Beyond the pulmonary vein isolation—is alcohol substrate modification the best option for persistent atrial fibrillation?

Pulmonary vein isolation (PVI) is the cornerstone of invasive treatment for patients with atrial fibrillation (AF). The benefits of this therapy are reported in many scientific studies, starting with the research of Haïssaguerre et al. (1). The choice of this form of therapy is also confirmed by high-quality evidence recently found in successive guidelines from American and European societies (2-4). Unfortunately, the effectiveness of PVI depends on several variables, including the form of AF. The greatest therapeutic efficacy is observed in patients with the paroxysmal form of AF. Currently, the choice of the optimal additional intraoperative strategy in patients with persistent AF is still under investigation. The benefits of different management options, such as rotor modulation, ablation of fragmented potentials, and ablation of the arrhythmogenic substrate, have been suggested. Surprisingly, only a small proportion of these studies have demonstrated favorable results.

Preliminary studies using the focal impulse mapping and rotor modulation (FIRM) technique offered promising results, showing the potential elimination of AF. However, a subsequent multicenter study evaluating the benefits of adding FIRM to standard PVI did not indicate a significant improvement in rhythm control strategy compared to PVI alone (5,6). The authors achieved high AF termination rates using high-density mapping catheters to identify areas with rotor activity in AF. However, the study methodology did not exclude fragmented potentials in the dispersion analysis, potentially targeting the area with both fragmented and unfragmented potentials for ablation (5). Therefore, there are concerns about the potential for unintentional proarrhythmic scar formation during extensive ablation.

Patients undergoing for the first time endocardial catheter ablation (CA) for symptomatic persistent AF were enrolled in the CAPLA (Catheter Ablation for Persistent Atrial Fibrillation: A Multicenter Randomized Trial of Pulmonary Vein Isolation vs PVI With Posterior Left Atrial Wall Isolation) randomized trial (7). The cohort consisting of 338 patients came from three continents and three different countries (Australia, Canada, UK). The subjects were randomized 1:1 to either PVI with posterior wall isolation (PWI) or PVI alone in 11 ablation centers. After 12 months, 52.4% of those assigned to PVI with empirical addition of PWI were free from recurrent atrial arrhythmia without antiarrhythmic medication after a single procedure, as compared to 53.6% assigned to PVI alone. The lack of statistical significance did not indicate the benefits of PW ablation for long-term maintenance of sinus rhythm. This finding was in line with the results of a meta-analysis of 17 studies comprising 1,643 patients (8). Single-procedure 12-month freedom from atrial arrhythmia was 65.3% overall and 61.9% for PVI plus PW ablation. In turn, in the STAR AF II study (8), 589 patients with persistent AF were randomly assigned to endocardial ablation with PVI, PVI plus ablation of complex fractionated atrial electrogram (CFAE) or PVI plus additional linear ablation through the left atrial (LA) roof and mitral valve isthmus. After 18 months, 59% of patients who underwent PVI alone were free from recurrent AF. Additionally, causing additional empirical lesions beyond the PVs did not translate into significant differences among the three groups for the secondary end points, including freedom from AF after two ablation procedures and freedom from any atrial arrhythmia.

There are also data indicating that substrate ablation may increase the chance of maintaining sinus rhythm. In this approach, it seems important to achieve transmural modification of the substrate or tailored ablation strategy. Huo et al. (9) conducted a multicenter randomized study [Low-Voltage Myocardium-Guided Ablation Trial of Persistent Atrial Fibrillation (ERASE-AF)] to determine whether PVI plus tailored substrate ablation of atrial low-voltage myocardium could improve outcomes in patients with persistent AF. The first recurrence of an atrial arrhythmia lasting longer than 30 seconds after single ablation occurred in 50% of PVI-only patients and in 35% of PVI plus substrate ablation subjects. A significant difference was registered in favor of patients who underwent tailored ablation added to the PVI (P=0.006). Importantly, patients were encouraged to receive an implantable cardiac monitor for continuous automatic arrhythmia detection and remote data transmission. The importance of a transmural scar is highlighted by studies using surgical approaches or minimally invasive surgery, in which the substrate of the arrhythmia was modified using various protocols (10,11). For instance, in the CONVERGE study (Convergence of Epicardial and Endocardial Ablation for the Treatment of Symptomatic Persistent AF) (12), 153 patients were randomized. The subjects were recruited from the European and the United States population with long-standing persistent AF (LSPAF) and a significantly enlarged LA (≤6.0 cm). The authors reported freedom from any atrial tachycardia (AT) and increased dosage of previously failed/intolerant class I/III antiarrhythmic drugs through 12 months in 67.7% patients with double-stage endo-epicardial procedure, as compared to 50.0% with CA (P=0.036). Furthermore, at 18 months using 7-day Holter, 74.0% of hybrid treated patients experienced ≥90% AF burden reduction vs. 55% of CA patients. In addition to surgical procedures, percutaneous techniques, including alcohol ablation, are also reported to create extensive, transmural substrate elimination. The injection of a concentrated ethanol solution into selected vessels of the cardiac venous system vascularizing the atria results in extensive scar formation and damage to the left atrial appendage (LAA). Clinical benefits of ethanol infusion into the vein of Marshall (EIVOM) have already been demonstrated in several studies, including the randomized VENUS study (The Vein of Marshall Ethanol for Untreated Persistent AF) (13,14). In turn, in the randomized BELIEF trial (Effect of Empirical Left Atrial Appendage Isolation on Long-term Procedure Outcome in Patients With Persistent or Longstanding Persistent Atrial Fibrillation Undergoing Catheter Ablation) (15), the authors showed that, both after a single procedure and after repeat ablation in patients with LSPAF, empirical electrical isolation of the LAA improved long-term freedom from atrial arrhythmias without increasing complications rate.

In their research, Derval et al. went one step further (16). The suitability of combining alcohol ablation from epicardial access via the coronary sinus with the effect of complementary radiofrequency (RF) current applications from endocardial access was analyzed. LA sites were sequentially targeted as follows: (I) coronary sinus and the vein of Marshall; (II) PVI; and (III) anatomical (mitral, roof and cavotricuspid) isthmuses. In the subset of patients with complete AF also referred to as the Marshall-PLAN lesion set, 79% remained free from AF or any AT at 12 months. Re-treatment resulted in 89% of patients remaining AF/AT free without using any antiarrhythmic drugs. This high efficiency of the adopted procedure methodology was also confirmed by long-term monitoring precisely assessed with an implantable loop recorder (ILR). The findings of a small, single-center study showed a high rate of freedom from AT/AF at the follow-up (87%), considering that antiarrhythmic drugs were discontinued after 1 month of the follow-up in 74% of subjects (17).

In this context, the randomized PROMPT-AF trial (18) filled the gaps in current knowledge. In their study, the authors analyzed whether a linear ablation strategy involving EIVOM in addition to PVI could significantly reduce atrial arrhythmia recurrence compared with PVI alone. In particular, the 12-month freedom from any confirmed atrial arrhythmia recurrence without antiarrhythmic drugs was achieved in 70.7% of patients assigned to PVI plus EIVOM and linear ablation compared to 61.5% assigned to PVI alone. The intervention effect was consistent across all prespecified subgroups. The treatment results may suggest a possible clinical benefit in this patient group. A fairly large group of patients was included in the randomized comparative analysis. Importantly, of those enrolled in the study, almost 46% of patients were diagnosed with a persistent, long-standing arrhythmia, which is the form of AF associated with the highest risk of recurrence. Statistical differences were achieved, despite the anatomy of the venous tree limiting the optimal ethanol injections in all cases. Defining the primary endpoint of the study as the absence of any documented atrial arrhythmias, including AF, AT, or atrial flutter lasting longer than 30 seconds, is clinically crucial. Efficacy was assessed after discontinuation of antiarrhythmic drugs. From our point of view, the method still has an important aspect. Achieving conduction block in the mitral annulus more easily during the procedure is crucial. This is the main technical challenge on a day-to-day basis that hinders broader clinical application of linear ablation strategies, despite the use of contact-force catheters and the development of high-power technology (19).

Obviously, when analyzing the data, several limitations of this study must be noted, which was also mentioned by the authors, one of them being the difference in procedure duration. The combination of linear ablation plus EIVOM was associated with significantly longer mean procedure time (188.0 vs. 140.8 min) and fluoroscopy time (15.9 vs. 5.1 min). The difference was due to the need for additional technical maneuvers. In addition to a longer learning curve, this fact may be related to a higher risk of perioperative complications. Another aspect is associated with the efficacy assessed by continuous monitoring for an average of 13 hours per day. It is also important to note adverse effects of the procedure (i.e., seven episodes of pericarditis or pericardial effusion not requiring drainage). The authors did not report whether pericardial effusion not requiring drainage was related to pericarditis. The comparison with the results of other studies on endocardial ablation does not indicate it (20,21). However, the pericardial reaction may be more severe, as seen in other papers on EIVOM (13). An explanation may be the extent of the substrate, which develops mainly on the epicardial side. Contact damage to adjacent tissues by the concentrated alcohol solution is also possible. These events may translate into longer hospitalization, which may ultimately lead physicians to limit the use of this procedure as the next step in the treatment of patients with recurrent arrhythmias after previous endocardial ablation. The cost of the hybrid procedure is also of importance and may be a limitation in daily practice.

It is not obvious whether the optimization of current therapeutic methods in patients with persistent AF will be associated with the improved rhythm control. The use of pulsed field ablation (PFA) in the group of patients is currently awaited. The initial findings from randomized trials are now available and are beginning to inform efforts to reduce specific procedural complications (22,23). The use of EIVOM combined with RF applications seems to be highly effective in maintaining sinus rhythm, yet the procedure is time-consuming and requires additional skills and experience of the operator. PFA may be a simpler, shorter and similarly effective alternative to the adopted methodology. Ultimately, however, the goal of high effectiveness may not be currently achievable. The review of the literature shows that either knowledge in understanding the mechanisms of persistent AF is incomplete or the tools used are imperfect.

Acknowledgments

None.

Footnote

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