Renal Artery Denervation Patient Selection and Results

Renal Denervation: Yale Vascular
Medicine Experience
Carlos Mena, MD. F.A.C.C., F.S.C.A.I
Assistant Professor Department of Internal Medicine
Medical Director Vascular Medicine Program
Section of Cardiovascular Medicine
Yale University School of Medicine

Definition of resistant HTN
“Resistant hypertension is defined as blood pressure
that remains above goal in spite of the concurrent
use of 3 anti-hypertensive agents of different classes.
Ideally, one of the 3 agents should be a diuretic and
all agents should be prescribed at optimal dose
amounts.”
AHA Scientific Statement. Hypertension 2008, 51:1403-1419

Kearney et al. Lancet 2005;365:217-23
Lloyd-Jones et al. Circulation 2010;121:e46–e215
Wolf-Meier et al. JAMA 2003;289:2363–2369
Journal of Human Hypertension 2004;18:911-912
More than one quarter of adults in developed
societies are affected by hypertension
45% 30M
Japan
21% 182M
China
21% 118M
India
38% 78M
Latin America
44% 81M
Europe
34% 75M
U.S.2
34% 75M
U.S.

Global Burden of Hypertension is
Substantial and Growing
972M
1,560M
26.4%
29.2%
400
800
1200
1600
25
26
27
28
29
30
2000 2025
TotalHypertensivePopulation(M)
GlobalPrevalence(%)
Year
Kearney PM: Lancet 2005;365:217–223

Hypertension leads to an increased risk of
death from stroke and heart disease
2x
4x
8x
Systolic BP / Diastolic BP (mmHg)7
CardiovascularMortalityRisk
CV mortality risk doubles for every 20 mmHg
increase in systolic blood pressure.1,2
1Chobanian et al. Hypertension 2003;42:1206-1252
2Lancet 2002;360:1903-1913

Chronology of Anti-hypertensive
Drug Development
1940s 1950s 1960s 1970s 1980s 1990s 2000s
Effectiveness
Side Effects
Peripheral
Sympatholytics
Ganglion
Blockers
Veratrum
Alkaloids
Direct
Vasodilators
Thiazide
Diuretics
Central
Alpha2
Agonists
Non-DHP
CCBs
Beta Blockers
Alpha
Blockers
DHP CCBs
ACE
Inhibitors
ARBs DRIs
Blessing, Leipzig Interventional Course, 2010.
38% of HTN population remain
Uncontrolled
9% of HTN population remain
resistant
ACE = angiotensin-converting-enzyme; ARB = angiotensin receptor blocker;
CCB = calcium channel blocker; DHP = dihydropyridine;
DRI =direct renin inhibitors

Afferent Nerve Activity:
• Systemic Sympathetic Neural Stimulation
• LV Hypertrophy
• Systolic Heart Failure
• Heart Failure with preserved ejection
fraction (HFpEF)
• Arrhythmia
Efferent Nerve Activity:
• Renal Artery Vasoconstriction
• Sodium and Fluid Retention
• Enhanced Renin Release
The Hyperactive Sympathetic Nervous
System is a Driver of Hypertension
Doumas et al. Am J Cardiol 2010;105:570-576
Cleveland Clinic Journal of Medicine 2012; 79: 501-10

MDT
Symplicity
MDT
Spyral
STJ
EnligHTN
ReCor Gen-2
Paradise
JNJ
ThermoCool
BSC
Vessix
CE Mark  No   No 
Catheter Design
Catheter with
single electrode
Pigtail Catheter
4 electrodes
Basket with four
electrodes
Balloon catheter;
internal cooling;
Circumferential
treatment
Pigtail catheter
with 5 electrodes
and cooling
Balloon catheter
4-8
electrodes
Balloon No No No  No 
Guidewire No  No  No 
Energy
Monopolar
RF
Monopolar
RF
Monopolar
RF
Ultrasound
Monopolar
RF
Bipolar
RF
Power 8W Unknown 8W ~12W Unknown ~1W
Energy Delivery
Time
2 min. 1 min. 60 sec 30 sec. Unknown 30 sec.
Total Treatment
Time
16-24 min. 2 min. 4 min. 3 min. Unknown 2 min.
Renal Denervation Technologies
None of these devices are available for sale in the US.
Medtronic Website, March 2013; The New Medtronic Device, Weil, TRENDS Frankfurt 2013;
Worthley, S. EuroPCR 2013; The ReCor Device, Weil, TRENDS Frankfurt 2013;
Sievert, Live Case, TRENDS, Frankfort 2013; LINC 2013, Live Case ReCor;
J&J Thermocool Bertog, TRENDS Frankfurt 2013.

SymplicityHTN-1
• 50 pts
• 12 mo.
• BP may
take
months
to fall
Krum H, et al. Lancet 2009; 373: 1275–81
-14/10 -21/10 -22/11 -24/11 -27/17

SymplicityHTN-2 Results 12 mo
Circ 2012;126:2976

Recent Allegations about RDN
“Small wonder that the cookie is finally crumbling,
bigger wonder that it actually took so long. The
irrational exuberance for renal denervation in
resistant hypertension was entirely driven by
uncontrolled non-randomized observational office-
based blood pressure studies.”
F. Messerli
“This is probably the most extreme case I have
ever seen of inadvertent bias in measurement
producing – concordantly across several studies
– massive overestimation of an effect size”
D. Francis
Forbes 9/10/2013
Kirtane, A. TCT 2013.

Clinical Decision Making
Clinical
Practice
• Observational registries
• Randomized controlled trials
• Meta- (or pooled) analyses
• Treatment strategy studies
Evidence-
based
Medicine
Leon, M. ISET 2014.

• Clinical “judgement”
• Patient and physician
expectations
• Operator-related issues
• Socio-economic factors
Clinical
Practice
Other
Factors
Clinical Decision Making
Leon, M. ISET 2014.

RDN: What Are The Problems
• Problem Definition
• Patient Compliance
• Sham – Procedure
• Device Related issues

• NHANES 2003-2008 data
• N = 5,530
• 539 resistant (12.8% of treated hypertensives)
HOWEVER…
• Spanish ABPM registry, N = 8,295
• Prevalence of office RH = 12.2%
• 37.5% normal ABPM (ie, “office resistance”)
How common is resistant HTN?
Persell. Hypertension 2011; 57: 1076-80
De la Sierra. Hypertension 2011; 57: 898-902

• Retrospective study
• 304 patients over 8 years seen at a HTN Center “at least 3 times for
at least 6 months”.
• 29 (~10%) remained >140/90 mmHg:
– Higher baseline BP (175/97 vs. 158/89 mmHg)
– More co-morbidity
• Stroke 28% vs. 8%
• CHF 24% vs. 4%
Resistance within a Hypertension Specialist
Practice (“Refractory HTN”)
Acelajado, Calhoun et al. J Clin Hypertens 2012; 14: 7-12

Long term prognosis in resistant HTN is
better predicted by ABPM
Salles et al. Arch Intern Med 2008; 168: 2340
Adjusted HR 2.11 [1.34-3.34] Adjusted HR 2.0 [1.12-3.55]
N=556, F/U 4.6 years

Howard et al. Heart 2013
Office vs. Ambulatory BP in Open Label Drug Trials
OBP Reductions were 5.6 mm Hg > Ambulatory BP Reductions (p<0.0001)
Study or subgroup
Office Ambulatory
Mean Total Mean Total Weight
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CI
Total (95% CI) 2779 2779 100.0% 5.60 [2.98, 8.22]
Antonicelli (2002)
Calhoun (2008)
Coca (1997)
Coca (2003)
De Souza (2010)
Finkielman (2005)
Mancia (1997)
Martina (1994)
Middlemost (1992)
Mion (2004)
Omboni (2001)
Oren (1996)
Ouzan (2002)
Parra Carrillo (2004)
Scholze (2011)
Spratt (2001)
White (2006)
25
17.6
10.4
26.3
14
14.2
26
21
23
12
20
16
35.6
20.6
29.2
22
20.2
24
52
30
57
173
228
184
35
39
65
50
19
25
89
77
17
1615
13
12.2
9.5
22.7
16
9.5
18
17
31
12
13
12
24
9.9
11.1
16
10.7
24
52
30
57
173
228
184
35
39
65
50
19
25
89
77
17
1615
4.7%
6.0%
5.1%
6.3%
7.1%
7.3%
7.1%
5.4%
5.5%
6.2%
5.9%
4.3%
4.8%
6.6%
6.0%
4.1%
7.6%
12.00 [4.49, 19.51]
5.40 [0.30, 10.50]
0.90 [-5.82, 7.62]
3.60 [-0.81, 8.01]
-2.00 [-4.80, 0.80]
4.70 [2.54, 6.86]
8.00 [5.29, 10.71]
4.00 [-2.22, 10.22]
-8.00 [-13.89, -2.11]
0.00 [-4.56, 4.56]
7.00 [1.80, 12.20]
4.00 [-4.44, 12.44]
11.60 [4.24, 18.96]
10.70 [6.80, 14.60]
18.10 [13.01, 23.19]
6.00 [-2.93, 14.93]
9.50 [8.58, 10.42]
Ambulatory
drop larger
Office
drop larger
-20 -10 0 10 20Heterogeneity: Tau2=23.19; Chi2=137.37; df=16; (P<0.00001); I2=88%
Test for overall effect: Z=4.19 (P<0.0001)

Office vs. Ambulatory BP in Placebo-treated patients
in randomized blinded placebo-controlled drug trials
OBP reductions were 2.9 mmHg > ambulatory pressure reductions (p=0.002)
Study or subgroup
Office Ambulatory
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CI
Total (95% CI) 1342 1342 100.0% 2.90 [1.06, 4.74]
Blanchett (1990)
Fogari (1997)
Guthrie (1996)
Lacourcière (1992)
Lacourcière (1998)
Mancia (1997)
Myers (2000)
Neutel (1999)
Omboni (1998)
Staessen (1994)
Starmans-Kool (1998)
Svensson (2001)
Van der Meiracker (1995)
Václavík (2011)
3
3.9
-2.1
3
3
10
5
-0.4
5.5
7
11
4
0
8.1
34
101
61
42
104
128
123
262
50
233
13
38
42
111
5
-1.6
-2.3
2
1
0.5
3
-0.4
2
1
8
2
2.6
4
34
101
61
42
104
128
123
262
50
233
13
38
42
111
4.6%
8.2%
6.5%
5.3%
8.3%
8.9%
8.8%
10.8%
8.9%
10.5%
2.2%
3.2%
5.3%
8.5%
-2.00 [-8.95, 4.95]
5.50 [1.47, 9.53]
0.20 [-4.99, 5.39]
1.00 [-5.25, 7.25]
2.00 [-1.97, 5.97]
9.50 [5.92, 13.80]
2.00 [-1.65, 5.65]
0.00 [-2.50, 2.50]
3.50 [-0.11, 7.11]
6.00 [3.35, 8.65]
3.00 [-8.24, 14.24]
2.00 [-7.00, 11.00]
-2.60 [-8.85, 3.65]
4.10 [0.25, 7.95]
Ambulatory
drop larger
Office
drop larger
-20 -10 0 10 20Heterogeneity: Tau2=6.50; Chi2=31.99; df=13; (P=0.002); I2=59%
Test for overall effect: Z=3.09 (P=0.002)

Office vs. Ambulatory BP in Active Drug-treated Pts
in randomised blinded placebo-controlled drug trials
Similar effect on office and ambulatory BP (p=0.45)
Study or subgroup
Office Ambulatory
Mean Difference
IV, Random, 95% CI
Mean Difference
IV, Random, 95% CI
Total (95% CI) 1342 1342 100.0% -0.88 [-3.18, 1.43]
Blanchett (1990)
Fogari (1997)
Guthrie (1996)
Lacourcière (1992)
Lacourcière (1998)
Manda (1997)
Myers (2000)
Neutel (1999)
Omboni (1998)
Staessen (1994)
Starmans-Kool (1998)
Svensson (2001)
Van der Meiracker (1995)
Václavík (2011)
5
7.7
17.7
11
11
8
18
12.6
6.5
16
6
8
12
6.5
34
101
61
42
104
128
123
262
50
233
13
38
42
111
6
11.3
25.2
9
13
14.5
15
12.8
7
10
5
10
9.5
9.8
34
101
61
42
104
128
123
262
50
233
13
38
42
111
5.4%
8.1%
6.9%
6.0%
8.1%
8.5%
8.4%
9.5%
8.5%
9.4%
3.0%
4.1%
6.0%
8.2%
-1.00 [-7.95, 5.95]
-3.60 [-7.63, 0.43]
-7.50 [-12.69, -2.31]
2.00 [-4.25, 8.25]
-2.00 [-5.97, 1.97]
-6.50 [-10.08, -2.92]
3.00 [-0.65, 6.65]
-0.20 [-2.70, 2.30]
-0.50 [-4.11, 3.11]
6.00 [3.35, 8.65]
1.00 [-10.24, 12.24]
-2.00 [-11.00, 7.00]
2.50 [-3.75, 8.75]
-3.30 [-7.15, 0.55]
Ambulatory
drop larger
Office
drop larger
-20 -10 0 10 20Heterogeneity: Tau2=12.96; Chi2=50.85; df=13; (P<0.00001); I2=74%
Test for overall effect: Z=0.75 (P=0.45)

Medication adherence is poor in patients referred to a
hypertension service for resistant hypertension
375 referrals = (optimized Rx) = 108 true resistant HTN => 76 “taking all meds”
Analysis by urine LC-MS
Percentage of prescribed drugs taken by
non-adherent patients
Adherence to therapy according
to drug class
Jung. J Hypertens 2013: epub ahead of print
30% complete non-
adherence

Mechanism of Action: RDN Bipolar?

Vessix™ Renal Denervation System
Bipolar RF Energy for Renal Denervation
• Localized energy delivery from positive to
negative poles; no grounding pad
• No need for cooling
• Reduced impact of treatment variability
• Low energy of ~1W delivered
• Energy dispersed through the body; terminates
in grounding pad
• Cooled via blood flow and/or irrigation
• Increased impact of treatment variability
• Higher energy required
Bipolar
RF
Monopolar
RF

RF=Radiofrequency
• Renal nerves follow the renal artery to the kidney; only location that renal
efferent and afferent nerves travel together
• Catheter-based delivery of low-power RF energy administered at multiple
sites, facilitates denervation
• Bilateral denervation is the current standard of care
Sympathetic Nerves
Sympathetic Renal Nerve Anatomy
Anatomic Target for Renal Denervation

90
10
0
40
31 29
53
23 24
0
10
20
30
40
50
60
70
80
90
100
0 < 2 mm 2 < 4 mm > 4 mm
PercentofNerves
Distance from lumen (mm)
Atherton Virmani Tunstall*
Virmani, R. TCT 2012
Atherton DS. Clin Anat 2012.
BSC data on file
*Includes nerve count prior to parsing out plaque /no plaque
Human Renal Nerve Anatomy Studies
Similar Findings with Varying Methodologies

• Renal Denervation with injury depth of
3-4mm
Vessix Preclinical Studies (Swine)
Depth of penetration
• Efficacy comparable to surgical
denervation
b.
a.
Lumen
Renal
Artery
5mm
H&E, 0.38x
0
50
100
Vessix™Treatment, 68°C, 30 sec
(n=19)
Surgical Denervation
(n=3)
74% NEPI
Reduction
77% NEPI
Reduction
=
PercentreductioninNEPI
BSC data on file. Swine model results not necessarily indicative of clinical performance.

• Histology shows endothelialization at 7
days
• No thrombosis
7 days
Lumen
Tunica
Media
IEL
90 days
• Histology confirms no adverse effect
on surrounding tissue
• All treated arteries were patent
• No dissections, aneurysms, or changes
in blood or urine chemistry
Vessix Preclinical Studies (Swine)
Vascular safety through 90 days

10%
28%
0
5
10
15
20
25
30
35
40
45
50
Nerves(%)withinzoneof
treatmentamongallnerves
Full treatment affected more nerves within the treatment zone (p<0.05)
and caused the highest decrease in NEPI levels 14 days post treatment
The group with
surgical
denervation
showed a 75%
reduction in NEPI,
compared to the
endogenous NEPI
level of the
untreated controls.
-46% NEPI
At 14 days
-78% NEPI
At 14 days
One treatment per
artery
n=6 arteries
Full artery length
treatment
n=6 arteries
Kidney Norepinephrine Reduction (14d)
Following One and Full Artery Treatment in Swine

Nerves in treatment zone in swine
23.6
35.8
0
5
10
15
20
25
30
35
40
45
50
Totalnumberofnervesinplaneswith
treatedzones
p<0.05
One treatment per artery
N=5
Full artery length treatment
N=5

22 18
33
23
29
44
16 15
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
One treatment per
artery
Full artery length
treatmet
%ofnerves
0 1 2 3
50 µm
50 µm
50 µm
50 µm
Score 0 = Normal Score 1 = Degenerate
Score 2 = Necrotic Score 3 = Chronic
Nerve Morphology at 7 days
Following Bipolar RF Treatment in Swine

Accessory Renal Arteries
Using the Vessix™ Catheter
RF=RadiofrequencyCase courtesy of Ian Meredith, AM. Results from case studies are not predictive of results in other cases. Results in other cases may vary.
• Small renal and accessory renal arteries were treated with the Vessix™
Catheter in the REDUCE-HTN post market study
• Patients with small or accessory renal arteries were excluded from other
trials

Significant Office Blood Pressure
Reductions
P≤.0005 for each timepoint vs baseline.
Error bars represent 95% confidence bounds.
-23.2
-17.8
-21.0
-12.6 -11.4 -12.3
-35
-30
-25
-20
-15
-10
-5
0
1 Month 3 Months 6 Months
MeanBPChangefromBaseline
(mmHg)
Change in Office Systolic BP Change in Office Diastolic BP
Patients with Treated Accessory Renal Arteries
(n=24)
Sievert, H. CRT 2014.

Camparison between the Vessix™ and the
Symplicity™ System
-11
-1
-4
1
-30
-25
-20
-15
-10
-5
0
5
ReductioninBP(mmHg)
Systolic Diastolic
• CardioVascular Center Frankfurt, Sankt Katharinen, Frankfurt, Germany
– 15 consecutive patients denervated using the Vessix system
– 30 consecutive patients denervated using Symplicity (participating in HTN1 and HTN2 studies)
– Primary Endpoint – Office and Ambulatory blood pressure reduction at 6M post denervation
Group
Baseline
OBP
Baseline
Ambulatory
Mean Age
(years)
Male
(%)
Diabetes
Mellitus (%)
# of
Antihypertensives
Vessix 172/90 mmHg 156/86 mmHg 62.4 ± 8 60 40 5.4 ± 1.6
Symplicity 166/85 mmHg 152/81 mmHg 67.9 ± 9 64 33 5.8 ± 1.5
-16 -16
-1
-6
-30
-25
-20
-15
-10
-5
0
5
ReductioninBP(mmHg)
Systolic Diastolic
Vessix
(n=14)
Symplicity
(n=28)
Office Based BP
6M
Ambulatory BP
6M
Vessix
(n=14)
Symplicity
(n=28)
“We can see a propensity for a more pronounced ambulatory BP reduction in the Vessix group”
Jost UL, Bertog S, Ziegler A-K, Gafoor S, Kulow JP, Hofmann I, Vaskelyte L, Sievert H. TRENDS 2014.

Arguments on Both Sides
• Unethical (risk without benefit)
• How can there be a placebo
effect on objectively measured
BP (especially ABPM)?
• Can’t “fake” a painful procedure
• Enrollment deterrent
• Data and durability of effect
argues against substantial
placebo effect
• Clinicians can “exercise
judgment” and BP readings are
inaccurate and show regression
to the mean
• Data differences between ABPM
and Office BP (and even home
BP) suggest significant
variability and raise doubts
regarding effectiveness of RDN
• RDN studies need to be
bulletproof in the current
environment
No Sham! Pro Sham!

Evidence-Based Medicine
What’s the Problem?
Millenson, ML. Demanding Medical Excellence: Doctors
and Accountability in the Information Age. 1997
“There is an unsettling truth about
the practice of medicine…
…study after study shows that few
physicians systematically apply to
everyday treatment the scientific evidence
about what works best.”
Leon, M. ISET 2014.

Why Have We Grown More Used to
the Concept of a Sham Control?
The lack of readily measurable surrogates for reduced sympathetic outflow
combined with the variability of BP measurements makes us want to be more
rigorous…
Mahfoud, F. Bhatt, D. JACC: Cardiovascular Interventions, October 2013.

What Does Blinding Really Do?
• Patient blinding: can influence adherence and
expectations (and interactions with treating
physicians)
• Physician blinding (for ascertainment):
– Can influence concomitant medications
– Can influence ascertainment of blood pressures (office
BP in particular)
• What is debatable: To what real extent is a sham design
necessary in order to eliminate these confounders?
• Can study processes (during follow-up / ascertainment)
obviate the need for a sham procedure?

> 1200 Patients
planned worldwide
Boston Scientific Renal Denervation
Program
REDUCE-HTN Clinical Series
Studies evaluating the Vessix System technology
in the currently defined hypertension space:
• REDUCE-HTN FIM Study
• REDUCE-HTN Post Market Study
• REDUCE-HTN Global Pivotal Study
• REDUCE-HTN Regional Reg. Approval Studies
• REDUCE-HTN EU Post Market Trial
RELIEVE Clinical Series
Includes pre-clinical, clinical and investigator initiated
research evaluating the Vessix System technology in
additional disease states:
• RELIEVE - End Stage Renal Disease
• RELIEVE - Heart Failure
• RELIEVE - Atrial Fibrillation
• RELIEVE - Diabetes
Vessix™ Global Clinical Program

REDUCE HTN FIM – CE Mark and TGA Approval
Multicenter, Non-randomized, feasibility
N = 18
REDUCE HTN Post Market Study
Multicenter, Non-randomized, post market surveillance
N = 128
Boston Scientific Renal Denervation
REDUCE-HTN Clinical Series
Enrollment Complete /
In Follow-Up
Year 1
Global Pivotal Study
Multicenter, randomized (2:1), superiority
N = 550
European Post Market Trial
Multicenter, Non-randomized, post market
N = 500
Planning /
Target Enrollment
to begin
1H 2014
Regional Regulatory Approval Studies
Multicenter, Non-randomized, prospective, single cohort
N = TBD

Renal Artery Denervation Patient Selection and Results

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