What is radiofrequency ablation/what is renal denervation?
Radiofrequency (RF) ablation is a common medical treatment that uses heat generated from high frequency energy to ablate dysfunctional tissue. Renal denervation (RDN) is a catheter based procedure to disrupt the nerves traveling in the adventitia of the renal arteries in patients diagnosed with resistant hypertension. By ablating the efferent nerves the vicious cycle of sympathetic stimulation is hindered by interrupting the cross-talk between the kidney and the brain.
In multiple clinical trials RF RDN has shown significant office BP reduction at 36 months with minor procedural related complications and without any major side effect to kidney function. While tremendous success is seen in reduction of office blood pressure, the skepticism prevails about the ambulatory blood pressure reduction and nonresponders (Patients without improvements of >10 mm Hg in SBP). For more on outcome trials, please visit Research/Science.
Endovascular Renal Denervation Devices
The RDN device is a catheter (plastic tube with wire coils or balloon catheter) with an electrode that can measure-impedance and temperature as well as deliver energy (high frequency current). The automatic generator delivers energy via an algorithm that monitors and adjusts power outputs based on these impedance and temperature measurements.
The RF RDN catheter can be a single electrode or an multi-electrode. The electrode can be an irrigation catheter or non-irrigation catheter, over the wire or non- over the wire catheter. Each of these characteristics has its benefits and shortcomings.
One of the concern of using RF energy is trauma to the renal artery intima while targeting the adventitial nerves. Optical Coherence Tomography (OCT) studies have shown heat injury at the intima can lead to thrombus formation, charring and edema with unknown clinical significance. Till date in clinical trials, non-irrigated RF RDN technology has not raised concern of increased renal artery stenosis or decline in renal function. Irrigated RDN systems have an active cooling fluid flowing within the electrode tip, preventing access heating of the renal artery intima. Animal studies have shown that the irrigated system can reduce thrombus formations, charring, and edema and offer deeper penetration into the tissues.1 The cooling fluid can flow via a closed or an open loop.
- Closed loop: Liquid circulates within the tip
- Open loop:Liquid discharges via holes or pores, similar to a showerhead.
Following are the RF RDN devices currently being investigated around the world at different level of investigation.
|RF Catheters||Multi/Single electrode||Design||Catheter requirement||Irrigated?||Ablation Time/artery||CE Mark Approval||FDA Approved Clinical Trial|
|Medtronic SymplicityTM||Single||Catheter electrode||6F||Nonirrigated||20mins||2010||June 2012|
|Symplicity SpyralTM||Multielectrode||RX* catheter||6F||Nonirrigated||1-2mins||n/a||n/a|
|St. Jude EnligHTN||Multielectrode||Basket||8F||Nonirrigated||6-12mins||February 2012||July 2013|
|Covidien OneShot||Multielectrode effect||OTW*Balloon||7F||Irrigated||2mins||February 2012|
|Boston Scientific VessixTM Renal Denervation System||Multi-electrode||OTQ*Balloon||8F Guide Sheath||Non-Irrigated||30sec-1min||May 2012||n/a|
SymplicityTM RDN System
Pioneering the RDN technique, SymplicityTM consists of a single electrode catheter and a generator. The generator automatically controls RF energy delivery and maintains it at 5-8 W. The generator automatically shuts off after 2 mins or when either impedance or temperature exceed programmed limits. The SymplicityTM catheter is 6F compatible and requires no balloon or wire. The catheter has a self-orienting flexible tip and deflectable shaft. The Symplicity catheter system has received CE (Conformite Europeene) Mark approval in 2010 for resistant hypertension patients.
Symplicity Safety Clinical Trials Enrollment Complete/In Follow-up
Symplicity HTN-1: First in Man Trial The SymplicityTM HTN-1 first-in-man trial was a non-randomized trial for proof of concept on 45 patients with resistant hypertension, which was expanded to a 153 patients. The median duration of the procedure was 38 minutes with an average of 4 ablations per artery. Six months after the RDN procedure, the mean systolic blood pressure reductions of 25mm Hg and mean diastolic pressure reduction of 11mm Hg was seen in 86 patients.4 The adverse events included: one patient suffered renal artery dissection due to manipulation of the guiding catheter and 3 patients suffered from femoral access related complications.2 The 36 months follow-up data were presented at ESC 2013. The BP reduction was persistent up to 36 months with a mean reduction of 32/14 mm in SBP/DBP respectively. The BP reduction was equal when further analyzed for age, diabetes or eGFR. Symplicity HTN-2: Safety Study Symplicity HTN-2 is a randomized controlled clinical trial conducted in 24 centers in Europe, Australia, and New Zealand. The trial consisted of 106 patients with resistant hypertension randomized 1:1 for treatment with renal denervation vs control. The primary endpoint was the change in office blood pressure from baseline at 6 months.5 After 6 months the office blood pressure was reduced by a mean of -32/-12mm Hg for those that had the RDN procedure. Furthermore, 41 of the 49 patients that underwent denervation had a decrease in systolic blood pressure of 10mm Hg or more at 6 months compared with baseline values, with 19 having reduction in systolic pressure to less than 140 mm Hg. There were 5 patients that did not respond to the denervation therapy and showed no change in systolic blood pressure at 6 months.3 At the end of 6 months follow-up the controlled group (medical therapy arm) patients were crossed-over to treatment with RDN. The patients in control group had means reduction of -24/-8 mm Hg after 6 months follow-up.
Symplicity-HTN 2 data at three year follow-up on 40 patients still showed an average blood pressure reduction of -33/-14 mm Hg. Which may suggest that clinically significant regeneration of sympathetic nerves at the end of 3 years is not a concern. Renal function remained unchanged at the end of 36 months. Symplicity HTN-3 Safety and Efficacy USA Study In the USA, Medtronics recently completed enrollment for a pivotal phase 3 trial with hopes of FDA approval by 2014. Symplicity HTN-3 trial enrolled about 530 patients. Patients were prospectively randomized 2:1 with RDN treatment vs a “sham” procedure in the controlled group. Anticipation is that the 6 months outcome result would be presented at the ACC 2014 conference.
Symplicity Clinical Trials in Planning/Enrolling
Global Symplicity Registry The registry began in Germany and is now conducted in a 149 sites worldwide to evaluate the long-term safety and efficacy of Symplicity renal denervation in “real world” patient population with hypertension and/or other diseases characterized by elevated sympathetic drive. As of June 26, 2013 the study has enrolled 1097 patients within 3 subgroups:
- 86% of them with systolic blood pressure above 140mmHg
- 62% of patients with systolic blood pressure above 160 mmHg and treated according to the ESC guidelines
- 13% of the patient population had blood pressure readings above 180/100 mmHg.
299 patients evaluated at 6 months follow-up demonstrated an average of -19/-8mmHg blood pressure reduction regardless of the renal artery anatomy. However significant blood pressure reductions were seen with higher blood pressure readings. The only predictor of responsiveness to the RDN is severity of hypertension at the base line. Symplicity HTN-4 In the USA and Europe, Medtronics has also started enrollment for Symplicity HTN-4 the first randomized trial for to investigate renal denervation in less severe high blood pressure patients. The study will enroll 580 patients with systolic blood pressure ranging from 140-160 mmHg. Similar Symplicity HTN-3, the study will be blinded and include a sham control.
OneShotTM Renal Denervation System
The Covidien OneShotTM irrigated system is an over the wire balloon catheter with a surrounding electrode. With 8 evenly-spaced irrigation holes around the balloon on either sides of the electrode, the OneShotTM provides a cooling system for the nontreated regions of the artery preventing sticking of the electrode to the tissue. A 7Fr/8FR guide catheter is used to cannulate the renal artery with compatibility with a 0.014″ guide wire (standard angioplasty guide wire). A 20 mm long balloon catheter is advanced in to the renal artery. The helical electrode on the surface delivers RF energy in a circumferential manner to the renal arterial wall requiring only a single treatment per artery with 2 minutes treatment for each artery and claims to reduce pain associated with the RDN procedure. Radiofrequency energy is applied in a constant power mode for a pre-set duration. The balloon irrigation pump is integrated with the RF generator and has touch screen interface. The RF energy is shut off if impedance/temperature is out of range, if balloon looses the pressure or if the ground pad is disconnected.OneShotTM received CE Mark approval in February 2012 based on efficacy data from the RHAS clinical trial. The RAPID trial enrolled 50 resistant hypertension patients with the primary endpoints of acute and chronic procedural safety and clinical effectiveness of office systolic blood pressure reduction. At 6 month follow-up the average office blood pressure reduction was -20/-8 mmHg with ambulatory blood pressure reductions averaging -11/-6 mmHg. There were no deaths, stroke, MI, or other serious events reported. Two device related complications included bradycardia and flank pain, both of which were resolved. One patient also reported inflammation at access site due to closure device. The closure device was removed and the patient was treated with antibiotics.
The St. Jude EnligHTNTM has an unique multielectrode basket design that allows ablation of 4 precise sites, reducing the number of catheter manipulations, fluoroscopy time, and contrast usage. The first generation catheter generator activates each electrode sequentially for 90 seconds for a total treatment time of 360 seconds per basket activation and received CE Mark approval as of May 2012. The first-in-human EnligHTN (generation I) trial was a single arm trial of 46 patients to establish the initial safety and efficacy of the EnligHTN System. The study showed that EnligHTN is safe and has rapid treatment effect, with office BP reduced by 28/10mmHg at 1 month.
The second generation EnligHTN received CE Mark approval on September 3, 2013. The catheter performs simultaneous ablations with an intuitive touch screen generator, which potentially enables a faster procedure and reduces the total ablation time from 24 minutes to 4 minutes.4 EnligHTN III trial enrolled 39 patients with resistant hypertension to study the safety and efficacy of the new second-generation EnligHTN™ Renal Denervation System. At 3 month follow-up there was an average office blood pressure reduction of -26/9 mmHg with no device or procedure related events. The average total ablation time was 4.3 minutes.
In June 2013 St. Jude announced US Food and Drug Administration (FDA) approval to begin the EnligHTN IV Renal Denervation Study, the first US trial using EnligHTN to treat patients with drug-resistant high blood pressure. The study has been put on hold, St. Jude is working with FDA to develop a new protocol.
VessixTM Renal Denervation System
Boston Scientific’s VessixTM Renal Denervation System is a balloon catheter technology with a helical pattern of bipolar gold radiofrequency electrodes, which are good for thermal and electrical conductivity. Bipolar energy delivered is less than 1 Watt and the temperature controlled algorithm ensures energy delivery at 68oC. Once inserted into the renal artery, procedure time is 30 second inflation/treatment per renal artery delivering simultaneous RF therapy to all eight electrode pairs. The VessixTM catheter is available in various sizes and can accommodate renal artery diameters as small as 3.0mm and requires a 8Fr. guide sheath. VessixTM received CE Mark approval on May 2, 2012.The Reduce-HTN clinical series trials are studies evaluating the Vessix system technology in resistant hypertension. The Reduce HTN first in man was a multicenter non-randomized feasibility study in 18 resistant hypertension patients. Reduce HTN post market study is a multicenter non-randomized post market surveillance on 128 patients with resistant hypertension. Data combined from the first in man trial and the post marketing study showed an average office blood pressure reduction of -25.2/-10.2 mmHg at 6 month follow-up on 107 patients. There were 5 procedural related serious adverse event including 1 device related event.
Resistant hypertension related Reduce-HTN trials to begin enrollment in Q4 of 2013 include:
- Global Pivotal Study: A multi-center: inclusive of USA, single blinded non-randomized, controlled study enrolling 550 patients with resistant hypertension
- Regional Regulatory Approval: A multicenter, non-radomized prospective single cohort
- European Post Market Trial: A multi-center, non-randomized post market study enrolling 500 resistant hypertension patients.
The Relieve Clinical Series are pre-clinical and clinical investigation evaluating the Vessix Renal Denervation System in additional disease states:
- RELIEVE: End Stage Renal Disease
- RELIEVE: Heart Failure
- RELIEVE: Atrial Fibrillation
- RELIEVE: Diabetes
Cordis Multi-electrode Irrigation ThermoCool Renal Sympathetic Denervation System
- Nakagawa H, et al. Comparison of in vivo tissue temperature profile and lesion geometry for radiofrequency ablation with a saline-irrigated electrode versus temperature control in a canine thigh muscle preparation. Circulation. 1995;91:2264-2273.
- Thomas G, Shishehbor M, Bravo E, et al. Renal denervation to treat resistant hypertension: guarded optimism. Cleveland Clinic Journal of Medicine. 2012;79: 501-510.
- Symplicity HTN-2 Investigators, 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;376:1903-1909.
- Papademetriou V. EnligHTN I: Safety and efficacy of a novel multi-electrode renal denervation catheter in patients with resistant hypertension: a first-in-human multicenter study. Presented at AHA 2012 Congress, Los Angeles, USA, November 3-7, 2012.