Transcatheter Alcohol-Mediated Perivascular Renal Denervation With the Peregrine System: First-in-Human Experience.

OBJECTIVES: This study evaluated the first clinical use of a new endovascular approach to renal denervation, using chemical neurolysis, via periadventitial infusion of dehydrated alcohol (ethanol) to perform "perivascular" renal artery sympathetic denervation. BACKGROUND: Renal denervation remains a promising technology for the treatment of hypertension and other disorders. METHODS: A novel 3-needle delivery device (Peregrine System Infusion Catheter, Ablative Solutions, Inc., Kalamazoo, Michigan) was introduced into the renal arteries of 18 subjects with refractory hypertension. Microdoses of alcohol were infused bilaterally via the 3 needles into to the adventitial space (0.30 ml/artery, 37 arteries). Renal artery angiography was performed at the time of the procedure and at 6 months (n = 16). The primary safety endpoints were complications associated with the catheter insertion and delivery of the neurolytic agent or any major vascular access complications. The secondary performance endpoint was a reduction in office-based systolic blood pressure at 6 months compared with baseline. RESULTS: Procedural success was achieved in 100% of subjects (N = 18) and arteries (N = 37). There were no study-related adverse clinical events at follow-up. One death of a subject was recorded but determined by the investigator and an independent medical monitor to be non-study related. There were no angiographic observations of renal artery stenosis, aneurysms, or other renal artery abnormalities at 6 months (32 renal arteries). Sixteen of the 18 subjects had a 6-month follow-up. The mean office systolic blood pressure decreased from 175 ± 17 mm Hg to 151 ± 26 mm Hg (-24 mm Hg). There was an average reduction of antihypertensive medications from 3.4 (baseline) to 2.0 per subject at 6 months. CONCLUSIONS: Chemical renal denervation using the infusion of very low doses of alcohol directly into the adventitial space appears to be feasible and safe. This approach may be a promising alternative approach to perform catheter-based renal denervation. These results need to be confirmed in larger scale clinical studies.

Next generation renal denervation: chemical "perivascular" renal denervation with alcohol using a novel drug infusion catheter.

BACKGROUND/PURPOSE: We update the pre-clinical and early clinical results using a novel endovascular approach, to perform chemical renal denervation, via peri-adventitial injection of micro-doses of dehydrated alcohol (ethanol-EtOH). METHODS/MATERIALS: A novel, three-needle delivery device (Peregrine™) was used to denervate the renal arteries of adult swine (n = 17) and in a first-in-man feasibility study (n = 18). In the pre-clinical testing EtOH was infused bilaterally with one infusion per renal artery into to the perivascular space, using EtOH doses of 0.3 ml/artery (n = 8), and 0.6 ml/artery (n = 9), and with saline sham control (0.4 ml/artery n = 3). Renal parenchymal norepinephrine (NE) concentration (performed blindly), and safety were the primary endpoints. Data from the first-in-man study (n = 18) to evaluate device performance, safety and peri-procedural pain are reported. RESULTS: In the pre-clinical testing renal function was unchanged at 3-month follow-up. Angiography at 90 days (n = 34 arteries) demonstrated normal appearing renal arteries, unchanged from baseline, and without stenosis or other abnormalities. The reductions in mean renal parenchymal NE reductions at 3 months were 68% and 88% at doses of 0.3 and 0.6 ml, respectively (p < 0.001 vs. controls). In the first-in-man study, there was 100% device success, no complications, a mean treatment time of 4.3 ± 3 minutes/artery, and minimal or no patient discomfort during treatment. Angiography at 6-months showed no evidence of renal artery stenosis, and evidence of a reduction of blood pressure from baseline. CONCLUSION: Perivascular RDN using micro-doses of alcohol is a promising alternative to energy-based systems to achieve dose-dependent, predictable, safe and essentially painless renal denervation. Further clinical evaluation is warranted. SUMMARY: (For annotated table of contents) This paper describes the preclinical results, in a porcine model, and the early first-in-man results, using the Peregrine™ chemical renal denervation catheter to perform renal sympathetic denervation using micro-doses of alcohol.

Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model.

AIMS: We report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation. METHODS AND RESULTS: A novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. EtOH was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using EtOH doses 0.15 ml/artery; n=3, 0.30 ml/artery; n=3, and 0.60 ml/artery; n=3, with saline injection as a sham control (0.4 ml/artery; n=3), and naive subjects (n=7) as a true negative control. The renal parenchymal norepinephrine (NE) concentration at two-week follow-up was the primary efficacy endpoint. The mean renal NE reduction was 54%, 78% and 88% at doses of 0.15 ml, 0.30 ml and 0.60 ml, respectively (p<0.0001 vs. controls). Histological examination revealed marked, and deep, circumferential renal nerve injury at depths of 2-8 mm from the intimal surface. There was no evidence of device-related or EtOH-induced injury to the intimal layers. In some samples at the higher EtOH doses, there was focal loss of smooth muscle cells in the outer media. Angiography at 45 days demonstrated normal appearing renal arteries with no detectable stenoses (n=8). CONCLUSIONS: Circumferential adventitial delivery of very low doses of EtOH may be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation. Further study is warranted.