Renal Denervation + PVI vs PVI Alone for Persistent AF

Pulmonary vein isolation (PVI) is the cornerstone of ablation strategies for atrial fibrillation (AF) and is the only cardio-centric approach consistently shown to be effective for reducing arrhythmia recurrence and improving symptom status. Catheter ablation is superior to medical therapy and current antiarrhythmic drug options are limited, can have significant adverse effects, and are associated with a high arrhythmia recurrence rate, especially for persistent AF. Catheter ablation is now commonly prescribed for symptomatic AF patients who do not respond to medications and carries a class II indication. Thousands of patients undergo catheter ablation in the US each year. Nonetheless, even with technical advances, PVI has a recognized and significant rate of short- and long-term failure, and often requires multiple procedures to establish success.

The mechanisms of AF are diverse, but increased central sympathetic outflow and efferent cardiac sympathetic nerve stimulation can lead to enhanced automaticity and triggered activity, and thus contribute to the development and perpetuation of AF. Reduction in cardiac sympathetic input has been proposed as a logical adjunctive approach to PVI but its technical application via cardiac ablation (targeting autonomic ganglia) has had mixed results at best.

The therapeutic objective of lesser cardiac sympathetic stimulation can be potentially accomplished by renal artery denervation (RDN), a technique originally developed for the treatment of resistant hypertension. RDN's potential for antiarrhythmic effect may be mediated by reduced central nervous sympathetic output and is exemplified by a decrease in whole-body norepinephrine spillover and muscle-sympathetic nerve activity.

The recently completed large-scale, randomized, multicenter, single-blind clinical trial, ERADICATE-AF, demonstrated that RDN plus PVI resulted in a relative 43% reduction (absolute change, 15%; P \< 0.001) in recurrent incident AF during one year of follow-up. The trial enrolled \> 300 patients with paroxysmal AF referred for ablation, all with poorly controlled hypertension despite medication. There was no difference in complications between the 2 groups, and the procedure with RDN was only lengthened by about 24 minutes.

The trial results suggested that a strategy of reducing cardiac autonomic input is an effective antiarrhythmic approach, in line with many preclinical models. It also represents a paradigm of the potential for complementary noncardiac ablation that is effective and safe when coupled with PVI. Until now, this approach has only been tested in patients with resistant and/or poorly controlled hypertension.

A randomized controlled pilot clinical trial has been proposed: "A Trial to Evaluate Renal Artery Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation" (ERADICATE-AF II), to test the hypothesis that RDN in addition to PVI enhances long-term antiarrhythmic efficacy in comparison to PVI alone for patients with persistent AF with controlled hypertension or without hypertension in a multicenter, single-blinded, longitudinal randomized clinical trial. The trial will be advantaged by performing implantable loop recordings (ILR) in all patients, which will facilitate the calculation of AF burden, now recognized as a powerful predictor of clinical outcome. With successful completion of this pilot program, we hope to launch a large-scale trial with cardiovascular and death events as endpoints.

The primary aim of the study:

To determine if patients with persistent AF with controlled hypertension or without hypertension who are referred for catheter ablation (PVI) and undergo adjunctive RDN have reduced AF burden at 12 months in comparison to patients who undergo only PVI

The following secondary aims will be tested:

In patients with persistent AF with controlled hypertension or without hypertension who are referred for catheter ablation (PVI) and undergo adjunctive RDN relative to patients who undergo only PVI:

1. To assess safety, blood pressure and autonomic nervous system outcomes

1. Procedural complications rates 2. Postural blood pressure changes over time 3. Ambulatory blood pressure monitor results 4. Cardiac sympathetic nervous system modulation 2. To evaluate clinical end points

1. Frequency of progression to recurrent persistent AF 2. Referral for repeat catheter ablation of AF 3. Need for cardiovascular emergency room visits and hospitalizations 3. To measure effects on quality of life

• Procedural complications, radiation exposure, and duration [Time frame: 30 days and 12 months]
• BP changes over time [Time frame: At 0, 1, 3, 6 and 12 months]
• BP changes over time [Time frame: 6 months vs baseline]
• Cardiac sympathetic nervous system modulation [Time frame: At 0, 1, 3, 6 and 12 months]
• Cardiac sympathetic nervous system modulation [Time frame: At 0, 1, 3, 6 and 12 months]
• Quality of life in response to ablation [Time frame: 6 months vs baseline]
• Quality of life in response to ablation [Time frame: 6 months vs baseline]
• Number of subject with recurrent atrial fibrillation [Time frame: From date of randomized procedure to 12 months]
• Number of subjects with CV hospitalization and/or ER visits [Time frame: From date of randomized procedure to 12 months]
• Total mortality rate [Time frame: From date of randomized procedure to 12 months]