**5. VOM-ETHO in setting of atrial fibrillation. Randomized clinical trials**

The VENUS-AF Trial (Vein of Marshall EthaNol in Untreated perSistent) completed in 2018 and published in 2020 [18], was a multicenter, randomized clinical trial comparing the rhythm-control effectiveness of 2 ablation strategies: catheter ablation alone or combined with vein of Marshall ethanol infusion in de novo ablation of AF in a 1:1.15 fashion (including 15% more patients in the VOM group predicting a 15% failure to complete the VOM procedure thus being able to compare VOM-completed patients with controls in a 1:1 ratio). Patients were recruited from 12 referral centers in the United States and were eligible if they were between 18 and 85 years of age and had symptomatic persistent AF (sustained AF lasting >7 days) refractory to at least 1 antiarrhythmic agent. Exclusion criteria included previous AF ablation attempts and left atrial diameter or volume exceeding 65 mm or 200 mL, respectively. The primary endpoint was freedom from AF or AT 30-second duration over 1-year follow-up, with 1-months continuous monitoring at 6 and 12 months, after a single procedure. A total of 343 patients were enrolled (185 randomized to VOM and 158 to PVI). VOM-ETHO was successfully completed in 155 of 185 patients. After a single procedure, 49.2% (91/185) in the VOM group resulted free from AT/ AF compared to 38% (60/185) in the PVI group (p = 0.04). Considering patients with VOM-ETHO procedure successfully completed (as-treated analysis), the primary outcome was reached in 80/115 patients in the VOM group (51.6%, p = 0.02). Notably, AF burden, freedom from AF after multiple procedures and mitral line block achievement were significantly improved in VOM-treated patients. Kaplan–Meier plots showed significant reduction in AF or AT recurrence in the VOM group, in both the as-randomized analysis (hazard ratio 0.73; 95% CI 0.53–1.00; P 5 0.05) and the as-treated analysis (hazard ratio 0.67; 95% CI 0.47–0.93; P 5 0.02) (**Figure 6**). Interestingly, considering subjects with mitral line bidirectional block achievement, patients randomized to VOM-ETHO group (75 of 138) showed a better outcome respect to patients randomized to "ablation only" group (30 of 81) in terms of freedom from AT/AF in 1 year follow-up (54.3% vs. 37%, OR 0.49; 95% CI 0.28–0.87; P 5 0.01) [29].

Marshall-PLAN trial from the Bordeaux group adopted VOM-ETHO added to routine workflow in AF catheter ablation. Marshall-PLAN (Marshall bundle elimination, Pulmonary vein isolation, and Line completion for ANatomical ablation) trial [30] prospectively enrolled 75 consecutive patients with persistent AF for a de novo ablation procedure. All patients underwent VOM-ETHO and coronary sinus

#### **Figure 6.**

*Outcomes of the VENUS trial. A: time-to-recurrence of atrial fibrillation/atrial tachycardia "as randomized". B: time to recurrence excluding patients "as-treated", excluding patients in whom VOM-ETHO procedure was not completed. From: Valderrábano et al. [18].*

## *Vein of Marshall Ethanol Infusion in Setting of Atrial Fibrillation Ablation DOI: http://dx.doi.org/10.5772/intechopen.105593*

musculature ablation, PVI and anatomical isthmuses linear ablation (mitral, roof and cavotricuspid isthmus) (**Figure 7**). The primary endpoint was 12-months freedom from AF/atrial tachycardia. VOM-ETHO was completed in 69 patients (92%). The full lesion set was successfully completed in 68 patients (91%). At 12 months, 54 of 75 patients (72%) were free from AF/AT after a single procedure (without antiarrhythmic drugs) in the overall cohort. In the subset of patients with a complete lesion set (VOM-ETHO and anatomical lines), the single procedure success rate was 79%. After 1 or 2 procedures, 67 of 75 patients (89%) remained free from AF/AT without antiarrhythmic drugs (**Figure 8**).

In the Marshall-PLAN trial anatomical structures considered critical to the fibrillatory process were targeted (PVs, CS and Marshall bundle network). VOM ethanol infusion was central to the Marshall-PLAN as it enhances the success of subsequent

#### **Figure 7.**

*Marshall-PLAN lesion set. Left: steps for ethanol infusion into vein of Marshall (VOM); A: contrast injection into the VOM with evidence of vein arborization (red arrows). B: (insertion of the angioplasty balloon inflated in the proximal portion of the VOM (yellow star: radiopaque marker of balloon). C: contrast injection in the VOM after alcoholization shows contrast staining. Middle: ablation set in the LA: targeting of CS musculature and "saddle" confirmed by fractionated local electrograms, pulmonary veins isolation and anatomical lines for roof and mitral isthmuses. Right: LA voltage map in sinus rhythm showing final lesion set. From: Derval et al. [30].*

#### **Figure 8.**

*Freedom from atrial fibrillation (AF)/Atrial tachycardia (AT)-Kaplan–Meier event-free survival curves after a single ablation procedure, without antiarrhythmic drugs (A), and after 1 or 2 procedures, without antiarrhythmic drugs (B). From Derval et al. [30].*

PVI and linear ablation. Patients experiencing AF/AT recurrences after the first procedure demonstrated gaps in the original lesion set. Interestingly, anatomical sites of gaps were clustered in the right posterior carina/roofline and mitral line. Reconnections was not related to conduction recovery through the VOM but rather due to reconnections at the CS/LA interface. These findings suggest that other epicardial structures could play important roles in achieving durable transmural lesions, such as the septopulmonary bundle (for right PVs and roof line), the CS (for the mitral line), and the CTI. It is important to note that patients with incomplete lesion set at the index procedures had arrhythmic recurrences. In the Marshall-PLAN trial two patients experienced a transient ischaemic attack with no neurologic sequelae and four patients had post-ablation pericarditis. Three patients experienced minor groin hematoma.

In terms of LA function, the analysis of A-wave velocities suggested significant improvements in LA function at 12 months in patients without arrhythmic recurrences after the index procedure.

PROMPT-AF (Prospective Randomized Comparison between upgraded "2C3L" vs. PVI approach for the catheter ablation of persistent atrial fibrillation) [31] aimed to compare VOM-ETHO added to PVI plus roofline, mitral line and CTI ablation to PVI alone with randomized design. Unlike the original project, the study published in 2021 [32] does not have a randomized design and enrolled 191 patients who underwent their first catheter ablation of persistent atrial fibrillation (PeAF). The 2C3L technique is a fixed ablation approach consisting of bilateral circumferential PVI and three linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavo-tricuspid isthmus. Patients were selected consecutively and compared for VOM-ETHO plus 2C3L approach (group 1) and 2C3L approach "RF only" (group 2). The follow-up duration was 12 months. The primary endpoint was the rate of documented atrial arrhythmias lasting >30 seconds without any antiarrhythmic drugs, in 12 months after index ablation procedures considering a blanking period of 3 months. The final population consisted of 191 patients (66 in the group 1 and 125 in the group 2). Successful VOM-ETHO was performed in 53 patients in group 1 (VOM not cannulated in 12, VOM dissection in one). At the index procedure, 100% of patients showed successful PVI, bidirectional roofline block and CTI block while mitral isthmus block was achieved in 95.5% of patients in group 1 and 80.8% in group 2 (p 0.006). At 12-months follow-up, 58 (87.9%) patients were free from AF/AT in group 1 compared with 81 (64.8%) in group 2 (p < 0.001) (2 in group 1 and 3 in group 2 patients were on AAD during the 12-months follow-up). Considering patients who received successful VOM-ETHO (53), freedom from AF/AT was achieved in 47 (88.7%). At the survival analysis, group 1 showed higher survival freedom from AT recurrence after adjustment for age, LA diameter, long-standing persistent atrial fibrillation, hypertension, and heart failure (HR 0.27, 95% CI 0.12–0.59) (**Figure 9**). Two patient experienced mild complication in the "VOM-ETHO" group: one mild pericardial effusion with self-relief and one fluid overload during the procedure. Eight complications occurred in seven (5.6%) patients in "ablation only" group including four fluid overload, one mild pericardial effusion with self-relief, two arteriovenous fistulae, and one pleural effusion. No severe complications like death, stroke or atrial-esophageal fistula were observed.
