Sham-Controlled Trial, and More, Bolster Pulsed-Field Ablation for AF

NEW ORLEANS, LA—Two new studies, both presented recently at the American Heart Association 2025 Scientific Sessions, tackle the different sides of the risk-benefit equation when it comes to the use of pulsed-field ablation (PFA) for atrial fibrillation (AF).

In the small PFA-SHAM trial, reported by Vivek Reddy, MD (Icahn School of Medicine at Mount Sinai, New York, NY), use of the Farapulse system (Boston Scientific) reduced recurrent atrial arrhythmias, improved quality of life, and eased psychological distress compared with a sham procedure in patients with paroxysmal or persistent AF.

And in MANIFEST-US, reported by Mohit Turagam, MD (Icahn School of Medicine at Mount Sinai), real-world use of the Farapulse system following its approval in early 2024 was associated with low rates of both major (0.63%) and minor (2.1%) complications, with no cases of atrioesophageal fistula, pulmonary vein stenosis, or persistent phrenic nerve injury observed.

Daniel Morin, MD (University of California, San Francisco), who discussed the trials following the presentations, said “we now have rigorous sham-controlled and real-world evidence that PFA is both efficacious and safe.”  

Though multiple trials have established that catheter ablation is superior to antiarrhythmic drug therapy for treating AF, most studies have been unblinded and subject to placebo effects, Reddy said.

SHAM-PVI addressed that concern, showing that cryoballoon ablation reduced AF recurrence compared with a sham procedure. But it had limitations of its own, Reddy noted, pointing to the fact that quality of life was an unpowered secondary endpoint and to the high percentage of patients in the control arm who underwent cardioversion. In addition, he said, cryoballoon ablation has been replaced to a large extent by PFA in many practices.

Compared with thermal ablation modalities, PFA is believed to be more specific for myocardial tissue, limiting damage to surrounding structures like the esophagus, phrenic nerve, and coronary arteries. The perception of improved safety has driven rapid adoption of the technology.

The PFA-SHAM Trial

PFA-SHAM, an investigator-initiated trial conducted at two centers in Czechia, tested ablation against a sham control. The study included 60 patients with paroxysmal or persistent AF who were highly symptomatic, defined as an AF Effect on Quality of Life Questionnaire (AFEQT) score of 50 or less. All received an insertable cardiac monitor and underwent an electrophysiology study to exclude supraventricular tachycardia before randomization to PFA under deep sedation or a sham procedure (an extension of deep sedation). Five patients ultimately crossed over from the sham arm to undergo PFA.

Mean patient age was 62 in the PFA arm and 66 in the sham arm, with women making up 50% and 57%, respectively, of the two groups. About three-quarters of patients had paroxysmal AF and the rest had persistent AF. Mean CHA₂DS₂-VASc score was 2.4. Antiarrhythmic drugs were used in 80% and 60% of the PFA and sham patients, respectively, and all were on oral anticoagulation.

The first coprimary endpoint was freedom from atrial arrhythmias at 6 months, with a rate of 94% in the PFA arm and 17% in the sham arm. The posterior probability of superiority of PFA was greater than 99.99%.

The second coprimary endpoint was the change in AFEQT score from baseline to 6 months, and here, too, the posterior probability of superiority of PFA was greater than 99.99%. Scores improved by about 40 points with PFA and 10 points with sham control, with consistent findings across domains covering symptoms, daily activities, and treatment concerns.

PFA also was associated with a lower residual AF burden, a greater reduction in AF burden, and a greater improvement in the Hospital Anxiety and Depression Scale (HADS) score compared with sham control.

The trial was limited by the relatively small patient cohort and the short duration of follow-up, but both were partially related to ethical concerns with withholding treatment from highly symptomatic patients assigned to the sham control arm, Reddy said.

Morin said the trial also was limited by inclusion of a patient population with a relatively low burden of AF overall. Still, it had strengths, too.

“It provides strong evidence of efficacy of the active treatment and evidence against it just being a placebo effect,” said Morin. “And it treats both the doctor and the patient. It treats us by reducing the detected amount of atrial fibrillation that we see with, importantly, a loop recorder in all of these patients. And also it treats the patient because there was subjective improvement in the AFEQT score and the HADS score as well.”

MANIFEST-US

MANIFEST-US, published simultaneously online in JACC, was a retrospective postapproval study of all consecutive patients with paroxysmal or persistent AF treated with the Farapulse PFA system at participating centers between February 2024 and June 2025. Of 435 US centers invited to participate, 102 (23.4%) provided data from electronic health records. These included 31 academic centers with 224 operators, 50 private centers with 208 operators, and 21 hybrid centers with 78 operators.

Overall, there were 41,968 patients (mean age 68.3 years; 43.9% women) treated, with most (73.5%) undergoing a first-time ablation. Most patients had paroxysmal AF (54.2%) and 36.8% had persistent AF. General anesthesia was used in 97.2% of cases.

Rates of major and minor adverse events were low, Turagam reported. Major events included vascular complications requiring intervention in 0.18%, pericardial tamponade in 0.16%, stroke within 7 days in 0.1%, coronary artery spasm in 0.1%, MI within 30 days in 0.05%, death within 30 days in 0.04% (including eight cases of unexplained sudden death/arrest), and acute renal failure requiring dialysis in 0.02%.

Minor events included hematoma (0.69%), pericarditis (0.52%), pericardial effusion without intervention (0.12%), TIA within 7 days (0.08%), esophageal/gastric dysmotility (0.04%), air embolism (0.04%), and transient phrenic nerve injury (0.01%).

In a root-cause analysis of the 40 cases of coronary vasospasm, 75% were proximity-related, most commonly stemming from cavotricuspid isthmus ablation. One out of every six of these cases had clinical sequelae, including one death in a patient who had a stroke related to air embolism during a concomitant PFA and left atrial appendage occlusion procedure.

One-quarter of coronary vasospasms were generalized spasms, with 80% occurring during the procedure and 20% after the ablation. Most cases (70%) had clinical sequelae, including three patients with cardiogenic shock, two with atrioventricular block, and one each with sinus arrest and ventricular fibrillation arrest.

The overall mortality rate was “quite low,” Turagam said, adding, however, that there was a “potential signal” for rare early cardiac arrest or sudden death (0.019% overall), which occurred 2 to 18 days after ablation. Most patients who died from cardiac arrest or sudden death with an unclear cause (62.5%) had a history of coronary artery disease.

Turagam acknowledged that the study was limited by the retrospective design, the potential for selection bias and limited representativeness, and the risk of underreporting of adverse events.

This “massive” registry shows that PFA “has a superb safety profile, even in the real-world setting,” Morin said.

He cautioned, however, that only 23% of invited centers participated, noting that those who responded could be the “super experts.” In the rest of the country, Morin added, “[Pulmonary vein isolation] may not have the same result and may have worse outcomes than what we saw in this registry.”