Renal Artery Denervation Patient Selection and Results

Renal Denervation: Yale Vascular Medicine Experience

Carlos Mena, MD. F.A.C.C., F.S.C.A.IAssistant Professor Department of Internal MedicineMedical Director Vascular Medicine ProgramSection of Cardiovascular MedicineYale 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;365:217-23Lloyd-Jones et al. Circulation 2010;121:e46–e215Wolf-Meier et al. JAMA 2003;289:2363–2369Journal of Human Hypertension 2004;18:911-912

More than one quarter of adults in developed societies are affected by hypertension

45% 30MJapan

21% 182MChina

21% 118MIndia

38% 78MLatin America

44% 81MEurope

34% 75MU.S.2

34% 75MU.S.

Global Burden of Hypertension is Substantial and Growing

2000 202525

26

27

28

29

30

400

800

1200

1600

972M

1,560M

26.4%

29.2%

Total Hypertensive Population (M)

Glob

al P

reva

lenc

e (%

)

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

Card

iova

scul

ar M

orta

lity

Risk

CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure.1,2

1Chobanian et al. Hypertension 2003;42:1206-12522Lancet 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

MDTSymplicity

MDTSpyral

STJ EnligHTN

ReCor Gen-2 Paradise

JNJThermoCool

BSCVessix

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 catheter4-8

electrodes

Balloon No No No No Guidewire No No No

Energy MonopolarRF

MonopolarRF

MonopolarRF 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 9/10/2013Kirtane, 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

Definition: Resistant HTN

• 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 TrialsOBP Reductions were 5.6 mm Hg > Ambulatory BP Reductions (p<0.0001)

Study or subgroupOffice Ambulatory

Mean Total Mean Total WeightMean Difference

IV, Random, 95% CIMean 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)

2517.610.426.314

14.2262123122016

35.620.629.222

20.2

24523057

173228184353965501925897717

1615

1312.29.5

22.7169.5181731121312249.9

11.116

10.7

24523057

173228184353965501925897717

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 trialsOBP reductions were 2.9 mmHg > ambulatory pressure reductions (p=0.002)




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)

33.9-2.1

33

105

-0.45.57

1140

8.1

341016142

10412812326250

233133842

111

5-1.6-2.3

21

0.53

-0.42182

2.64

341016142

10412812326250

233133842

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]


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 Ptsin randomised blinded placebo-controlled drug trialsSimilar effect on office and ambulatory BP (p=0.45)




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)

57.7

17.711118

1812.66.51668

126.5

341016142

10412812326250

233133842

111

611.325.2

913

14.515

12.87

105

109.59.8

341016142

10412812326250

233133842

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]


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)


Compliance: Resistant HTN?

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

BipolarRF

MonopolarRF

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

0 < 2 mm 2 < 4 mm > 4 mm0

10

20

30

40

50

60

70

80

90

10090

100

4031 29

53

23 24

Atherton Virmani Tunstall*

Distance from lumen (mm)

Perc

ent o

f Ner

ves

Virmani, R. TCT 2012Atherton DS. Clin Anat 2012.BSC data on file

*Includes nerve count prior to parsing out plaque /no plaque

Human Renal Nerve Anatomy StudiesSimilar 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

5mmH&E, 0.38x

Vessix™Treatment, 68°C, 30 sec (n=19)

Surgical Denervation (n=3)

0

50

100

74% NEPI Reduction

77% NEPI Reduction=

Perc

ent r

educ

tion

in N

EPI

BSC data on file. Swine model results not necessarily indicative of clinical performance.

• Histology shows endothelialization at 7 days

• No thrombosis

7 days

Lumen

TunicaMedia

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


0

5

10

15

20

25

30

35

40

45

50

10%

28%

Ner

ves (

%) w

ithin

zone

of

trea

tmen

t am

ong

all n

erve

s

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% NEPIAt 14 days

-78% NEPIAt 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


0

5

10

15

20

25

30

35

40

23.6

35.8

Tota

l num

ber o

f ner

ves i

n pl

anes

with

trea

ted

zone

sp<0.05


N=5

Full artery length treatment

N=5


Full artery length treatmet

0%10%20%30%40%50%60%70%80%90%

100%

22 18

3323

2944

16 15

0 1 2 3

% o

f ner

ves

50 µm

50 µm

50 µm

50 µm

Score 0 = Normal Score 1 = Degenerate

Score 2 = Necrotic Score 3 = Chronic

Nerve Morphology at 7 daysFollowing Bipolar RF Treatment in Swine


Accessory Renal ArteriesUsing 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.

1 Month 3 Months 6 Months

-25

-20

-15

-10

-5

0

-23.2

-17.8-21.0

-12.6-11.4

-12.3

Change in Office Systolic BP Change in Office Diastolic BP

Mea

n BP

Cha

nge

from

Bas

elin

e (m

mHg

)

Patients with Treated Accessory Renal Arteries (n=24)

Sievert, H. CRT 2014.

Camparison between the Vessix™ and the Symplicity™ System

-30

-25

-20

-15

-10

-5

0

5

-11

-1-4

1

Systolic Diastolic

Redu

ction

in B

P (m

mHg

)

• 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

BaselineAmbulatory

Mean Age (years)

Male(%)

DiabetesMellitus (%)

# 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

-30

-25

-20

-15

-10

-5

0

5

-16 -16

-1-6

Systolic Diastolic

Redu

ction

in B

P (m

mHg

)

Vessix(n=14)

Symplicity(n=28)

Office Based BP6M

Ambulatory BP6M

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.

Is Sham Necessary????

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!

Kirtane, A. TCT 2013.

Evidence-Based MedicineWhat’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 tothe 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.Kirtane, A. TCT 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?

Kirtane, A. TCT 2013.

> 1200 Patients planned worldwide

Boston Scientific Renal Denervation Program

REDUCE-HTN Clinical Series

Studies evaluating the Vessix System technologyin 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 ApprovalMulticenter, Non-randomized, feasibility N = 18

REDUCE HTN Post Market StudyMulticenter, Non-randomized, post market surveillanceN = 128

Boston Scientific Renal DenervationREDUCE-HTN Clinical Series

Enrollment Complete /In Follow-Up

Year 1

Global Pivotal StudyMulticenter, randomized (2:1), superiorityN = 550

European Post Market TrialMulticenter, Non-randomized, post market N = 500

Planning / Target Enrollment

to begin1H 2014

Regional Regulatory Approval StudiesMulticenter, Non-randomized, prospective, single cohort N = TBD

Renal Artery Denervation Patient Selection and Results

Health & Medicine

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