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Niraj Sharma: Welcome back to EP Edge Journal Watch. I'm Doctor. Sharma and thank you for joining me for Issue 22, May 2026. As always I appreciate the suggestions, the feedback and the conversations that come from each issue. They help shape the way we interpret the literature not just as abstract trial data, but as information that has to eventually land in real clinical practice.
This issue focuses on a more mature phase of the pulsed field ablation era. In the early phase the central question was simple: Could PFA isolate pulmonary veins quickly, efficiently, and with less collateral injury than thermal ablation? But in 2026, the questions are more nuanced. Is the lesion durable? Is the workflow safe?
Are there specific safety domains where PFA performs differently from radiofrequency ablation? And most importantly, are we still measuring success in AF ablation using endpoints that are too crude for the modern era? We begin with a provocative EHR A twenty twenty six safety signal comparing radiofrequency ablation and pulsed field ablation for neurologic events. Then we move to navigate phase two, a systematic remapping study of a second generation mapping integrated pentaspline catheter. From there we look at longer term real world recurrence patterns, concomitant plus left atrial appendage occlusion, and the Praetorian DFT trial, which challenges routine defibrillation testing after S ICD implantation.
We also cover a CT based score to predict difficult leadless pacemaker implantation, a fascinating phase two trial of memantine for premature atrial contractions, and finally a review article asking whether the traditional thirty second AF recurrence endpoint still makes sense. The theme running through this issue is accountability. PFA is no longer just about speed. Ablation success is no longer just about a binary recurrence endpoint, and procedural simplification is no longer acceptable unless it is backed by careful patient selection, imaging, anatomy, workflow, and outcomes. Let's start with the comparative safety signal from EHR twenty twenty six.
The first study is the EHRA twenty twenty six presentation by Enrico Giuseppe Ferro, comparative safety of radiofrequency versus pulse field ablation for atrial fibrillation in a high volume U. S. Medical center. The clinical context is important. PFA has entered practice rapidly because it appears fast, efficient, and potentially safer than thermal ablation for certain collateral injury endpoints, particularly esophageal injury and phrenic nerve injury, but neurologic safety is a different question.
Stroke and TIA after AF ablation are uncommon. That means even small absolute differences can matter, especially when procedure volumes are high. The rationale for this study was that early PFA datasets were not really designed to detect small differences in rare neurologic outcomes. Also real world PFA is not simply a swap of one energy source for another. PFA may change workflow.
It may encourage broader lesion sets, posterior wall isolation, more extensive ablation and concomitant procedures. So the key question was not only is PFA energy safe, the more precise question was is the contemporary PFA strategy associated with a different neurologic risk profile compared with radiofrequency ablation? This was an observational analysis from a high volume US center. The investigators analyzed 4,221 consecutive AF ablations from January 2022 to January 2026. There were two thousand one hundred and forty four PFA cases and two thousand and seventy seven radiofrequency cases.
Neurologic follow-up was assessed at thirty days using the electronic health record. Stroke and TIA events were adjudicated by two independent neurologists who were blinded to procedural data. Propensity weighting was used to balance patient characteristics and mediation analyses were performed to explore whether workflow differences might explain the signal. The key result was this: stroke or TIA occurred in ten of two thousand one hundred and forty four PFA cases or zero point four seven percent compared with two of two thousand and seventy seven radiofrequency cases or zero point one zero percent. The unadjusted absolute risk difference was 0.37%, with a 95% confidence interval from 0.05 to 0.69% and a p value of 0.02.
After adjustment, the absolute risk difference was 0.36%, with a 95 confidence interval from 0.03 to 0.7%, and a p value of 0.03. Let's translate that statistic. An adjusted absolute risk difference of 0.36% means approximately 3.6 additional stroke or TIA events per 1,000 ablations in the PFA group compared with the radiofrequency group in this dataset. The relative difference looks large because the baseline event rate is very low but clinically what matters is both the relative signal and the absolute number of additional events. The investigators also found that these neurologic events were distributed across the study period which argues against a simple learning curve explanation.
The signal was not clearly explained by patient level differences, operator level differences, double transseptal puncture, concomitant LAAO, or PVI plus ablation, although the total number of events was small. So how should we interpret the pharoEHRA twenty twenty six safety signal? First, this is not a reason to abandon pulsed field ablation. The absolute neurologic event rate remained low and this was a conference presentation, not yet a peer reviewed manuscript. It was also a single center observational study with a low number of total stroke and TIA events, but it does challenge the casual language that PFA is simply safer.
That statement is too broad. Safety in AF ablation is not one endpoint. Esophageal injury, phrenic nerve injury, vascular complications, hemolysis, coronary spasm and neurologic events are different safety domains. A technology may look better in one domain and still require careful monitoring in another. The most precise interpretation is this: in this single center cohort, a contemporary PFA strategy was associated with a higher observed thirty day stroke TIA risk compared with a radiofrequency strategy.
That does not prove that PFA energy itself caused the neurologic events. It may reflect workflow lesion set, anticoagulation practice, catheter manipulation, air management, patient selection, era effects, or some combination of factors that we do not yet fully understand. The EP Edge take is that PFA safety should be discussed by endpoint and by workflow, not as a single global claim. In practice, this means we should continue using PFA thoughtfully, but also demand prospective neurologic event tracking by platform, lesion set, anticoagulation workflow, operator practice, and procedural details. The PFA era does not eliminate the need for rigorous safety surveillance.
If anything, because adoption is so rapid, it increases the need for disciplined post market observation. Now let's move from safety to durability. The next study is Navigate Phase II which asks a different but equally important question. Once PFA acutely isolates the veins, do those lesions actually persist when the patient comes back for systematic remapping? Navigate Phase II was published in Circulation, Arrhythmia and Electrophysiology by Reddy et al.
The clinical context is familiar to every electrophysiologist. Acute pulmonary vein isolation is important, but acute isolation is not the same as durable isolation. EP history is full of technologies that produced excellent acute block but variable chronic lesion durability. The central question in Navigate was whether a second generation navigation enabled pentaspline catheter with integrated mapping could produce durable pulmonary vein and posterior wall lesions. This matters because much of what we know about lesion durability comes from redo ablation cohorts, but redo cohorts are biased.
Patients only come back for invasive mapping if they have recurrence, so redo data are enriched for failures. A systematic remapping study is different. Patients return for invasive reassessment regardless of whether they have clinical recurrence. That gives a cleaner look at lesion durability. This was a first in human phase two study.
Twenty patients were enrolled at a single center. Three operators performed the procedures. Forty percent had paroxysmal AF and sixty percent had persistent AF. The mean age was 62 years. All patients underwent PVY with the second generation pentaspline PFA catheter.
Posterior wall ablation was performed in fifteen patients. Remapping was planned at sixty days plus or minus fourteen days. Eighteen patients returned for remapping and seventeen had full chamber high quality remaps. The results were strong for an early mechanistic study. Acute PVI was achieved in all patients.
Posterior wall targets when performed were acutely isolated without gaps. At sixty day remapping, pulmonary vein durability was 95.5%. In practical terms, sixty three of 66 targeted pulmonary veins remained isolated. Durable posterior wall ablation was seen in eighty five point seven percent, meaning twelve of fourteen evaluable patients. Only three pulmonary vein gaps were observed, one in the right superior pulmonary vein and two in the right inferior pulmonary vein.
Only one patient had reported arrhythmia recurrence at sixty days, and that patient had right inferior pulmonary vein reconnection. Safety was also reassuring in this small cohort. Serious adverse device events included one femoral arteriovenous fistula and one transient AV block. There were no reported cases of hemolysis, coronary spasm, stroke, TIA, or transient phrenic nerve injury. The statistics in Navigate need to be interpreted carefully.
A ninety five point five percent pulmonary vein durability rate sounds excellent, but this was a small feasibility study. It means that 63 of 66 targeted veins remained isolated among the patients with high quality remapping. It does not mean that ninety five point five percent of all future patients will have durable PVI in broad clinical practice. The limitations are straightforward, only twenty patients were enrolled, the study was single center, only seventeen patients were included in the lesion durability analysis and remapping occurred at about sixty days, not at six or twelve months. Also the study was funded by Boston Scientific and several authors were company employees.
The EP Edge take is that Navigate Phase II is not yet a practice changing outcomes trial but it is an important engineering signal. PFA is moving from fast ablation toward visualized, tagged, anatomically accountable lesion creation. That is the right direction. In the next phase of PFA we should not only ask whether energy delivery is quick, we should ask whether the system allows us to know where lesions were delivered, whether the anatomy was covered, and whether the lesions remained durable after healing. That brings us naturally to the EBRL study in Europace, examined incidents and predictors of AF recurrence during long term follow-up after PFA.
This study asks a complementary question. Navigate gives us early systematic remapping under controlled conditions. Eberl and colleagues give us longer term real world outcomes after pentaspline PFA. This was a retrospective single center cohort of three thirty nine patients undergoing first PV isolation with a pentaspline PFA catheter. Sixty three percent had paroxysmal AF and thirty seven percent had persistent AF.
Median follow-up was seven fifty two days. Recurrence was defined conventionally as sustained atrial arrhythmia lasting more than thirty seconds after a ninety day blanking period. Redo procedure findings were analyzed in fifty five patients. Overall recurrence occurred in one hundred and sixteen of three thirty nine patients or thirty four percent. Single procedure success was seventy one percent for paroxysmal AF and fifty eight percent for persistent AF.
Multiple procedure estimated success was eighty six percent. Independent predictors of recurrence included electrical cardioversion at the end of the procedure with a hazard ratio of 1.97 and AF at the beginning of the procedure with a hazard ratio of 1.73. Let's translate the Eberl hazard ratios. A hazard ratio of 1.97 for cardioversion at the end of the procedure means that in this study, patients requiring cardioversion at the end had nearly double the risk of recurrence over follow-up compared with those who did not, after adjustment. A hazard ratio of 1.73 for AF at the beginning of the procedure means that presenting in AF was also associated with a higher recurrence risk.
In redo procedures, one hundred and four of two twenty one veins or forty seven percent were reconnected. Only nine percent of redo patients had no reconnected pulmonary veins, but this number should not be generalized to all ablated patients. Redo patients are a selected failure cohort. A forty seven percent vein reconnection rate among redo patients does not mean that forty seven percent of all treated veins reconnect in the overall PFA population. The EP Edge take is that PFA durability is real but not automatic.
The next phase of PFA optimization will focus on durable anterior pulmonary vein lesion formation, patient selection and separating recurrence due to pulmonary vein reconnection from recurrence due to progressive atrial substrate. In practice this means we should not assume that a fast PFA procedure equals durable disease control. We still need follow-up, rhythm monitoring, and a substrate aware interpretation of recurrence. The fourth study moves into the increasingly relevant one stop procedure: concomitant pulmonary vein isolation and left atrial appendage occlusion. Atasi et al.
Compared PFA plus left atrial appendage occlusion, radiofrequency ablation plus left atrial appendage occlusion and left atrial appendage occlusion alone, the clinical appeal is obvious. For patients who need rhythm control and also have a reason to avoid long term anticoagulation, combining AF ablation and appendage occlusion may reduce cumulative anesthesia exposure, vascular access, and procedural burden. But there is an important mechanistic issue. When ablation and left atrial appendage occlusion are performed together, edema near the left atrial ridge and appendage ostium may affect device sizing, compression, and delayed peri device leak. This may be particularly relevant with thermal ablation.
The hypothesis is that PFA, by avoiding thermal injury, may create less edema and therefore less delayed leak. This was a single center retrospective cohort of one hundred and seventy five patients undergoing LAAO with or without concomitant PVI. There were sixty one patients in the radiofrequency plus left atrial appendage occlusion group, thirty nine in the PFA plus left atrial appendage occlusion group, and seventy five in the left atrial appendage occlusion only group. The primary endpoint was peri device leak at forty five day TEE. In the PFA plus left atrial appendage occlusion group, no large peri device leak greater than five millimeters was observed.
Small peridevice leak at follow-up occurred in twenty three point three percent of the radiofrequency plus left atrial appendage occlusion arm group, five point one percent of the PFA plus left atrial appendage occlusion arm group, and nine point three percent of the left atrial appendage occlusion arm only group. The p value was 0.015. Procedure duration also favored PFA. The mean procedure time was sixty seven point one minutes for PFA plus left atrial appendage occlusion arm compared with ninety nine point six minutes for radiofrequency plus LAAO, with a p value less than 0.001. Device related thrombus and major complications were rare.
Esophageal ulceration occurred only in the radiofrequency plus LAAO group. Statistically the lower rate of small peri device leak is interesting, but this was not a randomized study. A p value of 0.015 supports an association. It does not prove causality. The major limitation is device generation imbalance.
Watchman FLX PRO was used far more often in the PFA group, so the lower leak rate may reflect PFA, better device design, improved sizing, later era workflow, or all of these together. The EP Edge take is that PFA plus left atrial appendage occlusion arm is an attractive one stop strategy, but the evidence is not yet definitive. In practice this supports the operational feasibility of combined procedures, but we still need device balanced multicenter data with longer follow-up for peri device leak, device related thrombus, stroke, bleeding and anticoagulation discontinuation. Now let's shift from AF ablation to device therapy. The fifth study is Praetorian DFT published in Circulation evaluating subcutaneous or S ICD implantation with or without defibrillation testing.
Defibrillation testing was historically used to confirm ICD shock efficacy. For transvenous ICDs, routine testing has largely been abandoned after randomized data showed no compromise in shock efficacy or mortality, but SICDs remained a special case because they are entirely extravascular. Their shock efficacy depends heavily on generator and lead position. The Praetorian score was developed to evaluate S ICD implant position on chest x-ray and predict defibrillation success. The rationale of Praetorian DFT was to test whether Praetorian score guided omission of defibrillation testing after de novo S ICD implantation is non inferior to routine defibrillation testing.
Praetorian DFT was a randomized international multicenter trial. Nine sixty five patients were included in the modified intention to treat analysis, four eighty three were assigned to no defibrillation testing and four eighty two were assigned to routine defibrillation testing. Median follow-up was forty one months. The primary endpoint was failed first shock for spontaneous ventricular arrhythmia. The primary endpoint occurred in one point seven percent of the no testing group and two point three percent of the testing group.
The absolute difference was -0.6 percent, with a 95% confidence interval from -2.6 percent to 1.4%. The p value was less than 0.001 for non inferiority. Here is the key statistical concept. This was not a superiority trial. The question was not whether skipping defibrillation testing was better.
The question was whether skipping testing was not unacceptably worse. The prespecified non inferiority margin was 3%. Because the upper bound of the 95% confidence interval was 1.4%, which is below three percent, the no testing strategy met the criterion for non inferiority. There was no significant difference in all cause mortality or arrhythmic death. Potential defibrillation testing related complications occurred in one point seven percent of the testing group.
Postoperative ICD revisions due to inadequate positioning were identical between groups with two in each group. The EP Edge take is that the future of S ICD implantation is optimized positioning, imaging based assessment and selective testing. This trial does not say that defibrillation testing should never be done. It says that routine VF induction should no longer be treated as mandatory when the implant geometry is favorable and praetorian score guidance is used. The sixth study is from Issue and colleagues in the Journal of Cardiovascular Electrophysiology, a CT based risk score for difficult leadless pacemaker implantation.
Leadless pacing avoids pocket complications and transvenous lead complications, but implantation is not always simple. The delivery catheter has to traverse the femoral vein, inferior vena cava, right atrium, tricuspid valve, and right ventricular septum. Geometry matters. Procedural difficulty can mean longer delivery time, multiple deployments, more fluoroscopy and potentially more complications. The Issue Study asked whether pre procedural CT could predict difficult micro implantation.
This was a single center retrospective study of 122 micro implantations. One hundred and eleven patients with pre procedural CT were included. The median age was 83 years and forty three percent were female. Procedural difficulty was defined as micro delivery system in and out time of at least thirty minutes or three or more deployment attempts. Procedural difficulty occurred in thirty seven of one hundred and eleven patients or thirty three percent.
The independent predictors were right atrial enlargement greater than 45 millimeters, an RV septal angle greater than 55 degrees or less than 45 degrees, an IVC to tricuspid valve angle less than 128 degrees, and a short IVC to tricuspid valve distance, approximately less than 34 to 35 millimeters. Each factor was assigned one point. The score performed well in the derivation cohort with an AUC of 0.87 and moderately in validation with an AUC of 0.69. A UC means area under the receiver operating characteristic curve. It measures how well a score separates patients with difficult implantation from those without difficult implantation.
An AUC of 0.87 is strong, and AUC of 0.69 is more modest. So this score is promising but it needs broader validation. The practical signal is useful. Difficulty increased with higher score, 0% with score 6% with score one, thirty five percent with score 75% with score 100% with score four in the derivation cohort. The EP Edge take is that difficult leadless implantation is not purely operator dependent.
Some of it is predictable from anatomy. High score candidates should prompt a different workflow. Senior operator involvement, longer scheduled lab time, careful access planning, and readiness for alternative catheter strategies. Now we come to one of the most interesting pharmacologic studies of the year, memantine for premature atrial contractions, a phase two randomized clinical trial published in Circulation. PACs have historically been treated as benign but that framing is increasingly incomplete.
Frequent PACs are associated with atrial fibrillation, stroke, heart failure, and mortality. They may be markers of atrial disease, but they may also actively contribute to atrial arrhythmias. There is no approved pharmacologic therapy specifically for PAC suppression. Memantine is interesting because it is not a conventional antiarrhythmic drug. It is a non competitive NMDA receptor antagonist used in Alzheimer disease.
NMDA stands for N methyl D aspartate. NMDA receptors are glutamate receptors best known in the nervous system where they regulate excitability, learning, memory and excitotoxicity. The novel idea in this trial is that atrial cardiomyocytes may also have a functional glutamatergic signaling system. Blocking NMDA receptor signaling may reduce atrial excitability without acting like a traditional sodium channel or potassium channel antiarrhythmic. In EP terms this is a possible non traditional atrial excitability pathway.
The study was an investigator initiated multicenter, randomized, double blind, placebo controlled phase two trial conducted at 15 tertiary hospitals in China. Adults 18 to 80 years old with symptomatic premature atrial contractions of at least one thousand per twenty four hours were enrolled. The full analysis set included two forty one patients, one hundred and twenty four assigned to memantine and 117 assigned to placebo. Treatment lasted six weeks followed by a two week observation period. The primary endpoint was percentage change in mean twenty four hour premature atrial contraction count from baseline to week six.
The results favored memantine. The between group difference in premature atrial contractions reduction was 47.1 percentage points with a 95% confidence interval from 14.6 to 79.5 and a p value of 0.0045. At least fifty percent premature atrial contractions reduction occurred in fifty two point four percent of the memantine group versus twenty three point one percent of the placebo group. The relative risk was two point two seven with a p value less than 0.0001. Let's explain this carefully.
The forty seven point one percentage point difference is an absolute difference in percent premature atrial contraction reduction between the groups. It is not the same as saying there was a forty seven percent relative reduction. The responder relative risk of two point two seven means patients receiving memantine were more than twice as likely to achieve at least a fifty percent premature atrial contractions reduction by week six compared with placebo. There were also reductions in non sustained atrial tachycardia burden, with a between group difference of 30.98 percentage points and a p value of 0.0043. New onset AF by week six occurred in four point eight percent of patients receiving memantine compared with twenty three point nine percent receiving placebo, with a p value less than 0.0001.
Importantly, there were no clinically meaningful differences in heart rate, PR interval, QRS duration, QTCF, LV function, LA diameter, renal function, hepatic function or NT proBNP. There were no drug related serious adverse events. The memantine trial is provocative but it is not practice changing yet. It was a phase II proof of concept trial with short follow-up. The population was predominantly Han Chinese.
There was no active comparator arm. The AF signal is intriguing but AF detection over six weeks may partly reflect subclinical pre existing AF in a high risk intensively monitored population. The study was not powered to prove long term AF prevention, stroke reduction, heart failure benefit, or clinical outcome reduction. The EP Edge take is that memantine is not ready for routine PAC suppression, but the larger story is the mechanism. This trial introduces a serious new concept.
Upstream pharmacologic suppression of atrial ectopy through a non ion channel pathway. The next trial needs longer follow-up, broader populations, active comparison and continuous rhythm monitoring. For practice today, I would view this as a signal to watch closely, not a reason to prescribe memantine broadly for PACs. The final article in this issue is a review by Natale, Mohanty, Andrade and Mansour in JACC, Clinical Electrophysiology, focused on defining success in ablation trial design and comparative outcomes in the era of PFA. This is an important conceptual paper.
For decades AF ablation trials have often defined success as freedom from atrial arrhythmia recurrence lasting more than thirty seconds after a blanking period. That endpoint is familiar, easy to adjudicate and regulatory friendly but it is increasingly inadequate. A thirty one second asymptomatic episode is not clinically equivalent to recurrent persistent AF. Similarly, a patient with a ninety 5% reduction in AF burden may still be labeled a failure by a binary recurrence endpoint. The review argues that trial design strongly affects reported AF ablation success, particularly in the era.
The key themes are straightforward. The thirty second recurrence endpoint is too blunt as a sole measure of success. Monitoring intensity strongly affects recurrence detection. Continuous monitoring detects more arrhythmia than intermittent monitoring. AF burden may better reflect symptoms, quality of life, healthcare utilization and clinical relevance.
And trials differ in how they count antiarrhythmic drug use, cardioversion, repeat ablation and blanking period events. The statistics here are not about one hazard ratio or one p value, they are about what we choose to measure. A binary recurrence endpoint asks, did any qualifying episode occur? Atrial fibrillation burden asks, how much arrhythmia occurred over time? Those are different clinical questions.
Burden may be more aligned with patient symptoms, healthcare utilization and practical treatment benefit. The EP Edge take is that the thirty second endpoint should remain part of trial reporting, but it should not define success alone. Future ablation evidence should report recurrence, AF and atrial tachycardia burden, repeat interventions, antiarrhythmic drug use, symptoms, quality of life, healthcare utilization and safety by domain. This is especially important in the PFA era, where different devices, monitoring protocols, endpoint definitions, and workflows make cross trial comparisons difficult. So let's recap this issue briefly.
The Pharo presentation at EHRA twenty twenty six analysis raises a neurologic safety signal for contemporary PFA strategy, reminding us that PFA safety must be interpreted by endpoint and workflow. Navigate Phase II suggests that mapping integrated pentaspline PFA can produce high early pulmonary vein and posterior wall lesion durability, but the study remains small and early. The Eberl long term follow-up study shows that PFA outcomes are good, but recurrence still occurs, and redo procedures reveal meaningful pulmonary vein reconnection among failures. PFA plus left atrial appendage occlusion appears operationally attractive and may reduce procedure time and short term peri device leak, but device generation imbalance limits causal interpretation. Praetorian DFT supports omission of routine subcutaneous ICD defibrillation testing when implant position is favorable and Praetorian score guidance is used.
The leadless pacemaker CT score shows that implantation difficulty is partly predictable from anatomy and should influence procedural planning. Memantine opens a novel therapeutic concept for PAC suppression through NMDA receptor antagonism, but it remains proof of concept. And finally, the Natale review reminds us that a thirty second recurrence threshold alone is no longer enough to define ablation success. Thank you for listening to EP Edge Journal Watch. All references and graphics are available on the LinkedIn newsletter, EP Edge Journal Watch, as well as on Substack at epedge.substack.com.
I appreciate you being here and I hope this issue helps you interpret the evolving EP literature with more precision and clinical context. If you have any questions, concerns or suggestions please email epedgecast@gmail . com. Until the next episode take care and bye for now.