Vein of Marshall Ethanol Infusion for Persistent Atrial Fibrillation
Condition: Ventricular Tachycardia; Atrial Fibrillation
MeSH terms: Atrial Fibrillation; Tachycardia; Tachycardia, Ventricular
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The broad, long-term objective of this project is to evaluate the therapeutic value of vein
      of Marshall (VOM) ethanol infusion when added to catheter ablation of atrial fibrillation
      (AF). AF is the most common sustained arrhythmia in adults, and it is a leading cause of
      stroke, disability and increased mortality. Catheter ablation - pulmonary vein (PV) antral
      isolation (PVAI)- can lead to cure, but is best suited for paroxysmal AF, in which ectopic
      beats arising from the pulmonary veins were shown to initiate AF. PVAI success is lower in
      persistent AF, in which the role of the cardiac autonomic system, particularly the intrinsic
      cardiac ganglia, is being increasingly recognized. Expanding the ablation lesions to include
      greater areas the left atrial (LA) anatomy marginally improves outcomes, but also leads to
      increases in procedural complexity and duration, need of repeat procedures, and complications
      such as atrial flutters, particularly perimitral flutter (PMF). The investigators have
      developed a technique to perform rapid ablation of atrial tissues in AF using ethanol
      infusion in the vein of Marshall (VOM), and have shown: 1) Effective, rapid and safe tissue
      ablation of LA tissue neighboring the LA ridge and left inferior PV; 2) Regional LA vagal
      denervation by reaching the intrinsic cardiac ganglia; and 3) Facilitation of cure of PMF by
      ablating most of the mitral isthmus.

      The investigators propose to evaluate outcomes differences yielded by VOM ethanol when added
      to conventional PVAI. The specific aims are: #1.To assesses the impact of VOM ethanol
      infusion in procedure success when added to de novo catheter ablation of persistent AF. The
      investigators will randomize patients with persistent AF undergoing a first AF ablation to
      standard PVAI vs. a combined VOM ethanol infusion plus PVAI (VOM-PV) #2. To assess the impact
      of VOM ethanol infusion added to repeat catheter ablation of recurrent AF after a failed
      ablation. Patients undergoing a repeat procedure for persistent AF after a failed PVAI will
      be randomized to either PVAI or VOM-PV as their repeat procedure. End points will include
      freedom from symptomatic or electrocardiographic AF after 12-15 months.
    

Detailed description: 
      Although the risk of stroke is comparable in persistent and paroxysmal AF, the prevalence of
      persistent AF increases dramatically with increasing age, and thus is an overall more
      significant cause of morbidity and mortality. In the United States, there are currently an
      estimated 3.0 million adults with AF, and this number is expected to double in the next 25
      years. Hospitalizations with a primary diagnosis of AF are close to half a million per year,
      which generates a tremendous economic burden on the health care system. When compared to
      health care costs of non-AF control subjects, patients with AF have greater annual healthcare
      costs (up to $8705 total annual incremental cost). On the basis of current prevalence data,
      it is estimated that AF leads to a national incremental health care cost of up to $26
      billion. Inadequacy of pharmacological treatment options for persistent AF Management
      strategies are directed at heart rate control and stroke prevention -mere palliation- or at
      rhythm control. It has been shown that rhythm control strategies using antiarrhythmic drugs
      offer no benefit in elderly patients or patients with heart failure. Most of the lack of
      benefit of such rhythm control strategy is thought to be due to the adverse effects and
      suboptimal efficacy of antiarrhythmic drugs that can potentially augment mortality. Indeed,
      preservation of normal sinus rhythm is associated with decreased mortality. Dronedarone, the
      only antiarrhythmic drug shown to improve outcomes in nonpermanent AF compared to placebo,
      has been shown to double mortality, stroke and hospitalization for heart failure in the
      PALLAS study in patients with permanent. Thus, antiarrhythmic drugs remain suboptimal at best
      for the treatment of AF.

      Shortcomings of catheter ablation of persistent AF Weak mechanistic rationale: Isolation of
      the pulmonary vein (PVs2) and adjacent LA (PV antrum) is the accepted procedural endpoint,
      based on the mechanistic concept that atrial extrasystoles arising from the PVs initiate
      paroxysmal AF. Other, non-PV triggers have been demonstrated.36 The link between PV extra
      systoles and AF is clear in paroxysmal AF, but not in persistent AF, in which the mechanisms
      of AF seem to be related more to a chronic atrial substrate than to acute triggers.4 Indeed,
      intramural reentry in the posterior LA seems to be particularly relevant in chronic models of
      AF. In persistent AF, the procedure has evolved, rather simplistically, to include additional
      lesions -besides isolation of the PVs, variably placed in the posterior wall, LA roof, and
      towards the mitral annulus, the superior vena cava,44 left atrial appendage, and other areas
      where complex fractionated atrial electrograms (CFAE) may be mapped. This brute force
      approach of simply destroying more tissue has yielded additional success, but new procedural
      targets with solid mechanistic bases are needed.

      Suboptimal success and need for repeat procedures. Despite the additional tissue destruction,
      ablation success in persistent AF is with much lower than in paroxysmal AF, with single
      procedure success reported as low as 27%, 36%, or 49%, but up to 61% or 67%, depending on
      study heterogeneities in: definitions of persistent AF and of recurrence of AF, the type of
      AF monitoring, and ablation technique and operator experience. In order to achieve overall
      acceptable success rates, (which can reach up to 79%-94%), there is a consistent need for
      repeat procedures (sometimes up to 4) and the concomitant use of antiarrhythmic drugs. The
      rate of repeat procedures in experienced centers can reach up to 70 to 80%.PMF after catheter
      ablation of persistent AF. Clinical failures of a first ablation procedure are caused, in a
      significant portion of patients, by atrial flutters, rather than recurrent AF, and recurrence
      as flutter portends a greater chance of success in a second procedure. Such atrial flutters
      may be caused by perimitral reentry in up to 33-60% of the patients. Catheter ablation of PMF
      involves the creation of a linear lesion from the mitral annulus to the left inferior PV (the
      so-called mitral isthmus).Achieving a complete ablation (defined by bidirectional conduction
      block across the ablation line) can be very difficult, with success rates reported as 32%,
      64%, or 71%. It sometimes requires ablation inside the coronary sinus (CS), in close
      proximity to the circumflex coronary artery, which could be damaged of note, incomplete
      ablation of the mitral isthmus is proarrhythmogenic, increasing the risk of recurrent flutter
      by up to 4 times.
    

Intervention name(s): Ethanol; Ablation
Intervention type(s): Drug; Procedure
Intervention description(s): We enter the CS with a sheath advanced from the right internal jugular vein. A sub-selector catheter with a ~90° angle at the tip (typically, a left internal mammary artery angioplasty guide catheter) is advanced through the CS sheath with its tip pointing superiorly and posteriorly.; The doctor will perform only the standard procedure. Throughout the procedure, the researchers will document the following information for ALL patients: measurements such as whether the treatment was successful or unsuccessful, X-ray exposure time, procedure time, whether there were any complications, and other general procedural measurements.
Other intervention name(s): Alcohol; standard catheter ablation procedure,
Intervention MeSH terms: Ethanol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment