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Renal Denervation: Fact or
Fiction.

A/Prof Michael Nguyen
Cathlab Director
Fremantle Hospital
Australia


Renal Sympathetic Activation: Afferent Nerves
Kidney as Origin of Central Sympathetic Drive

Vasoconstriction
Atherosclerosis

Insulin
Resistance

Sleep
Disturbances

Renal Afferent
Nerves

Hypertrophy
Arrhythmia
Oxygen Consumption

↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow

2


Renal sympathetic activity, assessed with renal norepinephrine spillover measurements in
patients with untreated essential hypertension, expressed in relation to age.

DiBona G F , and Esler M Am J Physiol Regul Integr Comp
Physiol 2010;298:R245-R253


Renal Nerve Anatomy
• Nerves arise from T10-L2
• The nerves arborize around the artery
and primarily lie within the adventitia
• Sympathetic Outflow > HT
Vessel
Lumen
Media

Adventitia
Renal
Nerves

4
4


Renal Nerve Anatomy Allows a
Catheter-Based Approach

Spacing of
e.g. 5 mm.

• Renal artery access via standard
interventional technique
• 4-6 two-minute treatments per artery
• Proprietary RF generator
– Automated
– Low power
– Built-in safety algorithms

5


Symplicity HTN-1

Lancet. 2009;373:1275-1281

Hypertension. 2011;57:911-917.

Initial Cohort – Reported in the Lancet, 2009:
-First-in-man, non-randomized
-Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a
diuretic; eGFR ≥ 45 mL/min)
- 12-month data
\

Expanded Cohort* – This Report (Symplicity HTN-1):
-Expanded cohort of patients (n=153)

-36-month follow-up

*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

6


Symplicity HTN-1: BP Reductions through
3 years

BP change
(mmHg)

P<0.01 for ∆ from BL
for all time points

*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)


Symplicity HTN-1: Percentage Responders
Over Time
Responder was defined as an office SBP reduction ≥ 10 mmHg

(n=143)

(n=148)

(n=144)

(n=130)

*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

(n=107)

(n=59)

(n=24)

(n=24)


Symplicity HTN-2

Lancet. 2010;376:1903-1909.

•

•
•

Purpose: To demonstrate the effectiveness of catheter-based renal
denervation for reducing blood pressure in patients with uncontrolled
hypertension in a prospective, randomized, controlled, clinical trial
Patients: 106 patients randomized 1:1 to treatment with renal denervation
vs. control
Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were
designated hypertension centers of excellence)

Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

9


Symplicity HTN-2 Trial
• Treatment-resistant
HTN population

Inclusion Criteria:
–

• BL OBP 178/97 mmHg

–

• 49 RDN, 51 Control

–

• Age 58 years

Exclusion Criteria:
–

• BMI 31 kg/m²
• 40% with Diabetes
• eGFR 77*
• Avg # meds 5.2

• RDN and Control groups

generally well-matched

*MDRD, ml/min/1.73m2
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Office SBP ≥ 160 mmHg (≥ 150 mmHg with
type II diabetes mellitus)
Stable drug regimen of 3+ more anti-HTN
medications
Age 18-85 years

–
–
–
–
–

Hemodynamically or anatomically significant
renal artery abnormalities or prior renal artery
intervention
eGFR < 45 mL/min/1.73m2 (MDRD formula)
Type 1 diabetes mellitus
Contraindication to MRI
Stenotic valvular heart disease for which
reduction of BP would be hazardous
MI, unstable angina, or CVA in the prior 6
months

EnligHTN™
Renal Renal
Denervation
System
EnligHTN™
Denervation
System




Terumo Iberis Catheter


Vessix Vascular V2
• RF electrodes and thermistors on
balloon
• 4-8 gold electrode pairs
• 30 sec inflation/ treatment per renal
artery



ReCor Medical Paradise

Non-focussed high-frequency ultrasound
Low pressure balloon with cooled fluid
Frictional heating of soft tissues
Uniform circumferential denervation

Mercator Bullfrog

• Balloon-sheathed microneedle
• Injection into adventitial tissues
• Guanethidine given locally induces
direct and immune-mediated
autonomic denervation


Kona Medical
• Low-intensity, focussed ultrasound
• Nerves are particularly sensitive to mechanical vibration and heat
• Ultrasound or MRI-guided: elastography, temperature mapping


Renal Denervation in Patients with
Uncontrolled Hypertension: Results
of the SYMPLICITY HTN 3 Trial
Deepak L. Bhatt, M.D., M.P.H., David E. Kandzari, M.D.,
William W. O’Neill, M.D., Ralph D'Agostino, Ph.D., John
M. Flack, M.D., M.P.H., Barry T. Katzen, M.D., Martin B.
Leon, M.D., Minglei Liu, Ph.D., Laura Mauri, M.D., M.Sc.,
Manuela Negoita, M.D., Sidney A. Cohen, M.D., Ph.D.,
Suzanne Oparil, M.D., Krishna Rocha-Singh, M.D.,
Raymond R. Townsend, M.D., George L. Bakris, M.D.,
for the SYMPLICITY HTN-3 Investigators


Trial Objectives

• SYMPLICITY HTN-3 is the first prospective, multi-center,
randomized, blinded, sham controlled study to evaluate
both the safety and efficacy of percutaneous renal artery
denervation in patients with severe treatment-resistant
hypertension.
• The trial included 535 patients enrolled by 88 participating
US centers.

Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014


Key Inclusion Criteria
• Age ≥18 and ≤80 years at time of randomization
• Stable medication regimen including full tolerated
doses of 3 or more antihypertensive medications of
different classes, including a diuretic (with no changes for a
minimum of 2 weeks prior to screening) and no expected

changes for at least 6 months
• Office SBP ≥160 mm Hg based on an average of 3 blood
pressure readings measured at both an initial and a
confirmatory screening visit
• Written informed consent
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014


SYMPLICITY HTN-3 Trial Design
2 weeks

2 weeks

1M

Home BP &
HTN med
confirmation

Screening Visit 1

Screening Visit 2

• Office SBP ≥160
mm Hg

• Office SBP ≥160
mm Hg

• Full doses ≥3
meds

• 24-h ABPM SBP
≥135 mm Hg

• No med changes
in past 2 weeks

• Documented med
adherence

• No planned med

changes for 6 M

3M

Home BP &
HTN med
confirmation

6M

Sham Procedure
Renal
angiogram;
Eligible
subjects
randomized
Renal
Denervation

1M 3M

Primary
endpoint

Home BP &
HTN med
confirmation

2 weeks

6M

• Patients, BP assessors, and study personnel
all blinded to treatment status
• No changes in medications for 6 M

Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

12-60 M


Patient Disposition
1441 subjects assessed for eligibility
Excluded:
• 880 not eligible for randomization
• 26 eligible but not randomized because
randomization cap was reached
535 subjects randomized
364 subjects randomly
allocated to renal
denervation

171 subjects randomly
allocated to sham
control

• 2 subjects died
• 1 subject withdrew
• 11 missed 6-month
visit

350 (96.2%) subjects with
6 month follow-up

• 1 subject died
• 1 missed 6-month visit

169 (98.8%) subjects with
6 month follow-up

Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014