Key Points
Question
Does the addition of linear ablation combined with ethanol infusion via the vein of Marshall (EIVOM) to pulmonary vein isolation (PVI) improve rhythm outcomes for patients with persistent atrial fibrillation (AF)?
Findings
In this randomized clinical trial that included 498 patients with persistent AF undergoing first-time ablation, linear ablation combined with EIVOM significantly improves freedom from atrial arrhythmia recurrence without antiarrhythmic drugs (70.7% vs 61.5%; hazard ratio, 0.73).
Meaning
Linear ablation combined with EIVOM provides additional benefit in rhythm outcomes for the ablation of persistent AF.
Abstract
Importance
Success rates of pulmonary vein isolation (PVI) are modest for persistent atrial fibrillation (AF). Additional linear ablation beyond PVI has not been proved superior to PVI alone in randomized trials. Ethanol infusion of the vein of Marshall (EIVOM) facilitates ablation at the mitral isthmus and may lead to improved effectiveness of a linear ablation strategy.
Objective
To determine whether linear ablation with radiofrequency energy combined with EIVOM added to PVI improves sinus rhythm maintenance compared with PVI alone in patients with persistent AF.
Design, Setting, and Participants
The PROMPT-AF trial is an investigator-initiated, multicenter, open-label, randomized trial involving 12 tertiary hospitals in China. A total of 498 patients aged 18 to 80 years, with AF persisting for more than 3 months, undergoing first-time AF ablation, were enrolled and randomized from August 27, 2021, to July 16, 2023.
Interventions
Patients were randomized to undergo PVI alone or PVI plus EIVOM and linear ablation (intervention). The latter group first underwent EIVOM, followed by PVI and linear ablation of the left atrial roof, mitral isthmus, and cavotricuspid isthmus.
Main Outcomes and Measures
The primary end point was freedom from any documented atrial arrhythmias lasting more than 30 seconds, without the use of antiarrhythmic drugs within 12 months. Secondary outcomes included freedom from atrial arrhythmia recurrence, AF, atrial arrhythmia recurrence after multiple procedures, and documented atrial tachycardia or atrial flutter with or without antiarrhythmic drugs; AF burden; and improvement in quality of life. Patients were monitored with wearable single-lead electrocardiographic (ECG) patches, worn for 24 hours a week, supplemented by symptom-triggered ECGs and Holter monitoring.
Results
Among 498 randomized patients, 495 (99.4%) were included in the primary analysis (mean age, 61.1 years [SD, 9.7] years, 361 male [72.9%]). After 12 months, 174 of 246 patients (70.7%) assigned to undergo PVI plus EIVOM and linear ablation and 153 of 249 patients (61.5%) assigned to undergo PVI alone remained free from atrial arrhythmias without taking antiarrhythmic drugs (hazard ratio, 0.73; 95% CI, 0.54-0.99, P = .045). The intervention effect was consistent across all prespecified subgroups. The comparison of secondary outcomes did not demonstrate significant results.
Conclusion
Among patients with persistent AF, linear ablation combined with EIVOM in addition to PVI significantly improved freedom from atrial arrhythmias within 12 months compared with PVI alone.
Trial Registration
ClinicalTrials.gov Identifier: NCT04497376
This clinical trial evaluates whether linear ablation combined with ethanol infusion of the vein of Marshall and pulmonary vein isolation (PVI) is more effective than PVI alone in patients with persistent atrial fibrillation.
Introduction
Pulmonary vein isolation (PVI) has been the cornerstone of catheter ablation for the treatment of atrial fibrillation (AF). However, PVI alone is less effective for persistent AF compared with paroxysmal AF, notably in patients with episodes lasting longer than 3 months. Therefore, many ablation strategies extending beyond PVI have been considered for persistent AF.1,2,3,4 Linear ablation, derived from the Cox-Maze surgical technique, is one of the strategies employed in this context. Nevertheless, the incremental benefit of linear ablation beyond PVI for persistent AF has not been demonstrated in prospective randomized trials, primarily due to difficulties in achieving durable lesions.2,5,6 Achieving mitral isthmus block remains a significant challenge despite optimal contact force sensing and power settings.7 Creation of linear lesion using radiofrequency ablation may be proarrhythmic and may increase the incidence of left atrial tachycardias,8 limiting the application of linear ablations when treating persistent AF.
Prospective multicenter studies of linear ablation with durable bidirectional conduction block are needed. Ethanol infusion via the vein of Marshall (EIVOM) effectively creates chemical lesions affecting both epicardial and endocardial mitral isthmus.9 The Vein of Marshall Ethanol for Unablated Persistent AF (VENUS) trial10,11 has demonstrated the potential benefits of EIVOM in improving rhythm outcomes in patients with persistent AF, with post hoc analyses suggesting a correlation between these outcomes and successful mitral isthmus block. However, a linear ablation strategy optimized with EIVOM alongside PVI compared with PVI alone has yet to be compared in a randomized clinical trial. Although the latest expert consensus indicated that EIVOM may be reasonable for persistent AF ablation, it is still categorized as an area of uncertainty.1
The Prospective Randomized Comparison Between Upgraded 2C3L Versus PVI Approach for Catheter Ablation of Persistent Atrial Fibrillation (PROMPT-AF) trial aimed to evaluate the efficacy of a linear ablation strategy with radiofrequency energy—incorporating mitral isthmus, left atrial roof, and cavotricuspid isthmus ablation—combined with EIVOM and PVI. This study investigated whether this combined approach is more effective than PVI alone in maintaining sinus rhythm in patients with persistent AF.
Methods
Trial Design
The PROMPT-AF trial was an investigator-initiated, multicenter, open-label, randomized study conducted across 12 tertiary hospitals in China. The principal investigators and the steering committee have designed the trial, with details published elsewhere.12 The full protocol and statistical analysis plan are available in Supplement 1. Ethics approval has been obtained from the institutional review boards of each participating center. This study followed the Consolidated Standards of Reporting Trials (CONSORT) guideline.
Study Population
Patients were eligible for inclusion if they were aged 18 to 80 years, diagnosed with persistent AF (with a sustained AF episode of at least 3 months), refractory to at least 1 antiarrhythmic drug, and had no prior history of AF ablation. Exclusion criteria included paroxysmal AF, a left atrial diameter greater than 60 mm, a left ventricular ejection fraction of less than 30%, a life expectancy of less than 1 year, and any contraindication to catheter ablation or anticoagulation. Detailed inclusion and exclusion criteria are provided in Supplement 1.
Randomization
Patients were randomly assigned in a 1:1 ratio to PVI plus EIVOM and linear ablation or to PVI alone. Randomization was performed using a computerized central randomization system. The randomization used minimization, including an 80% probabilistic element with stratification for the randomization site and sex. The randomization was hosted by the Heart Health Research Center in Beijing, China.
Study Procedures
Patients assigned to the intervention (PVI plus EIVOM and linear ablation) underwent EIVOM first, followed by bilateral PVI and linear ablation at the mitral isthmus, left atrial roof, and cavotricuspid isthmus, as depicted in Figure 1. Technical details regarding EIVOM and linear ablation have been described elsewhere13 and in Supplement 1. The procedural end point was successful PVI and bidirectional block of the ablation lines, validated through differential pacing techniques and activation mapping after restoring sinus rhythm. For patients assigned to PVI alone, the procedural end point focused solely on PVI without additional substrate ablation. For both randomized groups, cardioversion was conducted if sinus rhythm was not restored after ablation. If organized atrial tachycardia was identified during the ablation procedure, ablation targeting critical isthmus or focal activation was allowed. A fixed procedural flow for each group is detailed in Supplement 1.
Figure 1. Linear Ablation Combined With Ethanol Infusion via the Vein of Marshall in Addition to Pulmonary Vein Isolation.
A, EIVOM was the first step of the procedure. The upper panel shows the selective VOM venography (blue arrows) acquired via an over-the-wire balloon. The lower panel shows contrast staining (blue chain) after ethanol infusion. B, After EIVOM, bilateral pulmonary vein isolation (PVI) and linear ablation in the roof, mitral isthmus, and cavotricuspid isthmus were performed. C, Voltage map at the end of the procedure.
All ablations in this study were performed using a 3-dimensional anatomical mapping system (CARTO, Biosense-Webster Inc) with irrigated-tip, contact force catheters (ThermoCool SMARTTOUCH Catheter or ThermoCool SMARTTOUCH Surround Flow Catheter, Biosense-Webster Inc) using a power control mode. Ablation index was employed to guide lesion quality, targeting values of 500 to 550 in the anterior wall, 350 to 400 in the posterior wall, 450 to 500 in the cavotricuspid isthmus and roofline, and 550 to 600 in the mitral isthmus.7,14
Study Outcomes
The primary end point of the study was freedom from any documented atrial arrhythmia, including AF, atrial tachycardia or atrial flutter episodes lasting longer than 30 seconds without antiarrhythmic drugs, for 12 months after the index ablation procedure, excluding a 3-month blanking period. The continuation or reinitiation of class I or class III antiarrhythmic drugs after the 3-month postablation blanking period, as well as electric cardioversion or catheter ablation for any atrial arrhythmias, were considered treatment failures for the primary end point.
Secondary end points with or without antiarrhythmic drugs included freedom from atrial arrhythmias, atrial arrhythmias following repeated ablation, atrial tachycardia or flutter and assessment of AF burden during the 12 months after the procedure (percentage of time in AF, in single-lead electrocardiographic [ECG] patches and Holter monitorings), also excluding the 3-month blanking period. Changes in quality of life from baseline to 12 months after the procedure were evaluated using the AF Effect on Quality of Life (AFQT) and the EuroQol Health-Related Quality-of-Life 3-Level (EQ-5D-3L) instruments. Additionally, acute and subacute procedural complications were documented. Detailed definitions for the secondary end points are provided in the study protocol (Supplement 1).
Patient assessments were conducted at 1, 3, 6, and 12 months following the initial ablation. Antiarrhythmic drugs were discontinued after the blanking period. Anticoagulation therapy was maintained for a minimum of 3 months after the procedure and thereafter according to guideline recommendations.15,16 Continuous rhythm monitoring was performed using a single-lead ECG patch that patients were required to wear for a period of at least 24 hours each week during the entire 12 months of follow-up. Additional rhythm data—including but not limited to Holter monitoring, other licensed wearable devices, and symptom-triggered ECGs—were also collected. Atrial arrhythmias identified by wearable devices were adjudicated by 2 independent physicians who were blinded to the randomization.
Statistical Analysis
The statistical analysis plan was published prior to data availability. Sample size estimation was based on findings from previous studies, anticipating atrial arrhythmia recurrence in 40% for PVI plus EIVOM and linear ablation and 55% for PVI alone.17 A total of 224 patients included in each group would provide 90% power at a 2-sided type I error probability of .05. Accounting for a 10% loss to follow-up, a target enrollment of 249 patients per group was deemed necessary.
The primary analysis was performed according to the modified intention to treat principle, including all consented participants who had been randomized and had undergone an ablation procedure. Crossovers were not permitted for the initial ablation. We assessed time to first recurrence by the Kaplan-Meier product limit method and compared groups with the log-rank test, with patients censored at death, lost to follow-up, or 12 months after the procedure. The proportional hazard assumption was examined by the scaled Schoenfeld residuals test. Cox proportional hazard regression was applied to estimate hazard ratios (HRs). Stratified log-rank test, as well as Cox proportional hazard regression adjusted for stratification factors, were performed as a sensitivity analysis. We did no interim analyses. Subgroup analyses have been prespecified in the study protocol (Supplement 1), and interactions between each subgroup factor and treatment arm were also assessed.
Continuous baseline variables were presented as mean (SE) or as percentiles (median, 25th, and 75th percentiles) if skewed. Discrete variables were summarized as frequencies and percentages. The t test or the nonparametric Wilcoxon rank-sum test was employed as appropriate for comparisons of continuous variables. For group comparisons of discrete baseline variables, Pearson χ2 test or Fisher exact test was used as appropriate. A 2-sided P value of less than .05 was considered statistically significant. Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc).
Results
Patients
A total of 498 patients (mean age, 61.1 [SD, 9.7] years, 361 male [72.9%]) were enrolled and randomized from August 27, 2021, to July 16, 2023 (Figure 2). Among these, 495 patients completed the procedure and were included in the primary analysis; the other 3 patients withdrew consent before ablation. Two of 246 patients (0.8%) randomized to the intervention group and 7 of 249 patients (2.8%) randomized to PVI alone who had undergone but had not adhered to the assigned ablation protocol (details in eTable 1 in Supplement 2) were included in the primary analysis as randomized. Baseline characteristics are detailed in Table 1.
Figure 2. Patient Recruitment and Study Flow of the PROMPT-AF Trial.
AF indicates atrial fibrillation.
aScreening log was not systematically collected from the participating centers
Table 1. Baseline Characteristics of Study Population.
| No. (%) of patients | ||
|---|---|---|
| PVI + EIVOM and linear ablation (n = 246) | PVI alone (n = 249) | |
| Age, mean (SD), y | 61.3 (9.9) | 61.0 (9.5) |
| ≥65 | 103 (41.9) | 97 (39) |
| Female | 66 (26.8) | 68 (27.3) |
| Male | 180 (73.2) | 181 (72.7) |
| Duration of persistent AF diagnosis, median (IQR), months | 12 (5-24) | 12 (4-24) |
| Long-standing persistent AFa | 113 (45.9) | 89 (35.7) |
| Hypertension | 136 (55.3) | 130 (52.2) |
| Diabetes | 32 (13) | 27 (10.8) |
| Ischemic stroke or TIA | 14 (5.7) | 17 (6.8) |
| Coronary heart diseaseb | 11 (4.5) | 5 (2) |
| Heart failure | 22 (8.9) | 31 (12.4) |
| New York Heart Association >IIc | 13 (5.3) | 7 (2.8) |
| CHA2DS2-VASc score, median (IQR)d | 1 (1-2) | 1 (0-2) |
| LA diameter | ||
| Mean (SD), mme | 42.8 (6.1) | 42.8 (4.5) |
| >45 mme | 84 (34.1) | 83 (33.3) |
| Ejection fraction, mean (SD), %e | 61.3 (7.6) | 61.1 (8) |
| Ejection fraction <50%e | 15 (6.1) | 19 (7.6) |
Abbreviations: AF, atrial fibrillation; EIVOM, ethanol infusion via the vein of Marshall; LA, left atrium; PVI, pulmonary vein isolation; TIA, transient ischemic attack.
Defined as AF persisting more than 12 months.
Defined as any coronary stenosis of 50% or more under coronary angiography or computed tomographic angiography.
A categorization of cardiac function, ranging from class I to class IV. Higher class indicates worse cardiac function.
A score assessing individual risk of ischemic stroke in patients with nonvalvular AF, ranging 0 ≈ 9. A higher score indicates higher risk of ischemic stroke.
Echocardiogram was performed at baseline before the procedure.
During the follow-up period, 2 patients in intervention group dropped out after the procedure, and 4 patients died (2 in each group). During the 12-month follow-up, the mean (SD) rhythm monitoring time for the study population was 13.0 (8.0) hours per week, with no significant difference between groups (12.7 [8.7] hours for the intervention group vs 13.4 [8.4] hours for the PVI alone group, P = .39). Further details regarding rhythm monitoring adherence are provided in eFigure 1 in Supplement 2.
Procedural Characteristics
The procedural characteristics are presented in eTable 2 in Supplement 2. The combination of linear ablation plus EIVOM was associated with a longer mean (SD) procedure time (188.0 [54.1] min vs 140.8 [39.7] min, P < .001) and fluoroscopy time (15.9 [26.3] min vs 5.1 [5.9] min, P < .001). Bilateral PVI was successfully achieved in all patients except for 2 patients (1 in each group).
Among patients in the intervention group, EIVOM was successfully performed in 209 patients (85%). The VOM was not visualized under venography in 30 patients (12.2%), whereas VOM cannulation failed in another 7 patients due to complicated anatomy. Complete linear block was achieved in 233 patients (94.3%) for the cavotricuspid isthmus, 215 patients (87.4%) for the roofline, and 215 patients (87.4%) for the mitral isthmus. Additional ablation with the coronary sinus was performed in 154 patients (62.6%) to achieve mitral isthmus block.
Primary Analysis
Within 12 months of the procedure, freedom from any documented atrial arrhythmia—including AF, atrial tachycardia, or atrial flutter episodes lasting longer than 30 seconds, in the absence of antiarrhythmic drugs—was achieved in 174 patients (70.7%) randomized to the intervention group and 153 patients (61.5%) randomized to PVI alone. The HR was 0.73 (95% CI, 0.54-0.99; P = .045; Figure 3). The test for proportional hazard assumption is shown in eFigure 2 in Supplement 2. The Cox proportional hazard regression with stratification of sex and randomization site and the stratified log-rank tests are shown in eTable 3 in Supplement 2.
Figure 3. Freedom From Recurrence of Atrial Arrhythmias Without Antiarrhythmic Drugs.
Secondary End Points
Secondary outcomes are described in Table 2 and eFigures 3 through 6 in Supplement 2. Freedom from any atrial arrhythmia recurrence, with or without antiarrhythmic drugs, was achieved in 180 patients (73.2%) assigned to the intervention and 161 (64.7%) assigned to PVI alone (HR, 0.74; 95% CI, 0.53-1.01). The number of patients free from AF episodes was 188 (76.4%) in the intervention group and 174 (69.9%) in the PVI alone group (HR, 0.77; 95% CI, 0.55-1.09). Additionally, 34 patients (13.8%) in the intervention group and 43 patients (17.3%) in the PVI alone group had documented atrial flutter or atrial tachycardia (HR, 0.79; 95% CI, 0.51-1.24). During the 12-month follow-up, 11 patients in intervention group and 20 in the PVI alone group underwent a redo ablation. Freedom from atrial arrhythmia recurrence after multiple procedures at 12-month was achieved in 191 patients (77.6%) in the intervention group and 181 (72.7%) in PVI alone group (HR, 0.81; 95% CI, 0.57-1.16).
Table 2. Primary and Secondary Outcomes.
| No. (%) | (95% CI) | P value | |||
|---|---|---|---|---|---|
| PVI + EIVOM and linear ablation (n = 246) | PVI alone (n = 249) | Absolute difference | Hazard ratio | ||
| Primary outcome without antiarrhythmic drugs : 12-mo freedom from | |||||
| Atrial arrhythmias after single ablation | 174 (70.7) | 153 (61.5) | 9.2 (1.0 to 17.6) | 0.73 (0.54 to 0.99) | .045 |
| Secondary outcome with or without antiarrhythmic drugs: 12-mo freedom from | |||||
| Atrial arrhythmias | 180 (73.2) | 161 (64.7) | 8.5 (0.4 to 16.6) | 0.74 (0.53 to 1.01) | .06 |
| AF | 188 (76.4) | 174 (69.9) | 6.5 (−1.2 to 14.3) | 0.77 (0.55 to 1.09) | .14 |
| Atrial arrhythmias after multiple ablations | 191 (77.6) | 181 (72.7) | 5.1 (−2.6 to 12.6) | 0.81 (0.57 to 1.16) | .31 |
| AFL or AT | 212 (86.2) | 206 (82.7) | 3.5 (−2.9 to 9.8) | 0.79 (0.51 to 1.24) | .25 |
Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AT, atrial tachycardia; EIVOM, ethanol infusion via the vein of Marshall; PVI, pulmonary vein isolation.
The median of AF burden throughout the 12-month follow-up, excluding the 3-month blanking period but including patients taking antiarrhythmic drugs or after redo procedures, was 0.0% (IQR, 0.0% to 0.0%) for the intervention group and 0.0% (IQR, 0.0% to 0.1%) for the PVI alone (P = .67). Improvement in quality of life after the procedure observed at 12 months in both groups is shown in eTable 4 in Supplement 2, without intergroup difference. For AFEQT the median was −26 (IQR, −46 to −10) vs −27 (IQR, −44 to −11; P = .94), and for EQ-5D-3L, the median was 10 (IQR, 0 to 20) vs 10 (IQR, 0 to 25; P = .08).
Prespecified Subgroup Analysis
The comparison of the primary outcome was conducted in 8 prespecified subgroups, including age 65 years or older, sex, long-standing persistent AF (AF persisting ≥1 year), left atrial diameter 45 mm or more, left atrial volume greater than the 50th percentile of the study population, heart failure, left ventricular ejection fraction less than 50%, and the presence of low-voltage areas in the left atrium. The effect of the intervention remained consistent across all subgroups (eFigure 7 in Supplement 2).
Adverse Events
Procedure-related adverse events are described in Table 3. There was no significant difference in the overall incidence of procedural-related adverse events between groups (P = .15). However, 7 patients assigned to the intervention group experienced pericarditis or pericardial effusion compared with none in the PVI alone group.
Table 3. Procedure–Related Adverse Events.
| No. of adverse events | ||
|---|---|---|
| PVI + EIVOM and linear ablation | PVI | |
| Cardiac | ||
| Tamponade | ||
| Requiring pericardiocentesis | 1 | 1 |
| Requiring surgery | 1 | 0 |
| Pericarditis or pericardial effusion not requiring drainagea,b | 7 | 0 |
| Coronary eventc | 1 | 1 |
| Third-degree atrioventricular block | 0 | 1 |
| Vascular | ||
| Pseudoaneurysm of femoral artery | 1 | 1 |
| Deep venous thrombosis | 1 | 0 |
| Other | ||
| Postprocedural fever | 1 | 1 |
| Antiarrhythmic drugs related complication | 0 | 1 |
Abbreviations: EIVOM, ethanol infusion via the vein of Marshall; PVI, pulmonary vein isolation.
Diagnosis of pericarditis should meet at least 2 of the following criteria: pericarditis chest pain; pericardial rubs; incident widespread ST elevation or PR suppression on surface electrocardiograph (ECG); or pericardial effusion.
Defined as mild to moderate pericardial effusion without ECG changes and pericarditis chest pain, identified by opportunistic or other symptom-triggered echocardiograms within 30 days after the procedure.
Including transient ST-T elevation with chest pain during the procedure, which does not require further coronary intervention or prolonged hospitalization.
All serious adverse events throughout the study are described in eTable 5 in Supplement 2, without significant intergroup difference (P = .36). Four patients died during the 12-month follow-up. All deaths occurred after the blanking period. Three patients died after atrial arrhythmia recurrence, and 1 patient died without atrial arrhythmia recurrence. In patients randomized to intervention group, 1 patient died of COVID-19 infection and 1 patient died of myocardial infarction. Among patients randomized to PVI alone, 1 died of intracranial bleeding and 1 died of heart failure. All deaths were considered unrelated to the procedure by the event committee.
Discussion
The PROMPT-AF trial is the first randomized study to demonstrate that a linear ablation strategy including EIVOM in addition to PVI significantly reduced atrial arrhythmia recurrence compared with PVI alone. Specifically, freedom from atrial arrhythmia recurrence without antiarrhythmic drugs was achieved in 70.7% of patients assigned to PVI plus EIVOM and linear ablation compared with 61.5% assigned to PVI alone. The finding remained consistent across all prespecified subgroups.
Although various linear ablation strategies have been explored, none have conclusively improved rhythm outcomes when added to PVI in randomized trials.2,4 Linear ablation targeting anatomical isthmuses aims to eliminate the substrate maintaining AF through atrial compartmentalization, effectively preventing the proliferation of AF drivers within the atria.18 This approach has shown promising results in surgical ablation.19 However, when applied to catheter ablation, the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II2 (STAR-AF II) study failed to demonstrate additional benefit of linear ablation over PVI alone, primarily due to less durable linear lesions. Besides not using contact-force-sensing catheters, the lack of benefit with linear lesions in STAR-AF II may also be explained by the use of radiofrequency alone.
Mitral isthmus ablation represents a significant technical challenge that hinders the broader clinical application of linear ablation strategies, even with the progress in power settings and contact-force technology.7 Perimitral flutter subsequent to the unblocked or less durable mitral isthmus lesion has been identified as the most common type of recurrent tachycardia in patients undergoing linear ablation.20,21 Epicardial conduction via the ligament of Marshall hampers the achievement and validation of mitral isthmus block.22,23,24,25 The use of EIVOM not only abolishes epicardial conduction but also facilitates mitral isthmus ablation by creating chemical lesions in the mid to distal mitral isthmus where reconnections are most prevalent,26 thereby reinforces the durability of mitral isthmus lesions.27 Randomized trials have also shown that EIVOM significantly enhances the mitral isthmus block rate and reduces the incidence of acute reconnections,28,29 leading a current expert consensus to recommend its use to support mitral isthmus ablation.1 In this study, mitral isthmus block was achieved in 87.4% patients, compared with only 75% in the STAR-AF II trial, which may, in part, explain the discrepancy of the results between the 2 trials. Meanwhile, EIVOM may also benefit persistent AF ablation in other aspects, including facilitating left pulmonary vein isolation,30 eliminating nonpulmonary vein triggers,31 and modulating cardiac autonomic nerves,32 although these effects have only been reported in small observational studies.
Linear ablation strategies optimized with EIVOM for persistent AF have only been preliminarily assessed for feasibility and safety in observational studies.13,33 Although the VENUS10 randomized trial indicated a benefit of EIVOM in conjunction with catheter ablation, it was not a pure comparison with PVI alone because more than 95% of patients overall underwent either posterior wall isolation or ablation of complex fractionated electrograms. Notably, a post hoc analysis of the VENUS trial revealed an interaction between mitral isthmus block and the effects of EIVOM,11 further supporting the establishment of a linear ablation strategy combined with EIVOM.
Despite these improvements, there remains potential for further refinement of this ablation strategy to enhance atrial compartmentalization and prevent arrhythmia recurrence. In the present study, 12.6% of mitral isthmus attempts did not achieve linear block, which could be partly attributed to undetectable VOM or difficulties in VOM cannulation. Additionally, residual conduction along the annulus side of the mitral isthmus, particularly through epicardial connections via the coronary sinus myocardial sleeves, often remains unaddressed during the procedure.
This current trial also highlighted that the roofline block was achieved in only 87.7%, indicating that this area may pose an underestimated challenge when performing linear ablation. The presence of adipose tissue between the septopulmonary and septoatrial bundles complicates the creation of transmural lesions in this region.34 Residual epicardial conduction may also pose a risk for macroreentrant tachycardias.35 Targeting the thinner areas of the posterior wall with a floor line could better intercept the anatomical isthmus, although this approach carries an increased risk of esophageal injury. Meanwhile, targeting the posterior wall alone may be insufficient.4 Macroreentrant tachycardias are frequent after posterior wall ablation.8,36 In the extended follow-up of CAPLA trial,36 flutters dependent on mitral or cavotricuspid isthmus after posterior wall ablation accounted for 17.3% and 11.5% of the redo procedure in the PVI plus posterior wall isolation group, respectively, indicating the importance of integrated anatomical ablation strategy. The ongoing Marshall Ethanolization, Pulmonary Vein Isolation and Line Completion for Ablation of Persistent Atrial Fibrillation (Marshall-PLAN) randomized trial (NCT04681872), which employs a similar lesion set to this current trial, may yield further insights for clinical practice. Moreover, the advent of pulsed field ablation allows for the ability to create posterior wall lesions with increased safety and efficacy.37 The feasibility of linear ablation with pulsed field energy is also being investigated,38 and pulsed field ablation may ultimately play a role in addressing the VOM. Whether an ablation strategy including linear lesions using pulsed field ablation is superior to PVI alone remains to be confirmed in randomized trials.
Although adding a linear ablation strategy optimized with EIVOM to PVI improves success rate of catheter ablation for persistent AF, it comes at a cost. This approach inevitably increases procedural time and fluoroscopy exposure, which could be improved as the operators gets more technically proficient about EIVOM and linear ablation. Although the incidence of procedural adverse events did not differ significantly between groups, 7 patients assigned to PVI plus linear ablation experienced pericarditis or pericardial effusion not requiring drainage, which may result in additional medical therapy and prolonged hospitalization, compared with none in PVI group.
Limitations
The present trial has several limitations. First, implantable loop recorders for continuous monitoring of the primary end point were not used. This may underestimate atrial arrhythmia recurrence and explain the relatively high success rate for a persistent AF population. Patients wore single-lead ECG patches for a 24-hour period each week. These wearable devices are noninvasive, making them more acceptable to patients and contributing to a less selective enrollment process. Furthermore, based on a post hoc analysis from the Cryoballoon Versus Contact-Force Irrigated Radiofrequency Catheter Ablation (CIRCA-DOSE) trial,39 the 13-hour-weekly average monitoring time aligns well with loop recorders in assessing AF burden. Second, the PROMPT-AF trial exclusively included patients with persistent AF lasting longer than 3 months. As a result, these findings may not be generalizable to patients with shorter episodes of persistent AF.
Conclusions
Among patients with persistent AF, linear ablation combined with EIVOM in addition to PVI significantly improved freedom from atrial arrhythmias within 12 months compared with PVI alone.
Trial Protocol
eTable 1. Protocol deviations.
eTable 2. Procedural parameters
eTable 3. Effect estimates in Cox proportional hazard regression stratified with sex and randomization site
eTable 4. Change in quality of life from baseline to 12 months post-procedure
eTable 5. Serious adverse events
eFigure 1. Distribution of rhythm monitoring adherence among study population
eFigure 2. Graphical test of proportional hazard assumption for primary outcome (Shoenfeld residual test P = 0.25).
eFigure 3. Freedom from atrial arrhythmia recurrence with or without AADs
eFigure 4. Freedom from atrial fibrillation recurrence with or without AADs
eFigure 5. Cumulative incidence of AFL/AT with or without AADs
eFigure 6. Freedom from atrial arrhythmia recurrence after multiple procedures with or without AADs
eFigure 7. Forest plot for prespecified subgroup analysis
PROMPT-AF Nonauthor Collaborators
Data Sharing Statement
References:
- 1.Tzeis S, Gerstenfeld EP, Kalman J, et al. 2024 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2024;21(9):e31-e149. doi: 10.1016/j.hrthm.2024.03.017 [DOI] [PubMed] [Google Scholar]
- 2.Verma A, Jiang CY, Betts TR, et al. ; STAR AF II Investigators . Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med. 2015;372(19):1812-1822. doi: 10.1056/NEJMoa1408288 [DOI] [PubMed] [Google Scholar]
- 3.Marrouche NF, Wazni O, McGann C, et al. ; DECAAF II Investigators . Effect of MRI-guided fibrosis ablation vs conventional catheter ablation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: the DECAAF II randomized clinical trial. JAMA. 2022;327(23):2296-2305. doi: 10.1001/jama.2022.8831 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kistler PM, Chieng D, Sugumar H, et al. Effect of catheter ablation using pulmonary vein isolation with vs without posterior left atrial wall isolation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: the CAPLA randomized clinical trial. JAMA. 2023;329(2):127-135. doi: 10.1001/jama.2022.23722 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Yu HT, Shim J, Park J, et al. Pulmonary vein isolation alone versus additional linear ablation in patients with persistent atrial fibrillation converted to paroxysmal type with antiarrhythmic drug therapy: a multicenter, prospective, randomized study. Circ Arrhythm Electrophysiol. 2017;10(6):e004915. doi: 10.1161/CIRCEP.116.004915 [DOI] [PubMed] [Google Scholar]
- 6.Scott PA, Silberbauer J, Murgatroyd FD. The impact of adjunctive complex fractionated atrial electrogram ablation and linear lesions on outcomes in persistent atrial fibrillation: a meta-analysis. Europace. 2016;18(3):359-367. doi: 10.1093/europace/euv351 [DOI] [PubMed] [Google Scholar]
- 7.Wolf M, El Haddad M, Fedida J, et al. Evaluation of left atrial linear ablation using contiguous and optimized radiofrequency lesions: the ALINE study. Europace. 2018;20(FI_3):f401-f409. doi: 10.1093/europace/eux350 [DOI] [PubMed] [Google Scholar]
- 8.Lim MW, Morton M, Fernando R, et al. Impact of posterior wall isolation during AF ablation on the incidence of left atrial flutter. JACC Clin Electrophysiol. 2024;10(7 pt 2):1620-1630. doi: 10.1016/j.jacep.2024.04.008 [DOI] [PubMed] [Google Scholar]
- 9.Valderrábano M, Liu X, Sasaridis C, Sidhu J, Little S, Khoury DS. Ethanol infusion in the vein of Marshall: adjunctive effects during ablation of atrial fibrillation. Heart Rhythm. 2009;6(11):1552-1558. doi: 10.1016/j.hrthm.2009.07.036 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Valderrábano M, Peterson LE, Swarup V, et al. Effect of catheter ablation with vein of Marshall ethanol infusion vs catheter ablation alone on persistent atrial fibrillation: the VENUS randomized clinical trial. JAMA. 2020;324(16):1620-1628. doi: 10.1001/jama.2020.16195 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lador A, Peterson LE, Swarup V, et al. Determinants of outcome impact of vein of Marshall ethanol infusion when added to catheter ablation of persistent atrial fibrillation: a secondary analysis of the VENUS randomized clinical trial. Heart Rhythm. 2021;18(7):1045-1054. doi: 10.1016/j.hrthm.2021.01.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Liu XX, Liu Q, Lai YW, et al. Prospective randomized comparison between upgraded ‘2C3L’ vs PVI approach for catheter ablation of persistent atrial fibrillation: PROMPT-AF trial design. Am Heart J. 2023;260:34-43. doi: 10.1016/j.ahj.2023.01.019 [DOI] [PubMed] [Google Scholar]
- 13.Lai Y, Liu X, Sang C, et al. Effectiveness of ethanol infusion into the vein of Marshall combined with a fixed anatomical ablation strategy (the “upgraded 2C3L” approach) for catheter ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2021;32(7):1849-1856. doi: 10.1111/jce.15108 [DOI] [PubMed] [Google Scholar]
- 14.Das M, Loveday JJ, Wynn GJ, et al. Ablation index, a novel marker of ablation lesion quality: prediction of pulmonary vein reconnection at repeat electrophysiology study and regional differences in target values. Europace. 2017;19(5):775-783. [DOI] [PubMed] [Google Scholar]
- 15.Joglar JA, Chung MK, Armbruster AL, et al. ; Peer Review Committee Members . 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e1-e156. doi: 10.1161/CIR.0000000000001193 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Van Gelder IC, Rienstra M, Bunting KV, et al. ; ESC Scientific Document Group . 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2024;45(36):3314-3414. doi: 10.1093/eurheartj/ehae176 [DOI] [PubMed] [Google Scholar]
- 17.Clarnette JA, Brooks AG, Mahajan R, et al. Outcomes of persistent and long-standing persistent atrial fibrillation ablation: a systematic review and meta-analysis. Europace. 2018;20(FI_3):f366-f376. doi: 10.1093/europace/eux297 [DOI] [PubMed] [Google Scholar]
- 18.Spector P. Principles of cardiac electric propagation and their implications for re-entrant arrhythmias. Circ Arrhythm Electrophysiol. 2013;6(3):655-661. doi: 10.1161/CIRCEP.113.000311 [DOI] [PubMed] [Google Scholar]
- 19.Khiabani AJ, MacGregor RM, Bakir NH, et al. The long-term outcomes and durability of the Cox-Maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg. 2022;163(2):629-641.e7. doi: 10.1016/j.jtcvs.2020.04.100 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Dong JZ, Sang CH, Yu RH, et al. Prospective randomized comparison between a fixed ‘2C3L’ approach vs stepwise approach for catheter ablation of persistent atrial fibrillation. Europace. 2015;17(12):1798-1806. doi: 10.1093/europace/euv067 [DOI] [PubMed] [Google Scholar]
- 21.Sawhney N, Anand K, Robertson CE, Wurdeman T, Anousheh R, Feld GK. Recovery of mitral isthmus conduction leads to the development of macro-reentrant tachycardia after left atrial linear ablation for atrial fibrillation. Circ Arrhythm Electrophysiol. 2011;4(6):832-837. doi: 10.1161/CIRCEP.111.964817 [DOI] [PubMed] [Google Scholar]
- 22.Barkagan M, Shapira-Daniels A, Leshem E, Shen C, Anter E. Pseudoblock of the posterior mitral line with epicardial bridging connections is a frequent cause of complex perimitral tachycardias. Circ Arrhythm Electrophysiol. 2019;12(1):e006933. doi: 10.1161/CIRCEP.118.006933 [DOI] [PubMed] [Google Scholar]
- 23.Kawaguchi N, Tanaka Y, Okubo K, et al. Differential pacing maneuver from the vein of Marshall. Circ Arrhythm Electrophysiol. 2024;17(4):e012420. doi: 10.1161/CIRCEP.123.012420 [DOI] [PubMed] [Google Scholar]
- 24.Jiang CX, Dong JZ, Long DY, et al. Ridge-related reentry despite apparent bidirectional mitral isthmus block. Heart Rhythm. 2016;13(9):1845-1851. doi: 10.1016/j.hrthm.2016.06.018 [DOI] [PubMed] [Google Scholar]
- 25.Chen S, Zhou G, Lu X, et al. The importance of identifying conduction breakthrough sites across the mitral isthmus by elaborate mapping for mitral isthmus linear ablation. Europace. 2019;21(6):950-960. doi: 10.1093/europace/euy327 [DOI] [PubMed] [Google Scholar]
- 26.Rostock T, O’Neill MD, Sanders P, et al. Characterization of conduction recovery across left atrial linear lesions in patients with paroxysmal and persistent atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(10):1106-1111. doi: 10.1111/j.1540-8167.2006.00585.x [DOI] [PubMed] [Google Scholar]
- 27.Nakashima T, Pambrun T, Vlachos K, et al. Impact of vein of Marshall ethanol infusion on mitral isthmus block: efficacy and durability. Circ Arrhythm Electrophysiol. 2020;13(12):e008884. doi: 10.1161/CIRCEP.120.008884 [DOI] [PubMed] [Google Scholar]
- 28.Zuo S, Sang C, Long D, et al. Efficiency and durability of EIVOM on acute reconnection after mitral isthmus bidirectional block. JACC Clin Electrophysiol. 2024;10(4):685-694. doi: 10.1016/j.jacep.2023.11.027 [DOI] [PubMed] [Google Scholar]
- 29.Gillis K, O’Neill L, Wielandts JY, et al. Vein of Marshall ethanol infusion as first step for mitral isthmus linear ablation. JACC Clin Electrophysiol. 2022;8(3):367-376. doi: 10.1016/j.jacep.2021.11.019 [DOI] [PubMed] [Google Scholar]
- 30.Huang L, Gao M, Lai Y, et al. The adjunctive effect for left pulmonary vein isolation of vein of Marshall ethanol infusion in persistent atrial fibrillation. Europace. 2023;25(2):441-449. doi: 10.1093/europace/euac219 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Santangeli P, Marchlinski FE. Techniques for the provocation, localization, and ablation of non-pulmonary vein triggers for atrial fibrillation. Heart Rhythm. 2017;14(7):1087-1096. doi: 10.1016/j.hrthm.2017.02.030 [DOI] [PubMed] [Google Scholar]
- 32.Báez-Escudero JL, Keida T, Dave AS, Okishige K, Valderrábano M. Ethanol infusion in the vein of Marshall leads to parasympathetic denervation of the human left atrium: implications for atrial fibrillation. J Am Coll Cardiol. 2014;63(18):1892-1901. doi: 10.1016/j.jacc.2014.01.032 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Derval N, Duchateau J, Denis A, et al. Marshall bundle elimination, pulmonary vein isolation, and line completion for anatomical ablation of persistent atrial fibrillation (Marshall-PLAN): prospective, single-center study. Heart Rhythm. 2021;18(4):529-537. doi: 10.1016/j.hrthm.2020.12.023 [DOI] [PubMed] [Google Scholar]
- 34.Pambrun T, Duchateau J, Delgove A, et al. Epicardial course of the septopulmonary bundle: anatomical considerations and clinical implications for roof line completion. Heart Rhythm. 2021;18(3):349-357. doi: 10.1016/j.hrthm.2020.11.008 [DOI] [PubMed] [Google Scholar]
- 35.Lai Y, Guo X, Sang C, et al. Epicardial roof-dependent macro-re-entrant tachycardia after ablation of atrial fibrillation: electrophysiological characteristics and ablation. JACC Clin Electrophysiol. 2023;9(8 pt 2):1530-1539. doi: 10.1016/j.jacep.2023.03.017 [DOI] [PubMed] [Google Scholar]
- 36.William J, Chieng D, Curtin AG, et al. Radiofrequency catheter ablation of persistent atrial fibrillation by pulmonary vein isolation with or without left atrial posterior wall isolation: long-term outcomes of the CAPLA trial. Eur Heart J. 2024:ehae580. [DOI] [PubMed] [Google Scholar]
- 37.Reddy VY, Anic A, Koruth J, et al. Pulsed field ablation in patients with persistent atrial fibrillation. J Am Coll Cardiol. 2020;76(9):1068-1080. doi: 10.1016/j.jacc.2020.07.007 [DOI] [PubMed] [Google Scholar]
- 38.Davong B, Adeliño R, Delasnerie H, et al. Pulsed-field ablation on mitral isthmus in persistent atrial fibrillation: preliminary data on efficacy and safety. JACC Clin Electrophysiol. 2023;9(7 pt 2):1070-1081. doi: 10.1016/j.jacep.2023.03.021 [DOI] [PubMed] [Google Scholar]
- 39.Aguilar M, Macle L, Deyell MW, et al. Influence of monitoring strategy on assessment of ablation success and postablation atrial fibrillation burden assessment: implications for practice and clinical trial design. Circulation. 2022;145(1):21-30. doi: 10.1161/CIRCULATIONAHA.121.056109 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eTable 1. Protocol deviations.
eTable 2. Procedural parameters
eTable 3. Effect estimates in Cox proportional hazard regression stratified with sex and randomization site
eTable 4. Change in quality of life from baseline to 12 months post-procedure
eTable 5. Serious adverse events
eFigure 1. Distribution of rhythm monitoring adherence among study population
eFigure 2. Graphical test of proportional hazard assumption for primary outcome (Shoenfeld residual test P = 0.25).
eFigure 3. Freedom from atrial arrhythmia recurrence with or without AADs
eFigure 4. Freedom from atrial fibrillation recurrence with or without AADs
eFigure 5. Cumulative incidence of AFL/AT with or without AADs
eFigure 6. Freedom from atrial arrhythmia recurrence after multiple procedures with or without AADs
eFigure 7. Forest plot for prespecified subgroup analysis
PROMPT-AF Nonauthor Collaborators
Data Sharing Statement