Persistent atrial fibrillation (AF) ablation—is ethanol the solution or just another means to an end?

Introduction

Since the seminal work by Dr. Haïssaguerre et al. in establishing pulmonary veins as the commonest trigger sites for atrial fibrillation (AF) (1), the previously “untreatable” disease saw a flurry of development in ablative therapy. Since then, pulmonary vein isolation (PVI) has been established as the cornerstone for catheter ablation of paroxysmal and even persistent AF (2-4). While previously data was conflicting for rate versus rhythm control, contemporaneous evidence has now demonstrated better success rates and outcomes with catheter ablation compared to anti-arrhythmic drugs (AADs) (5-7). Despite that, the efficacy of PVI alone in persistent AF has remained modest at best with 1-year freedom from atrial arrhythmia recurrence at 43–67% to date (8). The pursuit for the most “optimal” ablation strategy for persistent AF ranging from adjunctive linear to complex fractionated atrial electrograms (CFAE) ablation has been dampened by many negative randomised trials with issues ranging from patient and methodology heterogeneity to difficulty in achieving durable lesions (9-11).

In recent years, there was increasing focus on adjunctive ethanol infusion into vein of Marshall (EIVOM) in persistent AF ablation. Vein of Marshall (VOM), a remnant of the embryonic left superior vena cava, has been implicated in the development of AF, either as trigger or as tract for modulating atrial sympathetic and parasympathetic innervations that contribute to maintenance of AF. EIVOM has been shown in several non-randomised studies to improve outcomes among patients undergoing first-time ablation of persistent AF (12,13).

Trial design and background

In the recently published issue of Journal of American Medical Association (JAMA), “Pulmonary Vein Isolation With Optimized Linear Ablation vs Pulmonary Vein Isolation Alone for Persistent AF: The PROMPT-AF Randomized Clinical Trial” studied the effect of EIVOM in 498 patients with symptomatic persistent AF of at least 3 months in duration who had previously failed at least 1 AAD (14). This investigator initiated, multicentre, open label randomised controlled trial (RCT) across 12 tertiary hospitals in China randomised participants to either PVI plus EIVOM and linear ablation or PVI alone in a 1:1 ratio. In the intervention arm, participants would undergo EIVOM first, followed by bilateral PVI and linear ablation of mitral isthmus (MI), left atrial roof and cavotricuspid isthmus (CTI). The primary endpoint was freedom from any documented atrial arrhythmia episodes lasting more than 30 seconds without AADs after a 3-month blanking period as assessed by frequent cardiac rhythm monitoring of at least 24 hours duration per week for the entire 12 months follow-up period. The patient population enrolled in PROMPT-AF, while relatively young for an AF cohort (mean age of 61.1 years old), had a median duration of 12 months of persistent AF diagnosis prior to ablation with at least one-third of the patients having longstanding persistent AF and high cardiovascular risk factor burden, particularly that of hypertension and heart failure.

The key finding of this study was that the addition of EIVOM and linear ablation reduced atrial arrhythmia recurrence, specifically without the use of AADs, at 12 months by 27% compared to PVI alone [70.7% vs. 61.5%, hazard ratio (HR): 0.73; 95% confidence interval (CI): 0.54–0.99; P=0.045]. There were no significant differences in any of the secondary outcomes, which included freedom of atrial arrhythmias with or without AADs, atrial arrhythmia recurrence after multiple ablations, AF burden and changes in quality of life (QoL) as measured by AF Effect on Quality of Life (AFQT) and EuroQOL Health-Related Quality-of-Life 3-Level (EQ-5D-3L) questionnaires at 12 months. In addition, none of the 8 pre-specified patient subgroups demonstrated a population that benefited more from additional EIVOM and linear ablation compared with PVI alone.

There were several notable procedural characteristics in the intervention arm. Firstly, 37 (15%) patients in the intervention group could not undergo EIVOM where the majority (12.2%) was due to the inability to visualise VOM using venography while the remaining (3.8%) was due to failure to cannulate the VOM due to complicated anatomy. Secondly, complete linear block of the MI and roof line was only achieved in 215 patients (87.4%). Lastly, additional ablation in the coronary sinus (CS) was also performed in 154 patients (62.6%).

While PROMPT-AF trial was a positive trial, the addition of EIVOM and linear ablation to PVI came at a cost. The intervention resulted in a longer procedure time by 47 min (188.0±54.1 vs. 140.8±39.7 min, P<0.001) and fluoroscopy time by 10.8 min (15.9±26.3 vs. 5.1±5.9 min, P<0.001). There were also numerically more complications compared to PVI alone mainly driven by higher incidence of pericarditis or pericardial effusion not requiring drainage in the intervention arm (7 vs. 0), albeit not statistically significant.

Discussion

Is EIVOM ready for prime time?

PROMPT-AF is the first RCT that demonstrated the positive impact of adjunctive EIVOM on top of PVI and provided the much-needed evidence as well as optimism in targeting non-pulmonary vein (non-PV) triggers to improve persistent AF ablation outcomes. Successful linear ablation of MI using thermal ablation sources has been and remains a technical challenge for electrophysiologists around the globe. Main challenges include the inability to deliver adequate trans-mural lesion to block the MI completely or less durable MI lesions leading to recurrent peri-mitral re-entry. Thus, the adjunctive use of EIVOM not only eliminates the epicardial connections but also facilitates additional chemical ablation of the MI to ensure durability and consequently lower risk of atrial arrhythmia recurrence (15,16).

Despite these encouraging results from PROMPT-AF, adjunctive EIVOM is unlikely going to be widely adopted for all de novo persistent AF ablations for several reasons. EIVOM can be technically challenging and time consuming as evidenced by the substantial proportion of patients who could not undergo EIVOM as well as the longer procedural and fluoroscopy time. This is further corroborated by several contemporary studies with a reported first time EIVOM success rates of 83.7–88.9% (13,16). Even with successful EIVOM and additional ablations within the CS in approximately 85% and 62.6%, respectively, 12.6% of the intervention cohort did not successfully achieve complete MI block acutely. It is also challenging to further evaluate the utility of EIVOM in creating transmural lesion as the authors did not provide the breakdown on number of patients who achieved MI line block after (I) EIVOM prior to endocardial MI line as well as (II) EIVOM with endocardial MI line after. It was noted that 154 (62.6%) patients in this intervention group necessitated additional intra-CS application to achieve complete MI line block which suggest that only 61 (24.8%) of the intervention cohort achieved transmural block with either EIVOM and/or endocardial MI line. In addition, the secondary outcome of freedom from atrial flutter or tachycardia was not significantly different in both groups suggestive that the difference in primary efficacy endpoint is less likely driven by MI re-entry/lack of durability.

Here comes a new contender—PFA

While PROMPT-AF serves to establish the role of EIVOM in AF ablation, it would be remiss of us to not discuss the meteoric rise of pulsed field ablation (PFA), which has proven to be a gamechanger for AF ablation. Through the delivery of short bursts of high energy electrical pulses, PFA results in selective irreversible electroporation followed by cellular apoptosis of cardiac myocytes. Hence, PFA results in a more targeted ablation of cardiac tissues while sparing adjacent critical structures such as phrenic nerve and esophagus. Hitherto, PFA has only been shown to be non-inferior to radiofrequency ablation (RFA) for PVI in paroxysmal AF patients but with shorter procedural times. Recently, the second phase of ADVANTAGE AF trial studied the impact of PVI, and posterior wall ablation (PWA) with or without CTI ablation using PFA in 255 persistent AF patients and showed promising outcomes with 73.4% freedom from any atrial arrhythmia at 1 year on continuous rhythm monitoring with a 99.6% acute procedural success and 2.4% complication rate (17). The patients enrolled had higher risk demographics compared to the PROMPT-AF population with a mean age of 66.7±9.3 years with significant burden of cardiovascular risk factors, heart failure and coronary artery disease and mean duration of 3 years of AF diagnosis. In addition, the procedures were accomplished with a total procedure time of 105±36 min including a mandatory left atrium (LA) wait time of 20 min as part of the study highlighting the efficiency of PFA even with these additional linear ablations.

Preliminary studies also suggest that linear ablation MI using PFA is feasible with 100% success for complete MI block acutely although there is a 20% recurrence rate (18). However, there are some unanswered questions for PFA. Coronary spasm during linear ablation using PFA of MI and CTI is extremely common but could be mitigated by intravenous glyceryl trinitrate (GTN) administration (19,20). Recent studies suggest possible delayed sequelae with mild coronary artery stenosis due to neointimal hyperplasia and tunica media fibrosis even when initial coronary spasm had resolved (21). Longer term randomised data on the use of PFA beyond PVI is still emerging and will be needed to shape our approach and practice for persistent AF ablation.

Conclusions

PROMPT-AF has boosted the role of adjunctive EIVOM in our armamentarium of persistent AF ablation beyond just catheter ablation. It is increasingly being recognised as a viable approach with improved outcomes, albeit with a trade-off of longer procedural hours and requires more technical expertise. Its future role will likely be determined by longer term outcomes of PFA studies.

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.