thermal
• Durable PVI per vein at redo: 64.8% (PFA) vs 64.9% (thermal) — comparable durability
• Durable PVI per patient at redo: 28.6% (PFA) vs 26.3% (thermal)

Quality of Life

• Catheter ablation improved QOL in both groups
• No between-group difference in QOL improvement

Limitations of the Document

• No continuous monitoring: Implantable cardiac monitors not used; asymptomatic AF recurrences may have been missed; relies on 72-hour Holter and weekly event monitoring
• 1-year follow-up only: Long-term comparative outcomes are unknown; authors note recurrence appears low between years 2–5 in PAF populations
• Single PFA technology: Pentaspline catheter only; results not generalizable to other PFA platforms (other systems use different waveforms and delivery strategies)
• PAF only: Not applicable to nonparoxysmal AF
• Operator learning curve: Most operators had no prior PFA experience (except one center); expert thermal operators — PFA efficacy may improve with experience
• Industry-funded: Farapulse–Boston Scientific designed the trial, collected and monitored data; potential for bias despite independent DSMB and core lab oversight
• Bayesian adaptive design: Noninferiority margins (15 pp efficacy, 8 pp safety) were deliberately broad; real-world differences could exist within these intervals
• MRI cerebral lesion signal: 3/33 PFA vs 0/37 thermal — small substudy; underpowered to conclude on this safety signal; further prospective evaluation needed

Key Concepts Mentioned

• concepts/Pulsed-Field-Ablation — primary intervention; mechanism (irreversible electroporation), tissue-selectivity, outcomes
• concepts/Catheter-Ablation-AF — broader AF ablation context; energy source comparisons
• concepts/Atrial-Fibrillation — target arrhythmia (paroxysmal subtype)

Key Entities Mentioned

• entities/Farapulse — manufacturer of the pentaspline PFA catheter system (later acquired by Boston Scientific)

Wiki Pages Updated

• wiki/sources/pfa-advent-nejm-2023.md — created (this file)
• wiki/concepts/Pulsed-Field-Ablation.md — updated with ADVENT RCT data; source count updated
• wiki/concepts/Catheter-Ablation-AF.md — ADVENT source added to references
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — Pulsed-Field-Ablation concept row updated