Renal Sympathetic Denervation: a Rapidly Evolving Field

Published date : 27 November 2012
Article date : 27 November 2012

 

Written by Dr. Sebastian Mafeld - Radiology Specialist Registrar, Freeman Hospital, Newcastle upon Tyne, UK and Dr. Gerard S Goh - Consultant Interventional Radiologist, St. George's Healthcare NHS Trust, London, UK.

 

Renal sympathetic denervation (RDN) has been a dominant theme in the endovascular community during 2012. With this excitement, the past year has seen the introduction of several new devices and the release of longer term trial data. Entering into 2013, this evolution is set to continue at an even faster pace. Given the disease burden of treatment resistant hypertension and the promising data thus far, RDN remains at the forefront of modern medicine. The future of RDN shows great potential but in an era of evidence based practice, questions regarding the technology remain. There have been several early studies examining other potential clinical benefits of RDN such as cardiac failure, sleep apnoea and insulin resistant diabetes. This article brings clinicians up to date with the latest devices, evidence and areas of controversy. 

 

Devices

 
Competition within the RDN market is rapidly expanding with a reported 60 companies currently developing devices (1). Forecasters predict this growth could mean a global market potential of $2.9Billion by 2021 (2). Only five devices currently hold a CE (Conformité Européenne) mark; Medtronic Symplicity, Covidien OneShot, St. Jude Medical EnligHTN, Vessix Vascular V2 and ReCor Medical Paradise. No device has yet received US FDA commercial approval. Radiofrequency (RF) ablation has been the dominant technology behind RSD, but innovation has led to the development of devices using ultrasound, radiation, nano particles and localised drug delivery (1). The technology behind delivery of radiofrequency ablation is evolving with the introduction of devices that improve safety, reproducibility and time efficiency. An overview of the current devices with relevant blood pressure reduction evidence is provided below:
 

Radiofrequency Ablation

 

Medtronic Symplicity

The Medtronic (Mountain View, Ca, USA) Symplicity device (formerly Ardian) remains the global leader. The Symplicity HTN-1 and HTN-2 trials currently form the largest body of evidence for RDN. Click here for the Which Medical Device overview. The 6F catheter is a single point ablation electrode connected to a RF generator. The current design requires the operator to apply multiple (4-6x) 2 minute RF applications with catheter rotation within the renal arteries to attempt to ablate the nerves evenly (3). Medtronic have recently reported a 2nd generation renal denervation system that features a simultaneously firing multi-electrode catheter and advanced RF generator (4). This will allow a single application of RF energy per artery and significant reduction in total energy delivery time (5). 
 
Evidence
 
Symplicity HTN-1 (6) with data presented at Transcatheter Cardiovascular Therapeutics (TCT) Miami 2012 (7)
ClinicalTrials.gov Identifier: NCT00664638
Baseline BP (n=153) 176/98±17/15
1 Months (n=143) -19/-9
3 Months (n=148) -21/-10
6 Months (n=144) -22/-10
12 Months (n=132) -27/-14
24 Months (n=105) -29/-14
30 Months (n=44) -34/-17
36 Months (n=34) -31/-16
Office based blood pressures, measured in mmHg
 
Symplicity HTN-2 (8) data presented at ACC 2012 (9)
ClinicalTrials.gov Identifier: NCT00888433
Baseline BP (n=52) 178.3/96.1±18.2/15.5
6 Month (n=49) -32/-12
12 Months (n=NA) -28/-9.1
Mean office based blood pressures, measured in mmHg
 
The HTN-3 (ClinicalTrials.gov Identifier: NCT01418261) trial is currently recruiting.
 

St. Jude EnlighHTN

The St. Jude Medical (Little Canada, MN, USA) EnlighHTN device uses an 8F catheter and RF generator. Click here for the Which Medical Device overview. The catheter tip is deflectable to minimise vessel trauma and contains 4 electrodes in a predetermined shape on the basket. This shape is reported to produce more consistent placement in the renal artery and reproducible ablation patterns (10). Ablation times are 90 seconds per electrode, with 8 ablation points recommended per renal artery. There are 2 catheter sizes available that can treat 4-6mm and 5.5-8mm renal arteries. Six Month data from the EnligHTN 1 study  was most recently presented at the American Heart Association (AHA) 2012 meeting in LA, USA:
 

EnligHTN 1 (11)

ClinicalTrials.gov Identifier: NCT01438229
Baseline BP (n=46) 176/96
1 Month (n=46) 148/87 
3 Months (n=46) 149/87
6 Months (n=45) 150/86
Mean office based blood pressures, measured in mmHg
 
The EnligHTN II trial (ClinicalTrials.gov Identifier:  NCT01705080) is expected to commence in the near future. 
 

Covidien OneShot

The Covidien (Dublin, Ireland) OneShot system (formerly Maya Medical) is an irrigated radiofrequency balloon catheter based denervation system. Click here for the Which Medical Device overview. The platform is an over the wire 0.014” system with 3 balloon sizes available (5, 6 and 7mm). The spiral electrode on the balloon allows a single RF energy application lasting 2 minutes per renal artery. The device also includes saline irrigation that in cardiac ablation has been shown to produce deeper and wider ablation zones, reduce the amount of char formation and to minimise damage to non-target tissue (12). Data for this device was most recently presented at the TCT 2012 meeting in Miami, FL, USA. 
 
The RHAS Trial (12)
“Feasibility study to evaluate the Maya Renal Hypertension Ablation System for chronic hypertension”
Baseline BP (n=8) 185.7/91.3 ± 18.7/14.5
30 Day (n=8) 155.6/86.2 ± 18.8/14.0
3 Months (n=7) 154.4/83.3 ± 19.6/15.8
6 Months (n=8) 143.7/76.0 ± 13.3/18.0
Mean office based blood pressures, measured in mmHg
 
The Rapid renal Sympathetic Denervation for Resistant Hypertension (RAPID I) trial is currently recruiting (ClinicalTrials.gov Identifier: NCT01520506) with expected completion in 2013. 
 

Vessix Vascular V2 System

Vessix Vascular is currently being acquired by Boston Scientific (Natick, MA, USA). The Vessix Vascular V2 System uses a variable sized balloon catheter. Click here for the Which Medical Device overview. The balloon catheter aims to occlude blood flow in the vessel to minimise RF heat loss into the bloodstream. The variable catheter size allows use in multiple vessel sizes and with potential for use in accessory renal arterial systems (13). The V2 system also includes safety features that deactivate electrodes not appropriately positioned against the vessel wall to minimise off-target RF ablation. Results from the REDUCE-HTN Pilot Study Cohort were recently presented at TCT 2012, but exact BP reduction figures are not yet publicly available, please check www.vessixvascular.com for the latest news.
 
The four CE marked RF ablation based RDN devices each demonstrate their own strengths and weaknesses. With the major body of evidence for RDN being based on RF technology, choosing a device is becoming increasingly challenging; the Medtronic Symplicity device has the strongest evidence base, however, the newer devices offer improvements in treatment time and safety. With multiple further devices set to enter the market, this competition will become increasingly complex. 
 
Ultrasound
Ultrasound (high frequency sound waves) has also been proposed as a method to ablate renal nerves. Ultrasound waves are focussed at specified depths to allow transmission of energy to a target region. Early data support ultrasound as an effective approach to RDN(14), but evidence is significantly less than that of RF ablation. 
 

ReCor Medical Paradise

The Recor Medical (Menlo Park, CA, USA) Paradise system uses a 6F catheter and ultrasound generator. This is the only ultrasound based RDN device that has CE certification. Click here for the Which Medical Device overview. The catheter balloon delivers non-focussed uniform ultrasound energy within the lumen of a renal artery with cooled fluid circulation during delivery. These features are proposed to reduce endothelial wall damage and use a shorter energy delivery cycle.(15). In vivo animal studies have shown this method of ablation to be effective in denervating sympathetic nerves (16). 
 
Recor Medical REDUCE Trial (16)
 
Baseline BP (n=15) 182/111
2 Weeks (n=15) -23/-11
1 Month  (n=15) -26/-12
2 Months (n=15) -27/-14
3 Months (n=15) -28/-13
6 Months (n=11) -32/-17
12 Months (n=3) -25/-13
Mean office based blood pressures, measured in mmHg
 
ReCor Medical are also listed under the REnAL denervation by ultrasound Transcatheter Emission (REALISE) trial (ClinicalTrials.gov Identifier:
NCT01529372) which is currently recruiting participants. 
 

Sound Interventions

Sound Interventions (Stony Brook, NY, USA) is a relatively new company that have presented a catheter delivered through a standard 8F sheath. Limited information is available regarding the specifics of their device. The company reports data using porcine carotid arteries demonstrating ultrasound nerve ablation as an effective means to ablate distant nerves while sparing intervening tissue (17). The first in man trial data was recently reported:
 
Sound-ITV Trial (18)
Baseline BP (n=10) 177.5/97.1
1 Month  (n=10) -19.2/-6.1
3 Months (n=10) -25.6/-12.5
Mean office based blood pressures, measured in mmHg
 
 

Kona Medical

The Kona Medical (Bellevue, WA, USA) SurroundSoundTM System is unique in that it offers the only potentially non-invasive method of RDN through externally focussed ultrasound. Specifics regarding the device are not yet fully released. A recent presentation suggests the company is developing two systems; one which involves catheter placement into the renal artery that serves as a marker for externally delivered ultrasound, the second is a fully non-invasive system that is currently in development. 
Kona Medical is recruiting in; A Safety Evaluation of Renal Denervation Using Focused Therapeutic Ultrasound on Patient With Refractory Hypertension (WAVE I) ClinicalTrials.gov Identifier: NCT01638195. 
 

Chemical Ablation

 
Mercator MedSystems (San Leandro, CA, USA) produce the Cricket™ and Bullfrog® Micro-Infusion Catheters. These catheters allow delivery of therapeutic agents directly and non-systemically into a blood vessel wall (19). In the 1950s chemical sympathectomy using medications such as Guanethidine was used as a treatment for hypertension, but due to systemic administration significant side effects limited their use (20,21). Given the nerve target for RDN is located in the adventitial layer, these catheters allow direct delivery of medication with less side effect potential. Mercator MedSystems have demonstrated promising denervation results in porcine kidneys using adventitial Guanethedine administration (22). Human data is needed to further verify these claims. Unlike the RF based RDN systems, the Mercator MedSystems microinfusion catheters and Guanethedine have FDA clearance. 
 
Ablative Solutions Inc. (Kalamazoo, MI, USA) has also suggested chemical ablation through perivascular micro needle delivery of ethanol as a neurolytic agent (23). Future localised drug delivery may include products like ApexNano’s mangnetic nano particles that contain neurotoxins (Botox B) that get ‘pulled’ into the artery wall by a magnetic field (1). Vincristine has also been proposed as pharmacological agent feasible method for chemical RDN (24).
 

Devices of the Future

With over 60 RDN devices in development, the future is likely to bring a host of innovative devices as well as improvements in existing technologies as second generation devices are introduced. Advances in ablation technology such as reproducible ablation patterns, reduction in catheter sizes (e.g. for radial access) and application of the technology to other body systems that could benefit from denervation seem to be common themes with newer generation devices. 

 

Areas of Controversy

 
Symplicity HTN-1 and HTN-2 Trial Design
Given the largest body of evidence for RSD is based on the Symplicity trials, these need appropriate critical appraisal before drawing definitive conclusions. The HTN-1 trial was a proof-of-principle trial with no randomisation and limited numbers at 24 month follow up (n=105). The HTN-2 trial attempted to improve the methodology using a control group, but this could have been further improved by using double blinding with a sham operation(25). The currently enrolling HTN-3 trial is a 2:1 randomisation of RDN vs sham with best medical therapy.
 
Ambulatory vs. office-based blood pressure measurement
Reported results from the RDN trials almost all focus on office-based blood pressure measurement as a primary endpoint. When comparing this to the ambulatory blood pressure measurements, there is a significant discrepancy. The ambulatory measurements are frequently much less impressive and represent a form of evaluation bias. The reasons for these measurement differences remains unclear, but future studies eg  the HTN-3 trial will need to include more data on ambulatory measurements to ensure accurate blood pressure reduction claims are presented. 
 
Renal Vessel Damage
No histological human studies have been conducted on ablated renal arteries. Current safety data is based on limited swine studies that have concluded no significant renal artery findings are seen at 6 months post ablation (26). However, the authors indicate the histological studies show when RF energy is applied, the media of the artery is affected. The HTN-2 trial reported a significant stenosis as being >60%, it is therefore unknown how many patients have new stenoses <60%. In addition there has been a single reported case of significant renal artery stenosis post RDN (27) that occurred approximately 6 months post RF RDN.
 
Non-Responders
The initial HTN-1 proof-of-principle trial demonstrated 13% (n=6) of participants showed less than 10mmHg reduction in office based blood pressure. The non-responder rate has been shown to be higher (up to 39%) when using ambulatory blood pressure measurement compared with office based (28). The reason for non-response in uncertain but may be related to device failure or inclusion of patients with secondary types of hypertension. Unfortunately current devices do not allow a way to monitor success of ablation at the time of the procedure. 
 

Conclusion

RDN continues to demonstrate successful and sustainable results in most recent studies. As the understanding of the nervous system grows, the application of RDN may have role in other pathologies including, glucose control, sleep apnoea and heart failure. The range of technologies and devices available for RDN makes device selection a potentially challenging task. Given the broad interest in this novel procedure, RDN will likely remain a hot topic for 2013.

 

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User comments: Renal Sympathetic Denervation: a Rapidly Evolving Field

 
 
References:
 
1. Sievert H. Catheter-Based Technology Alternatives for Renal Denervation [Internet]. TCT2012 TCT2012 Miami, FL, USA; 2012 [cited 2012 Nov 8]. 
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8. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010 Dec 4;376(9756):1903–9. 
9. Esler MD, Krum H, Schlaich M, Schmieder R, Bohm M, Sobotka P. RENAL SYMPATHETIC DENERVATION FOR TREATMENT OF RESISTANT HYPERTENSION: ONE YEAR RESULTS FROM THE SYMPLICITY HTN-2 RANDOMIZED CONTROLLED TRIAL. Journal of the American College of Cardiology. 2012 Mar;59(13):E1705. 
11. Papademetriou V. EnligHTNTM I, First-in-man Multi-center Study of a Novel Multi-electrode Renal Denervation Catheter in Patients with Drug-Resistant Hypertension. AHA 2012 LA, California, USA; 2012. 
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14. Mabin T, Sapoval M, Cabane V, Stemmett J, Iyer M. First experience with endovascular ultrasound renal denervation for the treatment of resistant  hypertension. EuroIntervention. 2012 May 15;8(1):57–61. 
15. ReCor Medical. ReCor Medical Technology | Technology [Internet]. 2012 [cited 2012 Nov 9]. 
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18. Reddy V. Sound Intervention [Internet]. TCT2012 Miami, FL, USA; 2012 [cited 2012 Nov 9]. 
19. MercatorMed. Mercator MedSystems?:: Micro-Infusion Catheters [Internet]. 2012 [cited 2012 Nov 10]. 
20. Freis E. Hypertension: Pathophysiology, Diagnosis and Managment. 2nd ed. New York, USA: Raven Press Ltd.; 1995. 
21. Moser M. Historical perspectives on the management of hypertension. J Clin Hypertens (Greenwich). 2006 Aug;8(8 Suppl 2):15–20; quiz 39. 
22. Seward K. Local Drug Delivery for Renal Adventitial Denervation: The Mercator Approach. Mercator MedSystems Inc.; 2012. 
23. Fischell T. PeriVascular Renal Denervation (PVRDTM) [Internet]. TCT2012 Miami, FL, USA; 2012 [cited 2012 Nov 8]. 
24. Stefanadis C. Vincristine Local Delivery for Renal Artery Denervation [Internet]. TCT2012 Miami, FL, USA; 2012 [cited 2012 Nov 8]. Available from: 2012-11-08
25. Doumas M, Douma S. Renal sympathetic denervation: the jury is still out. Lancet. 2010 Dec 4;376(9756):1878–80. 
26. Rippy MK, Zarins D, Barman NC, Wu A, Duncan KL, Zarins CK. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol. 2011 Dec;100(12):1095–101. 
27. Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure after renal denervation. Lancet. 2012 Aug 25;380(9843):778. 
 
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