ADVANTAGE AF Phase 2: Evaluating Pulsed Field Ablation for Persistent Atrial Fibrillation Using Continuous ECG Monitoring

Highlight

• First large multicenter study demonstrating safety and effectiveness of pulsed field ablation (PFA) for persistent atrial fibrillation (PerAF) with lesion sets beyond pulmonary vein isolation (PVI).
• Introduction of continuous rhythm monitoring with insertable cardiac monitors (ICMs) after PFA allows more precise evaluation of atrial arrhythmia burden and episode duration.
• Cavotricuspid isthmus (CTI) ablation with nitroglycerin prophylaxis using PFA is shown to be safe and effective in treating typical atrial flutter coexisting with PerAF.
• Atrial arrhythmia (AA) burden below 0.1% and episodes shorter than 1 hour correlated with significantly lower healthcare utilization, suggesting novel endpoints for procedural success.

Study Background and Disease Burden

Persistent atrial fibrillation (PerAF) represents a significant clinical challenge with a considerable burden of morbidity, stroke risk, and impaired quality of life. Catheter ablation remains a cornerstone treatment aimed primarily at pulmonary vein isolation (PVI). However, PerAF often requires ablating additional atrial structures such as the posterior wall, as the arrhythmogenic substrate extends beyond pulmonary veins. Traditional ablation energy sources, such as radiofrequency or cryoablation, carry risks including collateral damage to adjacent structures and protracted procedural times.

Pulsed field ablation (PFA) has emerged as an innovative nonthermal ablation modality that selectively targets myocardial cells through electroporation, potentially enhancing safety by sparing noncardiac tissues. Despite promising early data, there were scant high-quality safety and efficacy data on PFA in PerAF populations, particularly where ablation extends beyond PVI. Moreover, existing studies employed only intermittent electrocardiographic recording after ablation, which limits detection and quantification of recurrent arrhythmias.

The ADVANTAGE AF Phase 2 study addresses these gaps by assessing the clinical utility of PFA with continuous ECG monitoring via insertable cardiac monitors (ICMs), enabling comprehensive rhythm surveillance and precise quantification of arrhythmia recurrence patterns following PFA in PerAF.

Study Design

ADVANTAGE AF Phase 2 is a prospective, single-arm, open-label multicenter study involving 255 subjects with persistent atrial fibrillation. All patients underwent PFA treatment of pulmonary vein isolation plus posterior wall ablation using a pentaspline PFA catheter. A subcohort of 141 patients (55.3%) also received cavotricuspid isthmus (CTI) ablation using a novel focal-linear PFA catheter, targeting concomitant typical atrial flutter.

Before CTI ablation, intravenous nitroglycerin was administered prophylactically to mitigate potential coronary vasospasm risks. The procedural metrics including ablation time, pulsed field applications, and total procedural duration were recorded.

Post-procedurally, continuous ECG rhythm monitoring was conducted for one year via insertable cardiac monitors. This allowed emulation of traditional intermittent monitoring to evaluate freedom from atrial arrhythmias (AA) and provided detailed assessments of AA burden and episode duration for secondary exploratory analyses.

Key Findings

The cohort’s mean age was 66.7 years with 29% female representation, an average CHA2DS2-VASc score of 2.4, mean BMI of 30.9 kg/m2, and mean left atrial diameter of 4.3 cm.

Technical success was outstanding with 99.6% acute success in PVI and 100% for posterior wall ablation. In the CTI ablation subgroup, a 98.6% bidirectional block rate was achieved with no serious complications such as ST-segment changes or ventricular fibrillation. CTI ablation was efficient, requiring an average of 8 minutes and approximately 18 pulsed field pulses with concomitant intravenous nitroglycerin doses well tolerated.

The mean total procedure duration was approximately 105 minutes with an atrial dwell time of 59 minutes.

Using traditional monitoring simulation, freedom from atrial arrhythmias was 73.4% at 12 months with a low adverse event rate of 2.4% meeting endpoint criteria. Recurrent typical atrial flutter was rare with a freedom rate of 97.2%.

Continuous ICM data analysis refined arrhythmia assessment: freedom from atrial arrhythmias lasting longer than 30 seconds was only 52.0%, highlighting that standard intermittent monitoring might overestimate success.

Importantly, 94% of detected arrhythmia episodes were shorter than 24 hours, underscoring more benign episode profiles in this population. Both an AA burden exceeding 0.1% and longest episode duration exceeding one hour were independent predictors of increased healthcare utilization such as hospitalizations or outpatient visits.

Establishing newer success thresholds, the study reported one-year procedural effectiveness rates of 71.6% and 70.0% when using AA burden ≤0.1% and episode duration <1 hour, respectively, pointing to more nuanced definitions of clinical success.

Expert Commentary

ADVANTAGE AF Phase 2 stands as a pivotal study elucidating the role of PFA in complex substrates such as PerAF beyond PVI. The high acute success rates with a favorable safety profile are consistent with the targeted nonthermal cell specificity of pulsed field energy. The safe integration of CTI ablation with nitroglycerin prophylaxis expands the utility for concomitant arrhythmia substrates.

Continuous monitoring using ICMs is transformative for arrhythmia management research, providing rich datasets to better define subclinical recurrences and burden. This detection modality challenges traditional binary success/failure endpoints based solely on intermittent monitoring, advocating for burden and episode duration as meaningful clinical parameters.

Limitations include the single-arm design without a direct comparative control and an intermediate follow-up period. However, these findings are hypothesis-generating for future randomized controlled trials comparing PFA to conventional ablation energy sources and monitoring methodologies.

Conclusion

The ADVANTAGE AF Phase 2 trial significantly advances knowledge in catheter ablation therapy for persistent atrial fibrillation by demonstrating that pulsed field ablation with PVI plus posterior wall ablation and adjunctive cavotricuspid isthmus ablation is safe, effective, and efficient.

Continuous cardiac rhythm monitoring via insertable cardiac monitors refines outcome assessment, with atrial arrhythmia burden <0.1% and episode durations <1 hour emerging as relevant endpoints associated with reduced healthcare utilization.

These insights encourage adoption of PFA as a promising ablation strategy and promote the integration of continuous monitoring tools in clinical practice to optimize personalized arrhythmia management.

References

Reddy VY, Gerstenfeld EP, Schmidt B, Andrade JG, Nair D, Natale A, Saliba W, Sommer P, Metzner A, Verma A, Hounshell T, Amin A, Gentlesk P, Weiner S, Cuoco FA, Kim J, Turagam MK, Tomassoni G, Patel C, Issa Z, Shehata M, Anderson AM, Stoltz TJ, Raybuck JD, Schwartz T, Sutton BS, Mansour M; ADVANTAGE AF Investigators. Pulsed Field Ablation of Persistent Atrial Fibrillation With Continuous Electrocardiographic Monitoring Follow-Up: ADVANTAGE AF Phase 2. Circulation. 2025 Jul 8;152(1):27-40. doi: 10.1161/CIRCULATIONAHA.125.074485. Epub 2025 Apr 24. PMID: 40273320; PMCID: PMC12225731.