Author + information
- Tim A. Fischell, MD∗ ()
- ↵∗Michigan State University, Borgess Heart Institute, 1521 Gull Road, Kalamazoo, Michigan 49048
It is our pleasure to respond to the letter published by Dr. Toutouzas and colleagues in reference to our paper describing the first-in-human experience with the Peregrine System for chemical renal denervation (RDN) (1). We appreciate their enthusiasm for the concept and acknowledge their contributions in this space using the local delivery of vincristine to perform chemical RDN (2).
As pointed out in their letter, the failure of the sham-controlled SYMPLICITY HTN-3 trial (3) left many observers with a bias that RDN has failed. We agree with Toutouzas and colleagues, and others, that there is still promise for RDN but that the flaws in the SYMPLICITY HTN-3 trial made it challenging to demonstrate a therapeutic effect. Factors that may have contributed to the failure of that trial include: 1) a lack of operator experience, with no run-in procedures to allow the physicians to learn how to use the device properly; 2) a lack of adequate denervation due to challenges in achieving adequate depth and circumferential ablation using RF energy; 3) inadequate number and spatial orientation of ablations; and 4) challenges in controlling drug compliance, as well as the addition of antihypertensive medications during the study period (4).
In an important post hoc analysis, Kandzari et al. (4) reported “dose-response” findings with radiofrequency ablation suggesting that inadequate denervation was a root cause of the trial’s failure. In this publication, one can see a substantial “dose response” in blood pressure lowering as a function of the number of ablations performed per patient (4). We believe that the SYMPLICITY HTN-3 trial was flawed and should be interpreted not as a global failure of RDN but primarily as a failure to denervate.
In the aftermath of this trial, there has been extensive analysis of the inherent strengths and limitations of the different types of technologies used to perform RDN. It is evident that a successful denervation device must provide predictable, deep, and circumferential nerve inactivation. This is being taken into consideration with current trials of radiofrequency ablation, which are targeting distal ablation in the renal arteries, ablation in the distal branch vessels, and a substantially greater number of thermal ablations than were performed in the SYMPLICITY HTN-3 study. Alternatively, chemical RDN with alcohol, as performed by the Peregrine Catheter (1), may overcome the limitations of radiofrequency-mediated RDN.
In conclusion, much has been learned since the failure of SYMPLICITY HTN-3 about the pathophysiology of RDN. Anatomic, technical, and procedural variables, as well trial execution, must be carefully considered when evaluating RDN clinical trials. We remain optimistic that the refinements in technology will demonstrate the value of RDN for the treatment of difficult to control hypertension, as well as other cardiovascular disorders.
Please note: Dr. Fischell is a cofounder of Ablative Solutions, has equity, and is a paid employee of Ablative Solutions.
- American College of Cardiology Foundation
- Fischell T.A.,
- Ebner A.,
- Gallo S.,
- et al.
- Kandzari D.E.,
- Bhatt D.L.,
- Brar S.,
- et al.