- ADVENT was the first randomized controlled trial comparing pulsed field ablation (PFA) to conventional strategies for ablation (including either radiofrequency or cryothermal ablation).
- The success rate was 73.3% and 71.3% in the PFA and thermal groups, respectively. PFA met the prespecified criteria for noninferiority.
- PFA is as effective and safe as conventional thermal ablation for the treatment of paroxysmal atrial fibrillation.
Ablation of atrial fibrillation (AF) is the most commonly performed procedure in the electrophysiology lab in contemporary clinical practice. Until recently, AF ablation has been performed with one of two energy sources, namely radiofrequency ablation (RFA) or cryoballoon ablation (CBA). Both technologies are based on thermal energy, which have proven to be effective in ablating myocardial tissue yet come with their respective set of potential safety concerns – especially as the thermal wavefront propagates beyond the intended target to nearby critical structures via conductive heating – such as the esophagus or the phrenic nerve. More recently, a novel non-thermal energy source has been introduced, called pulsed field ablation (PFA). PFA has been available for clinical use in Europe for the past 1.5 years, though is not yet FDA approved in the US. PFA is innovative in that it uses pulses of high energy (around 1800-2000 V) for a very short duration (microseconds) to damage myocardial tissue by electroporation – i.e. creating holes in the myocyte cell membranes and ultimately provoking controlled cell death. Pre-clinical studies have been reassuring in repeatedly demonstrating that PFA has a much lower thermal signature and, in turn, this allows selectivity in damaging myocytes while sparing nearby non-cardiac structures. Subsequent single-arm clinical studies, such as the PULSED AF pivotal trial, have demonstrated remarkably low safety events, with effectiveness rates that were comparable to the two established thermal ablation modalities.
During the 2023 European Society of Cardiology Conference in Amsterdam, Dr. Vivek Reddy presented the results of the ADVENT clinical trial. This is a pivotal trial conducted across 30 centers in the United States (65 operators) among patients with paroxysmal AF who failed at least one anti-arrhythmic drug (AAD) and were subsequently randomized to first-time ablation with either PFA or thermal ablation with either RF or cryoablation, where each center was pre-specified as either an RF-only or a cryo-only site). The primary composite endpoint included both acute procedural success (pulmonary vein isolation) and chronic success through 12 months, defined as freedom from repeat ablation, cardioversion or use of AAD. The primary safety endpoint was a composite of specifically defined serious adverse events related to either the use of an ablation catheter or the ablation procedure itself with onset within 7 days of the primary procedure – including stroke/TIA, cardiac tamponade or perforation, pericarditis, gastric motility or pyloric spasm disorders, and pulmonary vein stenosis. The statistical analysis plan was based on Bayesian design to test for non-inferiority, with pre-specified interim analyses every 150 patients.
Overall, 305 patients received PFA, and among the other 302 patients in the control arm, an even number of patients received RF and cryoablation. The trial met its primary non-inferiority efficacy endpoint, namely 73.3% in the PFA arm versus 71.3% in the thermal ablation arm (posterior probability >99%). As PFA met the non-inferiority endpoint, a pre-specified superiority analysis was performed but was not significant. The trial also met its primary non-inferiority safety endpoint, with a composite complication rate of 2.1% in the PFA arm versus 1.5% in the thermal ablation arm (posterior probability >99%).
As commented by Dr. Reddy during the presentation of the trial results, these safety results are particularly reassuring in light of the fact that virtually all study centers and operators had minimal experience with the PFA technology, while they had accrued extensive experience with either thermal ablation modality. A secondary pre-specified safety endpoint compared aggregate pulmonary vein dimension at baseline compared to 3 months post-ablation (assessed by CT scan) – to investigate the hypothesis that PFA may lead to reduced tissue proliferation, compared to thermal ablation modalities. In the PFA arm, patients had minimal change in pulmonary vein dimensions at 3 months (about 3%), compared to a 17% reduction in pulmonary vein diameter in the thermal ablation arm (which met both non-inferiority and superiority in favor of PFA). While this difference is not considered to be clinically significant (i.e. overt pulmonary vein stenosis), it certainly provides additional data to support the reduced potential for PFA to cause pulmonary vein remodeling and stenosis, compared to thermal ablation. Consistent with prior clinical studies, PFA procedures also had a significantly shorter procedural time.
Finally, Dr. Reddy predicted that the comparable efficacy and safety profile, combined with significantly shorter procedural time, will likely facilitate rapid uptake of this technology in contemporary EP clinical practice. This has already been observed in Europe over the past 1.5 years, even though the significantly higher cost of PFA ablation platforms has limited uptake. This higher upfront cost may ultimately turn out to be cost-effective, both because of shorter procedural time and higher likelihood of same-day discharges. Therefore, Dr. Reddy anticipates PFA will soon become an integral part of EP clinical practice.