Renal Denervation: Suku Thambar

Suku Thambar
For distribution only in markets where the Symplicity renal denervation system is approved. Not for distribution in the USA or Japan.
Trademarks may be registered and are the property of their respective owners. 2012 Medtronic, Inc. All rights reserved. UC201205567EE
Renal Denervation
c
Single largest contributor to death

worldwide
30%
Untreated
35%
Treated but
Uncontrolled
35%
Treated &
Controlled
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 c
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
Chobanian et al. Hypertension. 2003;42(6):12061252.
Hypertension Epidemiology
Kidney as Recipient of Sympathetic Signals
Renal Efferent
Nerves
Renin Release RAAS activation

Sodium Retention
Renal Blood Flow
Renal Sympathetic Activation: Efferent 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
Renal Sympathetic Activation: Afferent Nerves
Nerves arise from T10-L2

The nerves arborize around the
artery and primarily lie within
the adventitia
Vessel
Lumen
Med
ia
Adventi
tia
Renal
Nerve
s
Renal Nerve Anatomy
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
Renal Nerve Anatomy Allows a

Catheter-Based Approach
First-in-Man
(AU)
Series of Pilot
Studies
(EU, US & AU)
Symplicity HTN-1
Symplicity HTN2
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)
Pilot Studies in
New Indications
(Approved
Regions)
SYMPLICITY HF
Trials under way
SYMPLICITY Clinical Trial Program follows over

5000 patients across multiple indications
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.)
Symplicity HTN-1
Demographics
Co-morbidities
Blood Pressure
Age (years)
57 11
Gender (% female)
39%
Race (% non-Caucasian)
5%
Diabetes Mellitus II (%)
31%
CAD (%)
22%
Hyperlipidemia (%)
68%
eGFR (mL/min/1.73m2)
83 20
Baseline BP (mmHg)
176/98 17/15
Number of anti-HTN meds (mean)

Diuretic (%)
Aldosterone blocker(%)
5.1 1.4
95%
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%
Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.
Baseline Patient Characteristics (n=153)
38 minute median procedure time

Average of 4 ablations per artery
Intravenous narcotics & sedatives used to manage pain

during delivery of RF energy
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
Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.
Brief Procedure with a Low Complication rate

(n=153)
10
BP change
(mmHg)
P<0.01 for from BL

for all time points
Symplicity HTN-1: BP Reductions through

3 years
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: Percentage Responders

Over Time
Responder was defined as an

office SBP reduction 10 mmHg
(n=45)
(n=45)
(n=44)
(n=39)
(n=17)
(n=8)
Symplicity HTN-1: Response Rate Among

Non-responders at 1 Month (n=45)
One progression of a pre-existing stenosis unrelated to

RF treatment (stented without further sequelae)
One new moderate stenosis which was not
haemodynamically 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
Symplicity HTN-1: Chronic Safety Out to 3

Years
The magnitude of clinical response is significant and

sustained through 3 years
Increasing responder rates indicate:
no loss of treatment effect out to 36 months
BP non-response at 6 months does not predict failure to respond
at 12 months or later
The treatment effect was consistent across subgroups

(age, diabetes status, and baseline renal function)
No late adverse events were seen
Conclusions from Symplicity HTN-1
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.
Symplicity HTN-2
16
Participating Centers
PI: Prof. Murray Esler
Universittsklinikum des Saarlandes, Homburg, Germany
CardioVascular Center Frankfurt, Frankfurt, Germany
Universittsklinikum Dsseldorf, Dsseldorf, Germany
Universitt Erlangen-Nrnberg, Erlangen, Germany
William Harvey Research Institute, Queen Mary University of London and Barts, London, UK
Pauls Stradins Clinical University Hospital, Riga, Latvia
Assistance Publique des Hpitaux de Paris, Hpital Europen Georges Pompidou, Paris, France
John Hunter Hospital, Newcastle, Australia
Cliniques Universitaires Saint-Luc, Brussels, Belgium
Universitaetsklinikum Schleswig-Holstein, Lbeck, Germany
Universitt zu Kln, Kln, Germany
The Alfred Hospital, Melbourne, Australia
Universitt Leipzig Herzzentrum, Leipzig, Germany
Allgemeines Krankenhaus der Stadt Wien, Vienna, Austria
Samodzielna Pracownia Hemodynamiczna, Warsaw, Poland
Hospital 12 de Octubre, Madrid, Spain
St. Vincents Hospital, Melbourne, Australia
Universittsklinikum Essen, Essen, Germany
Kent and Canterbury Hospital, Canterbury, UK
University Hospital Zurich, Zurich, Switzerland
University of Glasgow, Glasgow, UK
Auckland City Hospital, Auckland, New Zealand
Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany
The John Paul II Hospital, Krakow, Poland
Europe & Australia/NZ
Treatment-resistant
HTN population
Inclusion Criteria:
BL OBP 178/97 mmHg
49 RDN, 51 Control
Age 58 years
BMI 31 kg/m
40% with Diabetes
eGFR 77*
Avg # meds 5.2
RDN and Control groups
generally well-matched
*MDRD, ml/min/1.73m2
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:
Haemodynamically or anatomically significant

renal artery abnormalities or prior renal artery
intervention
eGFR < 45 mL/min/1.73m 2 (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 Trial
Assessed for Eligibility (n=190)

Excluded During Screening,
Prior to Randomisation (n=84)
Randomised (n=106)
Allocated to RDN
n=52 Treated
n=49 Analysable
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%)
Allocated to Control
n=54 Control
n=51 Analysable
Crossover
n=46
2 LTFU
12-month post-RDN
n=47
* Crossed-over with ineligible BP (<160 mmHg)
Per protocol, 6-mo

Post-RDN (Crossover)
n=35
Not-per-protocol*, 6mo Post-RDN

(Crossover) n=9
Symplicity HTN-2: Patient disposition
Baseline systolic BP (mmHg)

Baseline diastolic BP (mmHg)
Number anti-HTN medications
Age
Gender (female) (%)
Race (Caucasian) (%)
BMI (kg/m2)
Type 2 diabetes
Coronary artery disease
Hypercholesterolemia
eGFR (MDRD, ml/min/1.73m2)
Serum creatinine (mg/dL)
Urine alb/creat ratio (mg/g)*
Cystatin C (mg/L)
Heart rate (bpm)
RDN
(n = 52)
Control
(n = 54)
p-Value
178 18
97 16
5.2 1.5
58 12
35%
98%
31 5
40%
19%
52%
77 19
1.0 0.3
128 363
0.9 0.2
75 15
178 16
98 17
5.3 1.8
58 12
50%
96%
31 5
28%
7%
52%
86 20
0.9 0.2
109 254
0.8 0.2
71 15
0.97
0.80
0.75
0.97
0.12
>0.99
0.77
0.22
0.09
>0.99
0.013
0.003
0.64
0.16
0.23
n = 42 for RDN and n = 43 for Control. Wilcoxon rank-sum test for two independent samples used
for between-group comparisons of UACR.
n = 39 for RDN and n = 42 for Control.

*
Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)
RDN and Control Populations Well-matched,

Severe Treatment Resistant Hypertensives
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 post-procedural 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
Symplicity HTN-2: Procedural Safety
Primary Endpoint
(6M post Randomisation)
Latest Follow-up
(12M post Randomisation)
RDN (n= 47)
from
Baseline
to
6 Months
(mmHg)
Systolic Diastolic
Diastolic
Systolic
p <0.01 for
difference
between RDN
and Control
Primary Endpoint:
84% of RDN patients had 10 mmHg
reduction in SBP
10% of RDN patients had no reduction in SBP
from
Baseline
to
12 Months
(mmHg)
Diastolic
Systolic
p <0.01 for
from baseline
Latest Follow-up:
Control crossover (n = 35): -24/-8 mmHg
(Analysis on patients with SBP 160 mmHg
at 6 M)
Symplicity HTN-2: Primary Endpoint and Latest

Follow-up
RDN (n=47)
6 month
12 months
Decrease (# Meds or Dose)
20.9% (9/43)
27.9% (12/43)
Increase (# Meds or Dose)
11.6% (5/43)
18.6% (8/43)
Crossover (n=35)
6 months postRDN
Decrease (# Meds or Dose)
18.2% (6/33)
Increase (# Meds or Dose)
15.2% (5/33)
Physicians were allowed to make changes to medications

Once the 6 month primary endpoint was reached*
*Further analysis of Medications is ongoing
Symplicity HTN-2: Medication Changes at 6

and 12 Months Post-Renal Denervation
RDN
Treated at Randomisation
N=47
eGFR
Baseline
6 month
12 months
76.9 19.3 (n= 49)
77.118.8 (n=49)
78.217.4 (n=45)
0.910.25 (n=38)
0.980.36 (n=40)
0.980.30 (n=38)
(ml/min/1.73m )
2
Cystatin C
(mg/L)
Treated after
6-mo follow-up
Crossover
N=35
eGFR
Baseline
6 month
12 months
88.8 20.7 (n = 35)
89.319.5 (n = 35)
85.218.3 (n = 35)
0.78 0.17 (n=27)
0.820.16 (n=26)
0.890.20 (n=26)
(ml/min/1.73m )
2
Cystatin C
(mg/L)
Symplicity HTN-2 Investigators. The Lancet. 2010.
Symplicity HTN-2: Renal Function Results
Catheter-based renal denervation, done in a multicentre,

randomised trial in patients with treatment-resistant essential
hypertension, resulted in significant reductions in BP.
The magnitude of BP reduction can be predicted to affect the
development of hypertension-related diseases and mortality
The technique was applied without major complications.
This therapeutic innovation, based on the described neural
pathophysiology of essential hypertension, affirms the crucial
relevance of renal nerves in the maintenance of BP in patients with
hypertension.
Catheter-based renal denervation is beneficial for patients with
treatment-resistant essential hypertension.
Symplicity HTN-2: Lancet Conclusions
25
TGA approval in 2010-Renal Denervation.

18 months of negotiations with area to
commence program.
Funded by Renal, Radiology departments
and 2 donors.
20 cases over the next 12 months.
Indication-Similar to trials
Reimbursement at least 2 years away.
JHH Clinical Program
Multi disciplinary clinic to finalize case

selection.
All patients to be enrolled in Global
Registry.
JHH Clinical Program
Background
Female, 64 years of age.
Hypertension > 10 years, secondary causes excluded
IHD; UAP; type II diabetes; mild OSA; anxiety.
Medications: enalapril, Karvezide, metoprolol, nicorandil,
prn nitrate, metformin, glicazide, simvastatin, aspirin,
omeprazole.
Renal denervation procedure (8/3/10)
Angiogram: singles; small calibre left RA <4mm.
Case study: JPB
Results
Case study: JPB
Initial data derived from first generation

catheter.
Multi polar catheters may increase efficacy
and reduce duration of procedure.
Currently denervation is assumed at the
end of the procedure.
The ability to confirm denervation at the
end of the procedure will improve efficacy.
The Future is Bright for RDN
Every major catheter company will have a

RDN system.
Other modes of ablation (ultrasound,cryo)
will be developed.
Indications for RDN will expand.
The Future is Bright for RDN
Renal Department- Ranjith Nanra, Al

Gillies, Eswari Vilayur.
Radiology Department- Liz Holt, Siva
Rajaratnam, Ajay Thakorlal, Barry Soans,
Kerry Thomas and angio staff.
Cardiology- Peter Fletcher, Melissa
Chaplin.
c
Acknowledgements
ISCHEMIA (ACC Inv Meet 25Mar12)
Background
CVD is the leading cause of death among patients with CKD; the 4-year
mortality rate is >50% in patients with severe CKD (eGFR <30) or on
haemodialysis.
CKD patients are 5-10 times more likely to die than to reach ESRD .
Despite this, ~80% of contemporary CAD trials exclude CKD/ESRD
patients. Most of the treatments aimed at reducing their CV events are
therefore extrapolated from cohorts without CKD.
CKD patients are less likely to be prescribed statins and less likely to
be referred for cardiac catheterization and revascularization; the
optimal management approach for these patients is unknown.
Design
ISCHEMIA CKD would be conducted with the same screening,
enrolment and all study procedures (except CCTA) as the main trial,
and would be handled as a protocol amendment at participating sites.
ISCHEMIA CKD trial will randomize patients with severe CKD or those
on haemodialysis and at least moderate ischemia on stress imaging to
cardiac catheterization (cath) with revascularization + optimal medical
therapy (OMT) (INV strategy) vs. OMT alone (CON strategy).
ISCHEMIA Chronic Kidney Disease Companion Trial
Risks
Increased risk of contrast induced nephropathy in
subjects undergoing cath (dependent on volume of
contrast used mainly applicable to 25% of patients
who undergo cath + PCI). Special measures to be
recommended to reduce risk.
Benefits
Limited observational studies of revascularization
vs. medical therapy in this population suggest a
significant survival benefit from revascularization,
yet data show these patients often do not undergo
cath and revascularization.
ISCHEMIA Chronic Kidney Disease

Companion Trial cont

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Suku Thambar

Single largest contributor to death

Every 20/10 mmHg increase in BP

Dramatically increases risk of stroke,

Chobanian et al. Hypertension. 2003;42(6):12061252.

Kidney as Recipient of Sympathetic Signals

Renin Release RAAS activation

Renal Sympathetic Activation: Efferent Nerves

Kidney as Origin of Central Sympathetic Drive

Renin Release RAAS activation

Renal Sympathetic Activation: Afferent Nerves

Nerves arise from T10-L2

Renal Nerve Anatomy

Renal artery access via

Renal Nerve Anatomy Allows a

Trials under way

SYMPLICITY Clinical Trial Program follows over

Initial Cohort Reported in the Lancet, 2009:

Expanded Cohort* This Report (Symplicity HTN-1):

Diabetes Mellitus II (%)

Number of anti-HTN meds (mean)

Direct Renin Inhibitor

Calcium channel blocker (%)

Centrally acting sympatholytic (%)

Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Baseline Patient Characteristics (n=153)

38 minute median procedure time

Intravenous narcotics & sedatives used to manage pain

Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Brief Procedure with a Low Complication rate

P<0.01 for from BL

Symplicity HTN-1: BP Reductions through

Responder was defined as an office SBP reduction 10 mmHg

Symplicity HTN-1: Percentage Responders

Responder was defined as an

Symplicity HTN-1: Response Rate Among

One progression of a pre-existing stenosis unrelated to

Symplicity HTN-1: Chronic Safety Out to 3

The magnitude of clinical response is significant and

The treatment effect was consistent across subgroups

Conclusions from Symplicity HTN-1

Purpose: To demonstrate the effectiveness of catheter-based renal

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

Europe & Australia/NZ

BL OBP 178/97 mmHg

Office SBP 160 mmHg ( 150 mmHg with

Haemodynamically or anatomically significant

Symplicity HTN-2 Trial

Assessed for Eligibility (n=190)

BP < 160 at Baseline Visit (after 2-weeks of

* Crossed-over with ineligible BP (<160 mmHg)

Per protocol, 6-mo

Not-per-protocol*, 6mo Post-RDN

Symplicity HTN-2: Patient disposition

Baseline systolic BP (mmHg)

n = 39 for RDN and n = 42 for Control.

RDN and Control Populations Well-matched,

1 femoral artery pseudoaneurysm treated with manual compression

Symplicity HTN-2: Procedural Safety

Symplicity HTN-2: Primary Endpoint and Latest

Decrease (# Meds or Dose)

Increase (# Meds or Dose)

Decrease (# Meds or Dose)