Renal ablation.E. Infante de Oliveira

Renal Ablation – a new approach in resistant hypertension
E. Infante de Oliveira, Serviço de Cardiologia I, Hospital de Santa Maria, CHLN, Portugal
Ablação Simpática Renal
E. Infante de Oliveira, Serviço de Cardiologia I, Hospital de Santa Maria, CHLN
E. Infante de Oliveira
V. Ramalhinho
A. Bordalo
P. Canas da Silva
F. Pinto
J. Braz Nogueira
A. Nunes Diogo
Serviço de Medicina I
Serviço de Cardiologia I
C.H.L.N.
Renal Ablation
A new approach in resistant hypertension treatment
XI Kyiv Course of coronary revascularizations
April 27th 2012

Hypertension Epidemiology
• Single largest contributor to death
worldwide
• Every 20/10 mmHg increase in BP
correlates with a doubling of 10-year
cardiovascular mortality
• Dramatically increases risk of stroke, heart
attack, heart failure, & kidney failure
• Only half of all treated hypertensives are
controlled to established BP targets
• High prevalence:
• Affects 1 in 3 adults
• 1B people worldwide  1.6 B by 2025
35%
Treated &
Controlled
30%
Untreated
35%
Treated but
Uncontrolled
Chobanian et al. Hypertension. 2003;42(6):1206–1252.

Renal Sympathetic Efferent Nerve Activity:
Kidney as Recipient of Sympathetic Signals
Renal Efferent
Nerves
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow

Hypertrophy
Arrhythmia
Oxygen Consumption
Vasoconstriction
Atherosclerosis
Insulin
Resistance
Renal Sympathetic Afferent Nerves:
Kidney as Origin of Central Sympathetic Drive
Renal Afferent
Nerves
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
Sleep
Disturbances

Smithwick RH, Thompson JE. JAMA 1953

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

Renal Denervation
Preclinical Efficacy and Safety
• Extensive research in >300 swine
• Effectiveness:
– Significant reduction in renal
tissue NE
• Safety:
– Verification testing included
angiography, gross pathology,
histopathology, & clinical
pathology at 7, 30, 60, and 180
days
– Intact endothelium by 7 days
– Vascular healing observed at 30
and 60 days; by 180 days, arteries
were well healed (no inflammatory
cells) – treatment sites were
considered sterile and stable
– No stenosis or luminal reduction
seen in any treated artery through
180 days
RenalTissueNE(pg/mg)
P<0.0001
P=1.0
Data on file. Medtronic, Inc.

• Standard interventional technique
• 4-6 two-minute treatments per artery
• Proprietary RF Generator
− Automated
− Low-power
− Built-in safety algorithms
Renal Nerve Anatomy Allows a
Catheter-Based Approach
In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use.

Catheter Tip Features
Flexible Tip
(self-orienting)
5mm 12mm
Deflectable
Shaft

14
Shaft & electrode can rotate
independent from handle body
• Handle rotator has tactile “click” every
45°
• Dot on rotator gives relative rotational
reference
Deflect tip by pulling
lever towards back of
handle
Straighten tip by pushing
lever towards front of handle

Generator
Basic Advanced
• Per the Generator User Manual, using softkeys, it is possible to toggle
between Basic and Advanced displays
• During RF ON, in addition to time and temperature, the advanced
display also displays Power and % Impedance drop
• Generally, bigger impedance drops indicate better delivery of energy
RF ON
120 s 37°C
TIME TEMP
RF ONTIME
POWER
12 s
4.5 W
TEMP
57°C
IMPEDANCE
-12 %(213 Ω)

16
Renal Angiogram
Eligible Anatomy:
• Absence of flow limiting obstructions
• Diameter ≥ 4mm in targeted area

Renal Angiogram
• Prudently limit contrast dye exposure
– 50/50 dilution of contrast and use of DSA or biplane may help
• Verify entire kidney fills with contrast
Accessory
Vessel Partially
Supplies Lower
Portions of the
Kidney
Lower Pole Not
Completely
Filling
on Selective
Injection
Unfilled kidney sections may indicate multiple main arteries

Guide Catheter Selection
Alternate: LIMATypical: RDC-1
• Once suitable anatomy is confirmed, upsize to 6Fr (or larger) introducer and guide
• Consider guide shape based on renal anatomy (LIMA for inferior takeoffs)

Areas to Avoid
Atherosclerosis
(Ostial Stenosis)
Fibromuscular Dysplasia
(FMD)
Calcification
Avoid treating
in segment with
stenosis
Avoid energy delivery
to area with visible
calcification
Avoid treating
in segment with
FMD
• There is no clinical experience treating near any areas of visible
atherosclerosis, calcification, or fibromuscular dysplasia. Avoid
treating areas of visible disease.
• There is no clinical experience treating in vessels with renal artery
aneurysms

Angiographic Appearance: Typical
Pre-Procedure
Acute Post-Procedure
1 Month Follow-Up

Angiographic Appearance: Less Common
Pre-Procedure
Acute Post-Procedure
1 Month Follow-up
* Increased vessel reactivity, such as spasm, may be
encountered when treating in areas with reduced
blood flow, such as dual renal arteries or beyond
significant renal artery branch points

• Anxiolytic and Amnesic
– Midazolam (Dormicum, Versed) or similar recommended
• Anticoagulation
– Heparin: target ACT >250 sec
–
• Pain Management
– Patients may experience transient visceral pain during each ablation
– Fentanyl or Morphine (or similar) 2-5 minutes before first ablation; as needed
thereafter
• Vasodilatation
– IA nitroglycerine through renal guide is recommended before treating each artery
Patient Management

First-in-Man (AU)
Series of Pilot
Studies
(EU, US & AU)
Symplicity HTN-2
Initial RCT
(EU & AU)
SYMPLICITY HTN-3
US Pivotal Trial (US)
Global SYMPLICITY
Registry
(Approved Regions)
Expand HTN
Indication
(Approved Regions)
Post-Market
Registry
(US)
SYMPLICITY HF
Symplicity HTN-1
Pilot Studies in
New Indications
(Approved Regions)
Trials under way
SYMPLICITY Clinical Trial Program follows over
5000 patients across multiple indications

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
Lancet. 2009;373:1275-1281
Symplicity HTN-1
*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)
Hypertension. 2011;57:911-917.

Baseline Patient Characteristics (n=153)
Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.
Demographics Age (years) 57 ± 11
Gender (% female) 39%
Race (% non-Caucasian) 5%
Co-morbidities Diabetes Mellitus II (%) 31%
CAD (%) 22%
Hyperlipidemia (%) 68%
eGFR (mL/min/1.73m2) 83 ± 20
Blood Pressure Baseline BP (mmHg) 176/98 ± 17/15
Number of anti-HTN meds (mean) 5.1 ± 1.4
Diuretic (%) 95%
Aldosterone blocker(%) 22%
ACE/ARB (%) 91%
Direct Renin Inhibitor 14%
Beta-blocker (%) 82%
Calcium channel blocker (%) 75%
Centrally acting sympatholytic (%) 33%
Vasodilator (%) 19%
Alpha-1 blocker 19%

Brief Procedure with a Low Complication rate
(n=153)
• 38 minute median procedure time
– Average of 4 ablations per artery
• No catheter or generator malfunctions
• No major complications
• Minor complications 4/153:
– 1 renal artery dissection during catheter delivery (prior
to RF energy), no sequelae
– 3 access site complications, treated without further
sequelae
26
Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Symplicity HTN-1: BP Reductions 3 years
BP change
(mmHg)
P<0.01 for ∆ from BL
for all time points

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) (n=107) (n=59) (n=24) (n=24)

Symplicity HTN-1: Response Rate Among
Non-responders at 1 Month (n=45)
58% 57%
64%
82%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1 Month 3 Months 6 Months 12 Months 24 Months 36 Months
(n=45) (n=45) (n=44) (n=39) (n=17) (n=8)
Responder was defined as an office
SBP reduction ≥ 10 mmHg

Symplicity HTN-1: Chronic Safety Out to 3
Years
• One progression of a pre-existing stenosis unrelated to
RF treatment (stented without further sequelae)
• One new moderate stenosis which was not
hemodynamically relevant and no treatment
• 3 deaths within the follow-up period; all unrelated to the
device or therapy
• No hypotensive events that required hospitalization
• There were no observed changes in mean electrolytes
or eGFR

Reduction of Renal Contribution to Central Sympathetic Drive:
MSNA in Resistant Hypertension Patient
Baseline
1 mo
12 mo
MSNA
(burst/min)
BP
(mmHg)
56  161/107
41 (-27%)  141/90 (-20/-17)
19 (-66%)  127/81 (-34/-26)
Schlaich et al. NEJM. 2009; 36(9): 932-934.
* Improvement in cardiac baroreflex sensitivity after renal denervation (7.8 11.7 msec/mmHg)
* 59 year old male on 7 HTN meds

Proof of Principle:
Related Changes in Underlying Physiology
Schlaich et al. NEJM. 2009; 36(9): 932-934.
LV Mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m2) from baseline to 12 months

Norepinephrine
Spillover
Muscle Sympathetic
Nerve Activity (MSNA)
Central Sympathetic
Nerve Activity
Renal Sympathetic
Nerve Activity
Proof of Principle

Symplicity HTN-2 Trial
Inclusion Criteria:
– Office SBP ≥ 160 mmHg (≥ 150 mmHg with
type II diabetes mellitus)
– Stable drug regimen of 3+ more anti-HTN
medications
– Age 18-85 years
Exclusion Criteria:
– 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
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.
• Treatment-resistant
HTN population
• BL OBP 178/97 mmHg
• 49 RDN, 51 Control
• Age 58 years
• 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

Assessed for Eligibility (n=190)
Excluded During Screening,
Prior to Randomisation (n=84)
 BP < 160 at Baseline Visit (after 2-weeks of
medication compliance confirmation) (n=36; 19%)
 Ineligible anatomy (n=30; 16%)
 Declined participation (n=10; 5%)
 Other exclusion criteria discovered after consent
(n=8; 4%)Randomised (n=106)
Allocated to RDN
n=52 Treated
n=49 Analysable
6-month
Primary
End-Point
Screening
Allocated to Control
n=54 Control
n=51 Analysable
12-month Post-
Randomisation
12-month post-RDN
n=47
Per protocol, 6-mo
Post-RDN (Crossover)
n=35
Not-per-protocol*, 6-
mo Post-RDN
(Crossover) n=9
* Crossed-over with ineligible BP (<160 mmHg)
Symplicity HTN-2: Patient disposition
Crossover
n=46
2 LTFU

Primary Endpoint: 6-Month Office BP
Symplicity HTN-2 Investigators. The Lancet. 2010.
∆ from
Baseline
to
6 Months
(mmHg)
33/11 mmHg
difference between RDN and Control
(p<0.0001)
• 84% of RDN patients had ≥ 10 mmHg reduction in SBP
• 10% of RDN patients had no reduction in SBP
Systolic
Diastolic
Systolic Diastolic

BP
Change
(mmHg)
Symplicity HTN-2 Investigators. The Lancet. 2010.
Home & 24 Hour Ambulatory BP
Home BP
Change
(mmHg)
24-h ABPM:
• Analysis on technically sufficient (>70% of readings) paired baseline and 6-month
• RDN (n=20): -11/-7 mmHg (SD 15/11; p=0.006 SBP change, p=0.014 for DBP change)
• Control (n=25): -3/ -1 mmHg (SD 19/12; p=0.51 for systolic, p=0.75 for diastolic)
Systolic
Diastolic
Systolic Diastolic

Symplicity HTN-2: Primary Endpoint and Latest
Follow-up
∆ from
Baseline
to
6 Months
(mmHg)
Primary Endpoint:
•84% of RDN patients had ≥10 mmHg reduction
in SBP
•10% of RDN patients had no reduction in SBP
Systolic
Diastolic
Systolic Diastolic
Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)
-28
-10
-50
-40
-30
-20
-10
0
10
RDN (n= 47)
∆ from
Baseline
to
12 Months
(mmHg)
Systolic
Diastolic
Primary Endpoint
(6M post Randomisation)
Latest Follow-up
(12M post Randomisation)
Latest Follow-up:
•Control crossover (n = 35): -24/-8 mmHg
(Analysis on patients with SBP ≥ 160 mmHg at
6 M)
p <0.01 for 
from baseline
p <0.01 for
difference
between RDN
and Control

Symplicity HTN-2: Procedural Safety
• One renal artery dissection from injection of contrast into renal artery wall
during dye angiography. The lesion was stented without further
consequences
• One hospitalization prolonged in a crossover patient due to hypotension
following the RDN procedure. IV fluids administered, anti-hypertensive
medications decreased and patient discharge without further incident
• No radiofrequency-related renal artery stenosis or aneurysm occurred in
either Randomised group
• Minor adverse events (full cohort)
– 1 femoral artery pseudoaneurysm treated with manual compression
– 1 postprocedural drop in BP resulting in a reduction in medication
– 1 urinary tract infection
– 1 prolonged hospitalisation for evaluation of paraesthesias
– 1 back pain treated with pain medications and resolved after 1 month
Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

Witkowski A. Hypertension. 2011;

Effect of renal sympathetic denervation on glucose metabolism
E. Infante de Oliveira, P. Canas da Silva, J. Silva Marques, C. Jorge, A. Magalhães, A. Bordalo, V. Ramalhinho, F. Pinto, J. Braz Nogueira, A.
Nunes Diogo
Serviço de Cardiologia I & Serviço de Medicina I, Hospital de Santa Maria, CHLN
Hospital Santa Maria
Renal Denervation Program
Baseline characteristics:
– Age 47±9 years
– Males 71%
– Diabetes Mellitus type 2 – 57%
– Average # meds 5
– Office BP 180/104 ± 27/8 mmHg
Glucose metabolism evaluation:
– Fasting glucose
– HbA1c
– Fasting Insulin
– Fasting C-peptide
– HOMA-IR
– Glucose tolerance test
HOMA – Homeostatic model assessment

Effect of renal sympathetic denervation on glucose metabolism
E. Infante de Oliveira, P. Canas da Silva, J. Silva Marques, C. Jorge, A. Magalhães, A. Bordalo, V. Ramalhinho, F. Pinto, J. Braz Nogueira, A.
Nunes Diogo
Serviço de Cardiologia I & Serviço de Medicina I, Hospital de Santa Maria, CHLN
Hospital Santa Maria
Renal Denervation Program
Baseline 1-month p-Value
Systolic BP (mmHg) 180 ± 27 161 ± 29 0.04
Diastolic BP (mmHg) 104 ± 8 95 ± 4 0.04
Fasting glucose (mg/dL) 129 ± 66 120 ± 36 NS
HbA1C (%) 7.0 ± 0.8 6.7 ± 0.9 NS
Fasting Insulin (mU/mL) 19 ± 11 18 ± 11 NS
Fasting C-peptide (ng/mL) 2.5 ± 1.3 2.2 ± 1.0 NS
HOMA-IR (%S) 2.3 ± 1.4 1.8 ± 0.9 0.04
Glucose tolerance test (mg/dL) 256 ± 142 173 ± 52 < 0.001
HOMA – Homeostatic model assessment

Hospital Santa Maria Renal Denervation Program
• 62 years old lady
• Medical history
– Severe resistant hypertension
• LVH with diastolic dysfunction
• Hypertensive retinopathy
– Obesity
– Hirsutism (minoxidil)
• Medication
• Clonidine 0.15 mg 6x/dia
• Atenolol 50 1x/dia
• Enalapril 40 mg/dia
• Nifedipine 120 mg/dia
• Hydroclorotiazide 50 mg
• Spirinolactone 100 mg

ABPM

Renal Denervation
Before RDN After RDN
Metanephrine (urine) (μg/L) 270 60
Normetanefrine (urine) (μg/L) 123 51

Renal ablation.E. Infante de Oliveira

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