ABSTRACT
Background
Beyond pulmonary veins isolation (PVI), the ablation strategy that has prevailed over the past two decades remains controversial: (1) the left atrium partition using linear lesions (“cox-maze” strategy); (2) the mapping of the left atrium in atrial fibrillation (AF) to identify and localize the arrhythmia sources. Both methods have failed to demonstrate superiority compared to PVI alone. Whether the addition of a systematic vein of Marshall (VOM) ethanol infusion and empirical linear ablation to PVI (Marshall-Plan) improves outcomes in patients with persistent AF remains to be demonstrated.
Objectives
To compare the 2-year freedom from any atrial arrhythmia (atrial fibrillation [AF]/atrial tachycardia [AT]) between the Marshall-Plan approach and the PVI approach in patients with persistent AF.
Methods
The Marshall Plan is a multicenter, prospective, randomized, parallel- group, controlled clinical trial of superiority conducted in nine tertiary care centers across Europe (8 centers in France, 1 center in Belgium). A total of 262 patients will be randomized in two arms: Marshall-Plan, consisting of PVI with additional ablation, including vein of Marshall ethanol infusion, and lines of block at the mitral, dome, and cavotricuspid isthmuses versus PVI alone. The main outcome will be the 2-year freedom from any arrhythmia AF/AT <30 seconds) after a single ablation procedure with or without antiarrhythmic medication.
Conclusions
This randomized trial aims to determine the success and safety of adjunctive VOM ethanol infusion and linear ablation to PVI in patients with persistent AF.
Registration
URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04681872
Background and rationale
Atrial fibrillation (AF) is the most common arrhythmia worldwide, with increasing prevalence mainly due to an aging population. Maintenance of sinus rhythm in this population is crucial and associated with a significant reduction in stroke, heart failure, and cardiovascular mortality. In the last three decades, catheter ablation has earned evidence-based credentials as a safe and efficacious treatment in drug-refractory AF. However, the success rate in patients with persistent AF remains insufficient. Current ablation strategies for treatment of persistent AF can be broadly categorized into tailored approaches, aimed at eliminating sources of AF maintenance, and anatomic approaches in which the left atrium (LA) is electrically partitioned by predefined linear lesion sets. Although effective at terminating AF in the acute setting, tailored approaches have been associated with a high risk of subsequent organized atrial tachycardias (ATs) and impairment of atrial function. Anatomic approaches have shown promise, but creating durable linear lesions remains challenging.
The Vein of Marshall (VOM) is an embryological remnant from the lower portion of the anterior left cardinal vein. The VOM colocalizes with intrinsic cardiac nerves and is overlaid by an epicardial musculature: the Marshall bundle. These related structures have been identified as a potential source of focal activities, the substrate of reentries, and a strong parasympathetic modulator. They represent candidates’ targets in AF treatment beyond pulmonary vein isolation (PVI). Firstly described in 2,009 by the group of Valderrabano, their elimination can be achieved by retrograde balloon cannulation and ethanol infusion into the VOM (VOM-OH). This approach offers several advantages that improve the ablation strategy of persistent AF: (1) elimination of a proarrhythmogenic structure; (2) facilitation of left PVI; (3) destruction of an essential part of the mitral line responsible for residual gaps; (4) modulation of cardiac innervation.
We have recently reported an ablation strategy strictly based on anatomical considerations that would combine the principle of a linear atrial partition with systematic VOM-OH: The Marshall-Plan lesion set. In a prospective, monocentric randomized controlled trial, we have demonstrated that this strategy was superior to PVI only and was associated with a high rate of sinus rhythm maintenance at 12 months. The benefit of such an approach has recently been confirmed in a prospective multicentric randomized trial: the PROMPT-AF trial. Our main hypothesis is that the Marshall-Plan approach in patients with persistent AF will decrease AF recurrence compared to PVI alone in a larger multicentric trial.
Trial design
The Marshall Plan is a prospective, randomized, parallel-group, multicenter superiority clinical trial. The designed population will consist of patients suffering from symptomatic persistent AF. The patients will be randomly assigned to two arms: PVI only or the Marshall-Plan lesion set.
Methods: Participants, interventions, and outcomes
Study settings
The Marshall Plan trial will be conducted in 9 European tertiary care centers (8 centers in France and 1 center in Belgium).
Eligibility criteria
See Table 1 .
Table 1
Inclusion and exclusion criteria.
| Inclusion criteria |
|
| Exclusion criteria |
|
Inclusion criteria
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1.
Age > 18 years for both genders.
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2.
Suitable candidate for catheter and ablation of AF defined as: history of symptomatic persistent AF in the past year documented by electrocardiogram (ECG).
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3.
Patient affiliated or beneficiary of the social security scheme.
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4.
Free, informed, and written consent signed by the participant and the principal investigator (at least at the inclusion date and before all exams required for clinical research)
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5.
Effective contraception for women of childbearing potential.
Exclusion criteria
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1.
Prior left atrial heart ablation procedure.
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2.
Prior heart surgery, including atrial incision.
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3.
Documented left atrial thrombus or another abnormality that precludes catheter introduction.
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4.
Contraindication to anticoagulation therapy (heparin, warfarin, or novel oral anticoagulant [NOAC].
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5.
Contraindication to iodinated contrast products (history of major immediate reaction, thyrotoxicosis).
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6.
Ethanol hypersensivity.
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7.
Unstable angina or ongoing myocardial ischemia.
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8.
Myocardial infarction within 3 months before inclusion.
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9.
Congenital heart disease, where the underlying abnormality increases the ablation risk.
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10.
Severe bleeding, clotting, or thrombotic disorder.
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11.
Hypertrophic cardiomyopathy is defined by a left ventricular septum thickness > 1.5 cm.
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12.
Pregnant, parturient, or nursing women.
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13.
Person unable to give informed consent.
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14.
Patient detained by judicial or administrative order, patient under legal protection (guardianship, curatorship, safeguarding justice).
Feasibility and recruitments procedures
A total of 262 patients will be prospectively enrolled in 9 European ablation centers. The participating centers have been selected owing to their expertise in managing AF patients and in their electrophysiological and ablation skills. Moreover, these centers perform a high number of ablation procedures (>500 procedures/year/center) each year, maximizing the chance of reaching the number of selected patients. All centers have already been trained for VOM ethanolization and have been using that technique routinely for more than 3 months. This will avoid the study from being impacted by the learning curve of the VOM-OH technique.
Enrollment has started on September 21, 2021. To date, 262 patients have been included, and the follow-up period is scheduled to be completed by May 21, 2027.
Procedural management
Preablation
Baseline cardiac investigation includes an electrocardiogram (EKG) and ECG to assess left atrial size, left ventricular dimension, ejection fraction (EF, %), and diastolic function. The European Heart Rhythm Association (EHRA) symptoms score will be assessed.
Randomization method
The randomization list will be created by a statistician from the Methodology and Data Management Centre of the University Hospital of Bordeaux (USMR) before the start of the research project. The number of participants in the two treatment groups will be balanced, with a 1:1 ratio. Randomization will be stratified by investigator center. A confidential document describing the preparation of the randomization list will be kept within the Methodology and Data Management Centre.
Ablation procedure
General principles
Radiofrequency ablation (RFA) of AF will be performed under conscious sedation using the CARTO-3 mapping system (Biosense Webster, Diamond Bar, CA) or general anesthesia at the discretion of each center. In case of general anesthesia, an esophageal temperature probe will be placed in the midesophagus. A preprocedural computed tomography (CT) imaging will be systematically acquired to rule out intracardiac thrombus and subsequently used for merging with the electroanatomic map. Three catheters will be settled in heart cavities: (1) a steerable decapolar catheter in the coronary sinus (CS); (2) an ablation tip-irrigated catheter (ThermoCool SmartTouch SF, Biosense Webster); and (3) a multipolar mapping catheter (PentaRay NAV or OctaRay NAV, Biosense Webster). A steerable long sheath will be systematically used to improve the catheter’s contact and stability. The ablation technique is “dot-by-dot” using “power-control” mode, a temperature limited to 45 °C, and an irrigation between 8 and 20 mL/min. For each ablation dot, radiofrequency current will be delivered for 10 to 30 seconds with a power of 20 to 25 W in the CS, 30 to 50 W for the posterior wall, and 40 to 50 W for other sites. Interlesion distance will be 4 to 6 mm.
Real-time automated display of each RF application (VisiTag) will be systematic, using either (at the operator’s discretion):
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1.
Contact and stability parameters: catheter stability ≤ 2 mm for 4 seconds; the minimum force is 8 g for 60% of the shot.
OR
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2.
An indication parameter based on the integration of power, contact force, and time parameters, Ablation index with the following parameters: ablation index of 400 to 450 at the posterior wall/roof and 500 to 600 at the anterior wall.
Ablation strategy 1: PVI alone
By using the previously described ablation parameters, the goal will be to perform a wide PV disconnection at the antral level ( Figure 1 ). This ablation line will isolate ipsilateral PVs in the same circle. The end point of this step will be the demonstration of a complete entrance and exit block at each PV encirclement. If AF persists after PVI, an electrical cardioversion will restore sinus rhythm. A voltage map will be acquired at the end of the procedure in sinus rhythm.
