APPENDIX
Alternative and future approaches to renal denervation
Currently available clinical trial data has primarily been obtained with first- and second
generation Symplicity radiofrequency catheter systems and sparked substantial interest in
this area, resulting in the initiation of a large number of clinical trials and observational
studies in (resistant) hypertension and other potential indications. A total of 45 clinical
trials investigating various approaches to achieve RDN are currently listed on
clinicaltrials.gov and summarized in Online Table 1.
Furthermore, these initial promising results have led to the rapid development of
several alternative treatment modalities to achieve renal artery denervation:
Radiofrequency ablation
Recently, a report on the use of a saline-irrigated radiofrequency ablation catheter
(Celcius Thermocool, Biosense Webster, Diamond Bar, California) for RDN was
published. The ablation catheter was placed within the renal artery to allow energy
delivery in a circumferential, longitudinally staggered manner in 10 patients with
resistant hypertension. Energy titration was performed to achieve a 10% to 20% drop in
impedance. After 6-month, the systolic/diastolic blood pressure decreased by −21/−11
mm Hg. There was no evidence of renal artery stenosis or aneurysm at repeat
angiography, and the authors reported a significant decrease in metanephrine (−12±4;
p=0.003), normetanephrine (−18±4; p=0.0008), and aldosterone levels (−60±33ng/l,
p=0.02) at 3 months (JACC: Cardiovascular Interventions2012; 5, 758-765).
The EnligHTNTM catheter system (St. Jude Medical) has a basket-like design with four
separate electrodes allowing simultaneous or sequential activation. In the first-in-human
multi-centre, non-randomized study (EnligHTN I) in 46 patients with drug-resistant
hypertension the use of this system was safe and resulted in a significant office blood
pressure reduction by -28/10, -27/10 and -26/10mmHg at 1, 3 and 6 months, respectively
.
(Eur Heart J 2013: 34:2132-40)
The OneshotTM catheter system (Maya Medical, Saratoga, California, now Covidien)
delivers a single RF treatment per artery utilizing a balloon mounted helical electrode
configuration.
The Vessix V2 RDN system (Vessix Vascular) is a percutaneous noncompliant balloon
catheter system with RF electrodes and thermistors mounted on the exterior of the
balloon. Once inserted into the renal artery, a 30-second inflation/treatment per renal
artery delivers simultaneous RF therapy with independent temperature control to all
electrode pairs. It has received European CE Mark approval and is currently being trialled
in the international multicentre REDUCE-HTN study. Conference abstracts report BP
reduction similar in magnitude to those reported in the Symplicity studies.
Ultrasound ablation
Other systems use catheters emitting ultrasound energy to achieve RDN.
The TIVUSTM catheter (CardioSonic, Tel Aviv, Israel) is a high-intensity, nonfocused
ultrasonic catheter system. By applying ultrasonic energy, the TIVUS technology enables
localized thermal modulation of the renal vessel wall tissue containing the renal nerves,
presumably without thermal damage to the endothelium and media. Swine studies have
shown that kidney tissue NE concentrations was reduced by 50% or more at 30- and 90day follow-up without local tissue damage.
The PARADISETM catheter system (ReCor Medical, Inc, Ronkonkoma, NY), is an
ultrasound catheter placed inside a low-pressure balloon, which, when inflated, allows
symmetrical distribution of ultrasound energy into the surrounding artery. Preliminary
clinical data for PARADISE were previously reported at EuroPCR 2012 with an average
systolic blood pressure reduction of 31mm Hg in 7 patients at 60-days follow-up.
The use of external ultrasound is currently investigated by Kona Medical, Campbell CA,
The system is designed to deliver ultrasound energy from an external source to the renal
nerves. The basis of the non-invasive technique is low-intensity focused ultrasound
(LIFU).
Peri-vascular pharmacologic ablation
Catheter systems for local delivery of neurotoxic drugs are also being investigated.
The Mercator BullfrogTM catheter, (Mercator MedSystems, Inc, San Leandro, CA) is
composed of a catheter tipped with a balloon-sheathed microneedle. After advancement
of the catheter into the renal artery, the balloon is inflated with saline, securing the system
for injection and sliding the microneedle through the vessel wall. Guanethidine is
delivered through the vessel wall into the adventitia. Given locally, guanethidine is
known to induce an autonomic denervation directly and through an immune-mediated
pathway. Mercator’s preclinical experiments have shown that guanethidine, injected at
appropriate concentrations into the adventitial space around renal arteries, selectively
ablates the nerves in the adventitia around the renal artery after a single, 20-minute
procedure.
Online Figure 1. Discrepant effects of antihypertensive treatment and renal
sympathetic denervation on office and ambulatory blood pressure levels. Dark gray
squares represent the effects of renal sympathetic denervation on office and ambulatory
BP levels in subjects with true resistant hypertension receiving renal denervation in five
interventional studies. Light circles represent the effects of antihypertensive treatment in
office and ambulatory BP levels in different pharmacological studies. Regression line
(dotted line) and 95% confidence intervals (dashed lines) for pharmacological studies are
presented. (with permission from Parati et al. Circulation 2013: 128:315-7)
Online Table 1. Clinical trials on renal denervation [http://clinicaltrials.gov]
Company
Study name
Device
Inclusion c
(energy)
Ardian Symplicity™
*RDN in Patients With Refractory
RF
office SBP≥ 160 m
Catheter
Hypertension
dose of appropria
drugs
Ardian Symplicity™
Catheter
Symplicity Catheter
(Medtronic ®)
*RDN in Patients With Refractory
RF
Hypertension
*Renal Denervation in Refractory
office SBP≥ 160
least 3 anti-HT
RF
Hypertension
office SBP≥ 160 m
dose of at least 3
drugs
Symplicity Catheter
(Medtronic ®)
*RDN in Patients With Uncontrolled
RF
Hypertension (Symplicity HTN-2)
office SBP ≥1
(≥150mmHg in T
least 3 anti-HT
Ardian Symplicity™
Catheter
*RDN in End Stage RENAL Disease
RF
Patients With Refractory
least 3 anti-HTN
Hypertension
Ardian Symplicity™
*Native Kidney Denervation in
Catheter
Patients With End Stage Renal
dialysis>6
RF
(Medtronic ®)
RDN in Hypertension (DENER-
ESRD on dial
uncontrolled HT w
Disease
Symplicity Catheter
office SBP≥ 160
anti-HTN
RF
HTN)
office SBP>14
DBP>90mmHg
SBP≥135 and/o
mmHg) on at leas
drugs including
Symplicity Catheter
(Medtronic ®)
Renal Sympathetic Denervation in
Mild Refractory Hypertension
RF
RF on at least 3
drugs including
(daytime SBP 140
DBP 90-94m
Symplicity Catheter
(Medtronic ®)
RDN in Patients With Resistant
RF
RH (Office SBP≥1
daytime≥135 mmH
Hypertension and Obstructive Sleep
Apnea
Symplicity Catheter
(Medtronic ®)
Symplicity Catheter
(Medtronic ®)
RDN in Diabetic Nephropathy
RF
(DERENEDIAB)
RDN in Refractory Hypertension
Persistent Prote
T2DM
RF
(PRAGUE-15)
office SBP>14
daytime SBP>130
at least 3 an
Symplicity Catheter
(Medtronic ®)
Symplicity Catheter
(Medtronic)
Renal Artery Denervation in Chronic
RF
Heart Failure Study (REACH)
Renal Sympathetic Denervation and
LVEF<4
RF
Potential Effects on Glucose
diuretic or cert
Risk-Factors (Re-Shape)
(Medtronic ®)
Symplicity Catheter
(Medtronic ®)
Renal Nerve Ablation in Chronic
office BP>140/90
least 4 anti-HTN
Metabolism and Cardiovascular
Symplicity Catheter
HF (NYHA
intoleran
RF
CKD (stag
RF
office SBP ≥1
Kidney Disease Patients
The Effect of RDN on Biological
Variables
(≥150mmHg in T
least 3 anti-HT
including a di
intolerance t
Symplicity Catheter
RDN in Patients With Chronic Heart
(Medtronic ®)
Failure & Renal Impairment Clinical
RF
HF (NYHA II
LVEF<4
Trial (SymplicityHF)
Symplicity Catheter
RDN in Patients With Uncontrolled
(Medtronic ®)
Hypertension (SYMPLICITY HTN-
RF
least 3 anti-HT
3)
Symplicity Catheter
office SBP≥160m
including a d
Global SYMPLICITY Registry
RF
HT; DM; HF; C
Study of Catheter Based RDN
RF
RH on at least 3
(Medtronic ®)
Symplicity Catheter
(Medtronic ®)
Therapy in Hypertension (DEPART)
drugs including a
an attempt to t
spironolac
Symplicity Catheter
(Medtronic ®)
The Effects of RDN on Insulin
RF
Treatment resista
daytime ≥145mmH
Sensitivity
3 anti-HTN drugs
diureti
Symplicity Catheter
(Medtronic ®)
Denervation of the REnal Artery in
Metabolic Syndrome (DREAMS)
RF
FPG ≥5.6 mmol
SBP>130 mmHg
use of anti-diabe
HTN dru
Symplicity Catheter
(Medtronic ®)
Single-arm Study of Symplicity™
RF
RDN System in Patients With
office SBP≥160m
least 3 anti-HT
Uncontrolled HyperTensioN in India
including a d
(HTN-India)
Symplicity Catheter
(Medtronic ®)
Denervation of the REnal Artery in
RF
Metabolic Syndrome (DREAMS)
FPG ≥5.6 mmol/L
use of anti-diabet
ABPM with SBP
without the use o
drugs
Symplicity Catheter
Renal Sympathectomy in Treatment
RF
daytime SBP>145
(Medtronic ®)
Resistant Essential Hypertension, a
least 3 anti-HTN
Sham Controlled Randomized Trial
diureti
(ReSET)
MDT-2211 System
(Medtronic Vascular)
RDN by MDT-2211 System in
RF
Patients With Uncontrolled
least 3 anti-HT
Hypertension (HTN-J)
Standard steerable Marinr
RF ablation Catheter (5F
RDN in Patients With Advanced
office SBP ≥160m
including a d
RF
Heart Failure
HF (NYHA I
LVEF<3
or 7F)
Vessix V2 RDN System
Treatment of Resistant Hypertension
Using a Radiofrequency
RF
office SBP≥ 160
least 3 anti-HTN
Percutaneous Transluminal
therap
Angioplasty Catheter (REDUCEHTN)
Celcius Thermacool
Catheter or Chilli II Cooled
Ablation Catheter
Impact of Renal SympAthetic
RF
RH (BP>140/90
DEnerVation on Chronic
least 3 anti-HTN
HypErtension (SAVE)
a diuretic or treatm
HTN
Biosense Webster Celcius
Thermacool catheter
Renal Sympathetic Denervation for
RF
the Management of Chronic
least 3 anti-HTN
Hypertension (RELIEF)
THERMOCOOL®
Catheter
RDN in Patients With Uncontrolled
daytime BP>140
a diuret
RF
office SBP≥ 160 m
DBP≥90 mmHg o
Hypertension in Chinese
appropriate antiTHERMOCOOL®
Renal Sympathetic Modification in
catheter
Patients With Chronic Renal Failure
THERMOCOOL®
Renal Sympathetic Modification in
catheter
THERMOCOOL®
catheter
RF
definite kidney
RF
RF
Renal Sympathetic Modification in
catheter
Patients With Metabolic Syndrome
HF (NYHA II,
LVEF<40% o
Patients With Heart Failure
THERMOCOOL®
EH (office SBP≥
and/or DBP
Patients With Essential Hypertension
Renal Sympathetic Modification in
at least three mon
RF
Metabolic Syndro
of T2D
Circumferential PVI+RDN
Combined Treatment of Resistant
(catheter not provided)
Hypertension and Atrial Fibrillation
St. Jude Medical system
Safety and Efficacy Study of Renal
RF
RH on at least 3 a
persistent or paro
RF
Artery Ablation in Resistant
office SBP ≥1
(≥150mmHg in T
Hypertension Patients (EnligHTN 1)
least 3 anti-HT
including a d
Maya Medical OneShot
Rapid Renal Sympathetic
Ablation System
Denervation for Resistant
RF
least 3 anti-HT
Hypertension (RAPID)
not provided
ReCor Medical PARADISE
Efficacy and Safety of
including a d
RF
Ultrasound
office SBP≥16
Radiofrequency RDN in Drug
or DBP ≥100 on a
Resistant Hypertension
HTN drugs includ
Renal denervatIon by ultraSound
IVUSE
Transcatheter Emission (REALISE)
Kona Medical Focused
office SBP ≥160m
A Safety Evaluation of Renal
RH as defined i
ESH-ESC gu
US
Denervation Using Focused
office SBP≥ 160
least 3 anti-HT
Therapeutic Ultrasound on Patients
With Refractory Hypertension
not provided
Adjunctive Renal Sympathetic
Denervation to Modify Hypertension
RF
office SBP≥ 160 m
DBP≥100 mmHg
as Upstream Therapy in the
anti-HTN drugs a
Treatment of Atrial Fibrillation (H-
or paroxysm
FIB)
not provided
Sympathetic Activity and Renal
RH (office BP>14
Denervation (ReD)
on at least 3 a
includi
a diuret
not provided
RDN for Management of Drug-
---
Resistant Hypertension (INSPiRED)
EH under maxim
(daytime SBP≥13
mm Hg) on at leas
drugs including
not provided (drug
Effect of RDN on NO-mediated
intervention: NG-
Sodium Excretion and Plasma Levels
monomethyl-L-arginine (L-
---
EH (daytime B
mmHg on at least
of Vasoactive Hormones (RENO)
including a d
NMMA)
not provided
DENERVATION of the renAl
---
sympathetIc nerveS in hearT Failure
HF with evidence
dysfunction, LV
With nOrmal Lv Ejection Fraction
(DIASTOLE)
not provided
Renal Artery Denervation in Chronic
Heart Failure (REACH-Pilot)
STUDY COMPLETED
RF
Congestive HF(N
RF indicates radiofrequency; RDN, renal denervation; EH; essential hypertension; RH,
resistant hypertension; OSA, obstructive sleep apnoea, T2DM, type 2 diabetes mellitus;
HF, heart failure; CKD, chronic kidney disease; CRF, chronic renal failure; AF, atrial
fibrillation; anti-HTN, anti-hypertensive; LVEF, left ventricular ejection function; FPG,
fasting plasma glucose; PVI, pulmonary vein isolation; IVUSE, intravascular ultrasound
emission;
*Indicates ongoing study, not recruiting participants
Online Figure 1.