Comparing pulsed field electroporation and radiofrequency ablation for the treatment of paroxysmal atrial fibrillation: design and rationale of the BEAT PAROX-AF randomized clinical trial.

AIMS: Using thermal-based energy sources [radiofrequency (RF) energy/cryo energy] for catheter ablation is considered effective and safe when performing pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (AF). However, treatment success remains limited and complications can occur due to the propagation of thermal energy into non-target tissues. We aim to compare pulsed field ablation (PFA) with RF ablation in terms of efficacy and safety for patients with drug-resistant paroxysmal AF. METHODS AND RESULTS: The BEAT PAROX-AF trial is a European multicentre, superiority, open-label randomized clinical trial in two parallel groups. A total of 292 participants were recruited in 9 high-volume European clinical centres in 5 countries. Patients with paroxysmal AF were randomized to PFA (FARAPULSE Endocardial Ablation System©, Boston Scientific) or RF using the CLOSE protocol with contact force sensing catheter (SmartTouch© catheter and CARTO© Biosense Webster). The primary endpoint will be the 1-year recurrence of atrial arrhythmia, and the major secondary safety endpoint will be the occurrence of acute (<7 days) procedure-related serious adverse events, or pulmonary vein stenosis, or atrio-oesophageal fistula up to 12 months. Additionally, five sub-studies investigate the effect of PFA on oesophageal safety, cerebral lesions, cardiac autonomic nervous system, durability of PVI as assessed during redo ablation procedures, and atrial and ventricular function. The study began on 27 December 2021 and concluded recruitment on 17 January 2024. Results will be available in mid-2025. CONCLUSION: The BEAT PAROX-AF trial aims to provide critical insights into the optimal treatment approach for patients with paroxysmal AF.

Durability of Pulmonary Vein Isolation Using Pulsed-Field Ablation: Results From the Multicenter EU-PORIA Registry.

BACKGROUND: Pulsed-field ablation (PFA) is a novel nonthermal ablation technology with high procedural safety and efficiency for pulmonary vein isolation (PVI). Premarket data showed high PVI durability during mandatory remapping studies. Data on lesion durability in real-world patients with clinically indicated redo procedures are scarce. OBJECTIVES: This study sought to report PVI durability rates in patients undergoing a clinically indicated redo procedure after an index PVI using PFA. METHODS: Patients from 7 European centers undergoing an index PVI using PFA were included the EU-PORIA (European Real-world Outcomes With Pulsed Field Ablation in Patients With Symptomatic Atrial Fibrillation) registry. In patients with subsequent left atrial redo procedures due to arrhythmia recurrence, 3-dimensional electroanatomical maps were acquired. PVI durability was assessed on a per-vein and per-patient level, and sites of reconnections and predictors of lesion durability were identified. RESULTS: Of 1,184 patients (62% paroxysmal atrial fibrillation) undergoing an index PVI using PFA, 272 (23%) had an arrhythmia recurrence. Of these, 144 (53%) underwent a left atrial redo procedure a median of 7 (Q1-Q3: 5-10) months after the first ablation. Three-dimensional electroanatomical maps identified 404 of 567 pulmonary veins (71%) with durable isolation. In 54 patients (38%), all pulmonary veins were durably isolated. Prior operator experience with cryoballoon ablation was associated with a higher PVI durability compared to operators with only point-by-point radiofrequency experience (76% vs 60%; P < 0.001). Neither the operators' cumulative experience in atrial fibrillation ablation (≤5 vs >5 years) nor the size of the PFA device used (31 mm vs 35 mm) had an impact on subsequent lesion durability (both P > 0.50). CONCLUSIONS: In 144 patients with arrhythmia recurrence after PFA PVI, durable isolation was observed in 71% of the pulmonary veins during the redo procedure, and 38% of all patients showed durable isolation of all veins.

Pulmonary vein narrowing after pulsed field versus thermal ablation.

AIMS: When it occurs, pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is associated with significant morbidity. Even mild-to-moderate PV narrowing may have long-term implications. Unlike thermal ablation energies, such as radiofrequency (RF) or cryothermy, pulsed field ablation (PFA) is a non-thermal modality associated with less fibrotic proliferation. Herein, we compared the effects of PFA vs. thermal ablation on PV narrowing after AF ablation. METHODS AND RESULTS: ADVENT was a multi-centre, randomized, single-blind study comparing PFA (pentaspline catheter) with thermal ablation-force-sensing RF or cryoballoon (CB)-to treat drug-refractory paroxysmal AF. Pulmonary vein diameter and aggregate cross-sectional area were obtained by baseline and 3-month imaging. The pre-specified, formally tested, secondary safety endpoint compared a measure of PV narrowing between PFA vs. thermal groups, with superiority defined by posterior probability > 0.975. Among subjects randomized to PFA (n = 305) or thermal ablation (n = 302), 259 PFA and 255 thermal ablation (137 RF and 118 CB) subjects had complete baseline and 3-month PV imaging. No subject had significant (≥70%) PV stenosis. Change in aggregate PV cross-sectional area was less with PFA (-0.9%) than thermal ablation (-12%, posterior probability > 0.999)-primarily driven by the RF sub-cohort (-19.5%) vs. CB sub-cohort (-3.3%). Almost half of all PFA PV diameters did not decrease, but the majority (80%) of RF PVs decreased, regardless of PV anatomic location. CONCLUSION: In this first randomized comparison of PFA vs. thermal ablation, PFA resulted in less PV narrowing-thereby underscoring the qualitatively differential and favourable impact of PFA on PV tissue.

Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation.

BACKGROUND: Catheter-based pulmonary vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed field ablation, which delivers microsecond high-voltage electrical fields, may limit damage to tissues outside the myocardium. The efficacy and safety of pulsed field ablation as compared with conventional thermal ablation are not known. METHODS: In this randomized, single-blind, noninferiority trial, we assigned patients with drug-refractory paroxysmal atrial fibrillation in a 1:1 ratio to undergo pulsed field ablation or conventional radiofrequency or cryoballoon ablation. The primary efficacy end point was freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation. The primary safety end point included acute and chronic device- and procedure-related serious adverse events. RESULTS: A total of 305 patients were assigned to undergo pulsed field ablation, and 302 were assigned to undergo thermal ablation. At 1 year, the primary efficacy end point was met (i.e., no events occurred) in 204 patients (estimated probability, 73.3%) who underwent pulsed field ablation and 194 patients (estimated probability, 71.3%) who underwent thermal ablation (between-group difference, 2.0 percentage points; 95% Bayesian credible interval, -5.2 to 9.2; posterior probability of noninferiority, >0.999). Primary safety end-point events occurred in 6 patients (estimated incidence, 2.1%) who underwent pulsed field ablation and 4 patients (estimated incidence, 1.5%) who underwent thermal ablation (between-group difference, 0.6 percentage points; 95% Bayesian credible interval, -1.5 to 2.8; posterior probability of noninferiority, >0.999). CONCLUSIONS: Among patients with paroxysmal atrial fibrillation receiving a catheter-based therapy, pulsed field ablation was noninferior to conventional thermal ablation with respect to freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and with respect to device- and procedure-related serious adverse events at 1 year. (Funded by Farapulse-Boston Scientific; ADVENT ClinicalTrials.gov number, NCT04612244.).

EUropean real-world outcomes with Pulsed field ablatiOn in patients with symptomatic atRIAl fibrillation: lessons from the multi-centre EU-PORIA registry.

AIMS: Pulsed field ablation (PFA) is a new, non-thermal ablation modality for pulmonary vein (PV) isolation in patients with atrial fibrillation (AF). The multi-centre EUropean Real World Outcomes with Pulsed Field AblatiOn in Patients with Symptomatic AtRIAl Fibrillation (EU-PORIA) registry sought to determine the safety, efficacy, and learning curve characteristics for the pentaspline, multi-electrode PFA catheter. METHODS AND RESULTS: All-comer AF patients from seven high-volume centres were consecutively enrolled. Procedural and follow-up data were collected. Learning curve effects were analysed by operator ablation experience and primary ablation modality. In total, 1233 patients (61% male, mean age 66 ± 11years, 60% paroxysmal AF) were treated by 42 operators. In 169 patients (14%), additional lesions outside the PVs were performed, most commonly at the posterior wall (n = 127). Median procedure and fluoroscopy times were 58 (interquartile range: 40-87) and 14 (9-21) min, respectively, with no differences due to operator experience. Major complications occurred in 21/1233 procedures (1.7%) including pericardial tamponade (14; 1.1%) and transient ischaemic attack or stroke (n = 7; 0.6%), of which one was fatal. Prior cryoballoon users had less complication. At a median follow-up of 365 (323-386) days, the Kaplan-Meier estimate of arrhythmia-free survival was 74% (80% for paroxysmal and 66% for persistent AF). Freedom from arrhythmia was not influenced by operator experience. In 149 (12%) patients, a repeat procedure was performed due to AF recurrence and 418/584 (72%) PVs were durably isolated. CONCLUSION: The EU-PORIA registry demonstrates a high single-procedure success rate with an excellent safety profile and short procedure times in a real-world, all-comer AF patient population.

A randomized controlled trial of pulsed field ablation versus standard-of-care ablation for paroxysmal atrial fibrillation: The ADVENT trial rationale and design.

Background: Pulmonary vein isolation (PVI) is an effective treatment for paroxysmal atrial fibrillation (PAF). However, potential complications can occur due to the propagation of thermal energy into nontarget tissues adjacent to the targeted myocardium. Pulsed field ablation (PFA) is a novel ablation modality with the potential for preferential myocardial tissue ablation to minimize damage to collateral cardiac structures. A multielectrode pentaspline catheter has demonstrated safety and efficacy in treating PAF in single-arm, first-in-human studies. Objective: The study sought to perform a randomized clinical trial to directly compare this PFA catheter with conventional ablation-either radiofrequency or cryoballoon ablation. Methods: The ADVENT (Randomized Controlled Trial for Pulsed Field Ablation versus Standard of Care Ablation for Paroxysmal Atrial Fibrillation) trial is a multicenter, prospective, single-blind, randomized controlled trial to compare PVI using PFA vs conventional thermal ablation for drug-resistant PAF-with each site employing either (but not both) cryoballoon or radiofrequency ablation as a control condition. The sample size is adaptively determined based on Bayesian statistical methods. All patients will undergo PVI, and be followed for 12 months. Results: The primary effectiveness endpoint is a composite of acute procedural success and freedom from any documented atrial arrhythmia recurrence, repeat ablation, or use of antiarrhythmic drugs after a 3-month postablation blanking period. The primary safety endpoint is a composite of defined acute and chronic device- and procedure-related serious adverse events. Both primary endpoints will be evaluated for noninferiority of the novel PFA system compared with standard-of-care thermal ablation. Conclusions: By providing objective, comparative data, this study aims to scientifically determine whether the pentaspline PFA catheter is safe and effective for PVI ablation to treat drug-resistant PAF.

Electrophysiology, Pathology, and Imaging of Pulsed Field Ablation of Scarred and Healthy Ventricles in Swine.

BACKGROUND: Pulsed field ablation (PFA) has recently been shown to penetrate ischemic scar, but details on its efficacy, risk of arrhythmias, and imaging insights are lacking. In a porcine model of myocardial scar, we studied the ability of ventricular PFA to penetrate scarred tissue, induce ventricular arrhythmias, and assess the influence of QRS gating during pulse delivery. METHODS: Of a total of 6 swine, 5 underwent coronary occlusion and 1 underwent radiofrequency ablation to create infarct scar and iatrogenic scar models, respectively. Two additional swine served as healthy controls. An 8 Fr focal PFA catheter was used to deliver bipolar, biphasic PFA (2.0 kV) lesions guided by electroanatomical mapping, fluoroscopy, and intracardiac echocardiography over both scarred and healthy myocardium. Swine underwent magnetic resonance imaging 2-7 days post-PFA. RESULTS: PFA successfully penetrated scar without significant difference in lesion depth between lesion at the infarct border (5.9±1.0 mm, n=41) and healthy myocardium (5.7±1.3 mm, n=26; P=0.53). PFA penetration of both infarct and iatrogenic radiofrequency abalation scar was observed in all examined sections. Sustained ventricular arrhythmias requiring defibrillation occurred in 4 of 187 (2.1%) ungated applications, whereas no ventricular arrhythmias occurred during gated PFA applications (0 of 64 [0%]). Dark-blood late-gadolinium-enhanced sequences allowed for improved endocardial border detection as well as lesion boundaries compared with conventional bright-blood late-gadolinium-enhanced sequences. CONCLUSIONS: PFA penetrates infarct and iatrogenic scar successfully to create deep lesions. Gated delivery eliminates the occurrence of ventricular arrhythmias observed with ungated porcine PFA. Optimized magnetic resonance imaging sequences can be helpful in detecting lesion boundaries.

Effect of Epicardial Pulsed Field Ablation Directly on Coronary Arteries.

BACKGROUND: The unique tissue selectivity of pulsed field ablation (PFA) allows for minimizing collateral damage to the nerves/esophagus. However, the safety profile of epicardial PFA on coronary arteries (CAs) has not been well defined. OBJECTIVES: This study sought to evaluate the effect of epicardial PFA directly on CAs in a swine model. METHODS: In 4 swine, an 8-F linear quadripolar PFA catheter (FARAPULSE Inc) was introduced into the pericardial space via a subxiphoid puncture. After coronary angiography (Angio), QRS synchronized, biphasic, bipolar PFA was delivered directly on the left anterior descending artery, left circumflex artery, or normal myocardium (control) (2.0 kV × 4 applications per site). Angio was repeated immediately after ablation and repeated every 5 minutes to quantify the degree of CA narrowing. After 4- or 8-week survival, repeat Angio was performed followed by gross and histologic lesion analyses. RESULTS: A total of 15 lesions were delivered (8 left anterior descending arteries, 3 left circumflexes, and 4 controls). Target site Angio revealed median of 47% (IQR: 38%-69%) acute luminal narrowing immediately after PFA, which gradually resolved over 30 minutes. Epicardial PFA lesions extended into the myocardium with a median depth of 4.1 mm (IQR: 3.6-5.6 mm) passing across the CAs and adipose tissue. However, 87.5% of the CAs demonstrated minimal to mild CA stenosis associated with neointimal hyperplasia and tunica media fibrosis. CONCLUSIONS: In a swine model, epicardial PFA directly on CAs allowed the creation of myocardial lesions but led to a CA response characterized by acute moderate spasm and chronic mild stenosis via neointimal hyperplasia.

Method to quickly and accurately calculate absorbed dose from therapeutic and stray photon exposures throughout the entire body in individual patients.

PURPOSE: Photon radiotherapy techniques typically devote considerable attention to limiting the exposure of healthy tissues outside of the target volume. Numerous studies have shown, however, that commercial treatment planning systems (TPSs) significantly underestimate the absorbed dose outside of the treatment field. The purpose of this study was to test the feasibility of quickly and accurately calculating the total absorbed dose to the whole body from photon radiotherapy in individual patients. METHODS: We created an extended TPS by implementing a physics-based analytical model for the absorbed dose from stray photons during photon therapy into a research TPS. We configured and validated the extended TPS using measurements of 6- and 15-MV photon beams in water-box and anthropomorphic phantoms. We characterized the additional computation time required for therapeutic and stray dose calculations in a 44 × 30 × 180 cm3 water-box phantom. RESULTS: The extended TPS achieved superior dosimetric accuracy compared to the research TPS in both water and anthropomorphic phantoms, especially outside of the primary treatment field. In the anthropomorphic phantom, the extended TPS increased the generalized gamma index passing rate by a factor of 10 and decreased the median dosimetric discrepancy in the out-of-field region by a factor of 26. The extended TPS achieved an average discrepancy <1% in and near the treatment field and <1 mGy/Gy far from the treatment field in the anthropomorphic phantom. Characterization of computation time revealed that on average, the extended TPS only required 7% longer than the research TPS to calculate the total absorbed dose. CONCLUSIONS: The results of this work suggest that it is feasible to quickly and accurately calculate whole-body doses inside and outside of the therapeutic treatment field in individual patients on a routine basis using physics-based analytical dose models. This additional capability enables a more personalized approach to minimizing the risk of radiogenic late effects, such as second cancer and cardiac toxicity, as part of the treatment planning process.

A physics-based analytical model of absorbed dose from primary, leakage, and scattered photons from megavoltage radiotherapy with MLCs.

A burgeoning population of cancer survivors is at risk of late health effects following radiation therapy including second cancers, with the majority of these cancers occurring outside of the treatment volume of the primary cancer. Commercial radiotherapy treatment planning systems underestimate the out-of-field dose. Previous analytical models of out-of-field dose have assumed radial symmetry and/or approximated the dimensions of collimators as semi-infinite planes. The purpose of this work was to develop a physics-based analytical model of total absorbed dose from primary, scattered, and leakage radiation for square fields from a 6 MV beam at any arbitrary point in a phantom, including in-plane, cross-plane, and out-of-plane locations. The model includes the essential physics of radiation transport through beam-limiting-devices including rounded edges of MLC leaves. The model agreed well with measurements and Monte Carlo simulations of absorbed dose in a water-box phantom and was validated for field-sizes ranging from 2 [Formula: see text] 2 to 20 [Formula: see text] 20 cm2. The signed and unsigned average percent differences were [Formula: see text] and 15.9%, respectively, for all points and field-sizes considered. An extended gamma index analysis reveals a 92% pass rate with criteria of 3 mm distance-to-agreement, 3% relative dose difference in-field, and 3 mGy Gy-1 absolute dose difference out-of-field. The average wall-clock time to calculate dose to one million points was 3.3 min. These results suggest that it is feasible to calculate absorbed dose from both therapeutic and stray radiation using physics-based analytical models with good accuracy, thus overcoming a major obstacle to routinely assessing exposures. Additionally, this work demonstrates the importance of relaxing certain simplifications such as assuming a radially symmetric stray-dose distribution. Because the model is physics-based and may be reconfigured according to the dimensions of beam-limiting-devices, adapting it to other treatment units should be straight forward. Uses for such a model include clinical and research applications, such as clinical trials and epidemiological studies.

An objective method to evaluate radiation dose distributions varying by three orders of magnitude.

PURPOSE: Modern radiotherapy practices typically report the absorbed dose (D) within the 5% relative isodose volume (i.e., the therapeutic dose region) to an accuracy of 3%-5%. Gamma-index analysis, the most commonly used method to evaluate dosimetric accuracy, has low sensitivity to discrepancies that occur outside of this region. The objective of this study was to develop an evaluation method with high sensitivity across dose distributions spanning three orders of magnitude. METHODS: We generalized the gamma index to include an additional criterion, the absolute absorbed dose difference, specifically for the low-dose region (i.e., D ≤ 5%). We also proposed a method to objectively select the appropriate magnitudes for relative-dose-difference, absolute-dose-difference, and distance-to-agreement criteria. We demonstrated the generalized gamma-index method by first finding the appropriate generalized gamma-index agreement criteria at an interval of specified passing rates. Next, we used the generalized gamma index to evaluate one-, two-, and three-dimensional absorbed dose distributions in a water-box phantom and voxelized patient geometry. RESULTS: Generalized gamma-index passing rates for one-, two-, and three-dimensional dose distributions were 55.4%, 44.5%, and 8.9%, respectively. Traditional gamma-index passing rates were 100%, 97.8%, and 96.4%, respectively. These results reveal that the generalized method has adequate sensitivity in all regions (i.e., therapeutic and low dose). Additionally, the algorithmic determination of triplets of agreement criteria revealed that they are strong functions of the specified passing rate. CONCLUSIONS: The major finding of this work is that the proposed method provides an objective evaluation of the agreement of dose distributions spanning three orders of magnitude. In particular, this generalized method correctly characterized dosimetric agreement in the low-dose region, which was not possible by traditional methods. The proposed algorithmic selection of agreement criteria decreased subjectivity and requirements of user judgment and skill. This method could find utility in a variety of applications including dose-algorithm development and translation.

A descriptive and broadly applicable model of therapeutic and stray absorbed dose from 6 to 25 MV photon beams.

PURPOSE: To develop a simple model of therapeutic and stray absorbed dose for a variety of treatment machines and techniques without relying on proprietary machine-specific parameters. METHODS: Dosimetry measurements conducted in this study and from the literature were used to develop an analytical model of absorbed dose from a variety of treatment machines and techniques in the 6 to 25 MV interval. A modified one-dimensional gamma-index analysis was performed to evaluate dosimetric accuracy of the model on an independent dataset consisting of measured dose profiles from seven treatment units spanning four manufacturers. RESULTS: The average difference between the calculated and measured absorbed dose values was 9.9% for those datasets on which the model was trained. Additionally, these results indicate that the model can provide accurate calculations of both therapeutic and stray radiation dose from a wide variety of radiotherapy units and techniques. CONCLUSIONS: We have developed a simple analytical model of absorbed dose from external beam radiotherapy treatments in the 6 to 25 MV beam energy range. The model has been tested on measured data from multiple treatment machines and techniques, and is broadly applicable to contemporary external beam radiation therapy.

Maintenance of geometric alterations associated with percutaneous mitral valve repair: real-time three-dimensional echocardiographic assessment in an ovine model.

BACKGROUND AND AIM OF THE STUDY: Percutaneous catheter-based mitral annuloplasty (PTMA) exploits the anatomic proximity of the coronary sinus (CS) to the mitral valve apparatus. Acute results of PTMA have been favorable, but the durability of the geometric alterations associated with PTMA has not been reported. The study aim was to assess the three-dimensional (3D) geometry of the mitral annulus (MA) in normal sheep at 20 weeks after PTMA implantation. METHODS: A PTMA device was implanted percutaneously in the CS of 10 normal sheep without mitral regurgitation. All animals were followed for 20 weeks with real-time 3D echocardiography (RT3DE). The MA area, the diagonal diameters in four directions, and the angle alpha, representing the degree of the saddle shape of MA, were determined. RESULTS: No significant hemodynamic, pathologic or mechanical complications were observed during implantation or follow up. Both, the MA area (from 4.8 +/- 0.9 cm2 to 3.7 +/- 0.9 cm2) and anterior-posterior (A-P) diameter (from 21.4 +/- 3.0 mm to 17.6 +/- 2.4 mm) were reduced immediately after the procedure (both p <0.05). The angle alpha decreased after the procedure (from 142.0 +/- 11.5 degrees to 128.3 +/- 15.6 degrees; p <0.05). These changes remained stable over the 20-week follow up period. CONCLUSION: RT3DE demonstrates that PTMA reduces the MA area and A-P diameter and maintains the physiologic curved or saddle shape of the MA. These changes remained stable for 20 weeks after device implantation.