Promise of predictable renal denervation with dehydrated ethanol

Tim Fischell
Tim Fischell

Interventional News spoke to Tim A Fischell, professor of Medicine, Michigan State University, USA, about the first use of a novel, endovascular approach using chemical neurolysis via periadventitial injection of dehydrated ethanol to perform renal artery denervation. Catheter-based renal denervation is a novel treatment option for patients with resistant arterial hypertension

Fischell told Interventional News, “This is the first definitive publication demonstrating both the safety and the dose-dependent efficacy of ethanol delivered locally to the adventitia and periadventitial space to create predictable, and titratable renal sympathetic denervation (in a porcine model).

“This type of dose-dependent response to escalating (low) doses (of ethanol), has not been demonstrated with energy-based catheters used for renal denervation, such as radiofrequency and ultrasound systems. Furthermore, the magnitude of the denervation, using very low volumes of ethanol, appears equivalent to surgical denervation, and superior to limited (pre-clinical) data presented to date with energy-based renal denervation. The simplicity of delivering a single circumferential and deep dose of ethanol over 30 seconds, rather than burning the artery from the intima outward may have substantial advantages. With deep ‘perivascular’ chemical denervation, there is likely more effective sympathetic nerve kill, without thermal injury to the intima and media. This may reduce or eliminate the risk of intimal thrombus embolising into the kidney, and also reduce the risk of late renal artery stenosis.”

He previously reported on the results of the animal study at EuroPCR in 2013 (21–24 May, Paris, France) and suggested that circumferential adventitial delivery of very low doses of ethanol could be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation.

In Fischell et al’s study, a novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. Ethanol was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using 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 concentration at two-week follow-up was the primary efficacy endpoint. The mean renal norepinephrine reduction was 54%, 78% and 88% at doses of 0.15ml, 0.30ml and 0.60ml, respectively (p<0.0001 vs. controls). 

Fischell said at EuroPCR that histological examination had revealed marked, and deep, circumferential renal nerve injury at depths of 2–8mm from the intimal surface. There was no evidence of device-related or ethanol-induced injury to the intimal layers. In some samples, at the higher 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).

“The key message about the use of a three-micro-needle system (Peregrine catheter) to inject dehydrated ethanol, is that it is very safe, with minimal injury to normal renal arterial wall structures. It also appears to be very effective, with predictable dose-response to low doses of ethanol, as measured by renal parenchymal drops in norepinephrine. In addition, there is no cumbersome or expensive electronic (radiofrequency or ultrasound) ‘box’ required. We believe this will make this approach to renal denervation, quicker, safer, more efficient, predictable, cheaper and more efficacious than even the ‘second generation’ ‘burning’ energy-based approaches,” Fischell explained to Interventional News.

Further study is warranted

Speaking on the limitations of the study, Fischell noted that these data were collected from a porcine model, and used renal parenchymal norepinephrine drop (vs. control animals) as the surrogate endpoint.

Although the per cent nerve kill and norepinephrine drop seen with ethanol should correlate with blood pressure lowering efficacy in patients, this needs to be confirmed in the upcoming clinical trials.

Marc Sapoval, professor of Clinical Radiology and chair of the Cardiovascular Radiology department at Hôpital Européen Georges-Pompidou in Paris, France, told Interventional News, “Renal denervation is a very promising technique but it is still in its infancy. No catheter today gives any information on the actual denervation that the intervention produced. In other words, the currently available devices deliver, in the best case scenario, indirect information, based on impedance drop, temperature rise or other ablation-related parameters. Therefore it is very difficult for the interventionalist to be certain that the intervention was successful and that it actually interrupted the sympathetic flow in the afferent and/or efferent sympathetic nerves.

“On the other hand, clinical success is based on the measure of office or ambulatory blood pressure, data that needs careful methods to be appropriately recorded. In addition, one major point in the control of the blood pressure of any patient is their actual drug intake. Compliant patients (those who do take their drugs) and non-compliant ones are not separated by a clear divison. They represent a continuum that any physician finds difficult to evaluate in routine clinical practice.Therefore clarity about which patient is a “responder” and which one is not, is a very complex task. All interventionalists performing renal denervation find that clinical success can be very difficult to foresee. Some patients will have excellent blood pressure response, despite results that have some technical limitations. In contrast, some patients in whom the procedure was performed with the best technical result possible, sometimes do not ultimately respond to the intervention.”

Targeting the afferent nerves

Another preclinical study from Richard R Heuser, also published in EuroIntervention and presented at EuroPCR, introduced a new non-vascular system to treat resistant hypertension. The study noted that there are a host of intra-arterial devices that use the proximity of the renal nerves to the renal arteries, utilising a renal artery approach to the denervation procedure. Heuser reported that in contrast to the widespread distribution of the efferent sympathetic nerve fibres in the kidney, the majority of afferent renal sensory nerves are located in the renal pelvis. The abstract stated that the device from Verve Medical utilises a monopolar electrode catheter to deliver radiofrequency energy and is placed transurethrally into the renal pelvis in order to target these.

Identifying responders to renal denervation

A small study from Tübingen, Germany, has found that cardiac baroreflex sensitivity is a predictor of response to renal sympathetic denervation as impaired sensitivity identifies patients with resistant hypertension who respond to the procedure.
It was published online ahead of print in the Journal of American College of Cardiology in August 2013.

The baroreflex has been recognised as a key part of cardiovascular regulation and alterations in the baroreceptor-heart rate reflex (baroreflex sensitivity [BRS]) have been linked to playing a key role in the development and progression of many cardiovascular disorders.

Christine S Zuern and colleagues treated 50 patients with a mean systolic blood pressure of 157±22mmHg as calculated by ambulatory blood pressure monitoring with renal denervation. The patients had these blood pressure readings despite being on medication with several antihypertensive drugs. Prior to renal denervation being performed the investigators assessed patients for cardiac baroreflex sensitivity by phase-rectified signal averaging. The team also defined response to renal denervation as reduction of mean systolic blood pressure on ambulatory blood pressure monitoring by 10mmHg or more at six months post procedure.

The researchers noted that six months after renal denervation, mean systolic blood pressure was significantly reduced from 157±22mmHg to 149±20mmHg (p=0.003). Just over half (26) of the 50 patients (52%) were classified as responders. They also observed that the phase-rectified signal averaging values were significantly lower in responders than non-responders (0.16±0.75ms/mmHg vs. 1.54±1.73ms/mmHg; p<0.001). “On multivariable logistic regression analysis, impaired cardiac baroreflex sensitivity was the strongest predictor of response to renal denervation that was independent from all other variables tested.”

Jon G Moss, consultant interventional radiologist, Gartnavel General Hospital, Glasgow, UK, told Interventional News: “Renal denervation holds great hope for the large number of patient across the world with ‘resistant hypertension’. However, it is an invasive and probably irreversible procedure whose long-term effects are poorly understood. It should therefore still be used cautiously, until we have more information. As the procedure has become more widespread, one hears all too often from centres that ‘we have been unable to match the results of the trials’ and estimates for non-responders can be as high as 50%. The reasons for this are unclear but possibilities include poor selection and incomplete denervation. Any test or predictive model to improve response rates would be an important step forward.”

Blood pressure reductions with OneShot renal denervation device sustained at 12 months

John A Ormiston (Mercy Angiography, New Market, New Zealand) and others reported the 12-month results of the Renal Hypertension Ablation System (RHAS) trial in EuroIntervention, which showed that reduction in office blood pressure with the OneShot renal denervation device (Covidien) were sustained at 12 months. The study was also presented as an abstract at EuroPCR (21–24 May, Paris, France).

Ormiston et al reported that unlike the first-generation renal denervation devices, which use radiofrequency energy to ablate the sympathetic nerves in the renal artery adventitia in a distal-to-proximal, point-by-point pattern, the OneShot device is designed to achieve renal denervation “using a single two-minute ablation to each renal artery.” They added that the Renal Hypertension Ablation System (RHAS) study was a first-in-man, hypothesis-generating study that aimed to provide safety and feasibility data for the device. The primary endpoint was the ability to insert the OneShot balloon into each renal artery and to deliver low-level radiofrequency energy.

The authors commented, as have been previously reported, that the primary endpoint was achieved in eight of the nine patients in the study (89%). Mean systolic office blood pressure was significantly reduced from 185.67±18.7mmHg at baseline to 155.58±58±18.84mmHg at one month (p=0.0004), to 151.46±19.93mmHg at three months (p=0.002), and to 152.08±22.27mmHg at six months (p=0.021). Ormiston et al said that at 12 months, mean systolic office blood pressure was significantly reduced to 155.89±27.27mmHg (p=0.019).