Renal Denervation: Overview

James R. Margolis, MDMiami, FL USA

Disclosure

• Royalties Vessix Vascular/Boston Scientific• Stockholder Boston Scientific

Teaching Points

• Renal denervation is an effective way to lower blood pressure.

• The Symplicity system works, but there is a better way.

• Why HTN 3 was flawed.

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.

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

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

)G

loba

l Pre

vale

nce

(%)

Year

Kearney PM: Lancet 2005;365:217–223

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Hypertension leads to an increased risk of death from stroke and heart disease

2x

4x

8x

Systolic BP / Diastolic BP (mmHg)

Card

iova

scul

ar M

orta

lity

Risk

1Chobanian et al. Hypertension 2003;42:1206-12522Lancet 2002;360:1903-1913

CV mortality risk doubles for every20 mmHg increase in systolic blood pressure

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Systolic BP Reductionand CVD MortalityMeta-analysis of Hypertension Trials

Systolic BP (control - experimental, mm Hg)

Card

iova

scul

ar M

orta

lity

Odd

s Ra

tio

Staessen JA et al. Lancet. 2001;358:1305 -1315.

1.50

1.25

1. 00

0.75

0.50

0.25

-5 0 5 10 15 20 25

P =.003

MIDAS/NICS/VHASUKPDS C vs A

INSIGHTHOT L vs H

HOT M vs HMRC1

MRC2

SHEPHEP

EWPHE

RCT70-80

Syst-Eur

STONE

Syst-ChinaUKPDS L vs H

HOPE

PART2/SCATATMH

STOP1

CAPPP

STOP2/CCBs

STOP2/ACEIs

NORDIL

SBP Reductions as Little as 2 mm Hg Reduce the Risk of

CV Events by Up to 10%

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Courtesy Adam Witkowski, MD PhD

Efferent Nerve Activity:

• Renal Artery Vasoconstriction• Sodium and Fluid Retention• Enhanced Renin Release

Afferent Nerve Activity:• Systemic Sympathetic Neural

Stimulation• LV Hypertrophy• Systolic Heart Failure• Heart Failure with preserved

ejection fraction (HFpEF)• Arrhythmia

The Hyperactive Sympathetic Nervous System is a Driver of Hypertension

HF = Heart Failure; HFpEF= HF with preserved Ejection Fraction; LV = Left Ventricle; RAS = Renin-Angiotensin-Aldosterone

Doumas et al. Am J Cardiol 2010;105:570-576 Cleveland Clinic Journal of Medicine 2012; 79: 501-10

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• Hypertension begets hypertension.• Correction of hypertension resets the

feedback loop.

Feedback Loop

Surgical interruption of the sympathetic nervous system (Sympathectomy)Used to treat hypertension 75 years ago

Smithwick. JAMA. 1953

•Prolonged hospitalization

•Hypotension

Blood pressure levels 10 years after Sympathectomy in 31-year-old patient

Although effective, this procedure led to many adverse events:•Syncope• Impotence•Difficulty walking

103 58

9972

124 88 132

80

Blood Pressure Levels, mm/Hg

Time in YearsOperation

180122

8864

110 78

200

160

120

80

40

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

ACE = angiotensin-converting-enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; DHP = dihydropyridine; DRI =direct renin inhibitors

38% of HTN population remain Uncontrolled

9% of HTN population remain resistant

Medtronic Symplicity System

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Effect of renal sympathetic denervation on muscle sympathetic nerve activity (MSNA) over 12 months of follow-up (FU).

Krum H et al. Circulation 2011;123:209-215Copyright © American Heart Association

Proof of Concept Symplicity HTN-1: Human Feasibility, Safety and Efficacy RegistryChange in Office Blood Pressure Through 36 Months

DBP=diastolic blood pressure; SBP=systolic blood pressure

1 mo (n=141)

3 mo (n=148)

6 mo (n=144)

12 mo (n=132)

24 mo (n=105)

30 mo (n=93)

36 mo (n=88)

-40

-35

-30

-25

-20

-15

-10

-5

0

-19-21 -22

-27-29

-32 -32

-9 -10 -10-14 -14 -15 -14

SBP mmHgDBP mmHg

Krum, H. ESC 2013.

P<0.01 for ∆ from BL all time points

Lancet. 2010;376:1903-1909

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

• Study design: 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

16

Symplicity HTN-2

Primary Endpoint: 6-Month Office BP

-32

1

-12

0

-50

-40

-30

-20

-10

0

10

RDN (n=49) Control (n=51)

∆ 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

17

Systolic

Diastolic

Systolic Diastolic

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

Symplicity HTN-2

Symplicity HTN-2

From presentation by Michael Böhm

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SYMPLICITY HTN-2: BP Reductions Sustained to 3 Years*

Sustained Reductions in the Pooled (RDN and Crossover) Group**

p<0.01 at all time points

∆ fr

om B

asel

ine

to

36 M

onth

s (m

mH

g)

30Mn= 69

24Mn= 69

6Mn= 84

12Mn= 80

18Mn= 74

Systolic

Diastolic

36Mn= 40

Expanded results presented at the Transcatheter Cardiovascular Therapies annual meeting 2013

** Only patients in the RDN group reached the 36 month follow up visit

-50

-40

-30

-20

-10

0

10

-28-26

-31-30

-34-33

-10 -10-12 -11 -13 -14

* Reference: Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension. The Lancet. 2010; 376: 1903–1909.

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Response Rate ≥ 10 mmHg Sustained Through 36 Months

6 Months Post Procedure

12 Months Post Procedure

24 Months Post Procedure

30 Months Post Procedure

36 months Post Procedure

0%

20%

40%

60%

80%

100%

84%79% 80%

87% 85%

63%

52%

76% 77%

RDN Crossover

**

Expanded results presented at the Transcatheter Cardiovascular Therapies annual meeting 2013

** Only patients in the RDN group reached the 36 month follow up visit

* Reference: Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension. The Lancet. 2010; 376: 1903–1909.

MDTSymplicity

MDTSpyral

STJ EnligHTN

COVOneShot

ReCor Gen-2 Paradise

JNJThermoCool

BSCVessix

CE Mark No No

Catheter DesignCatheter with

single electrode

Pigtail Catheter 4 electrodes

Basket with four electrodes

Balloon catheter helical electrode and

cooling

Balloon catheter;

internal cooling; Circumferential

treatment

Pigtail catheter with 5

electrodes and cooling

Balloon catheter

4-8electrodes

Balloon No No No No

Guidewire No No No

Energy MonopolarRF

MonopolarRF

MonopolarRF

MonopolarRF Ultrasound Monopolar

RF Bipolar

RF

Power 8W Unknown 8W 25W ~12W Unknown ~1W

Energy Delivery Time 2 min. 1 min. 60 sec 2 min. 30 sec. Unknown 30 sec.

Total Treatment Time 16-24 min. 2 min. 4 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; Covidien (Maya) Presentation; Ormiston et al. EuroIntv. 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. * Vessix™ is an investigational device and not available for sale in the US.

RF=Radiofrequency;W=Watt

Vessix™ Renal Denervation System* Technology Overview

RF=Radiofrequency; TGA=Therapuetic Goods Administration, AU Regulatory Authority

• Balloon-based technology (4 - 7 mm diameters)

• Helical pattern of bipolar radiofrequency electrodes for uniform treatment

• 30 second treatment time• All electrodes activated simultaneously

• Bipolar energy delivery, ~1 Watt • Temperature-controlled algorithm

ensures energy delivery at 68°C• One button operation• CE-marked and TGA-approved

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 treatment can be tailored to length of the artery landing zone

• Electrodes that are unapposed to vessel wall are automatically deactivated

Vessix™ System RF Balloon Catheter

RF=Radiofrequency

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

> 1200

patients

planned

worldwide

* Vessix™ is an investigational device and not available for sale in the US.

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-UpYear 1

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

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

Planning / Target Enrollment

to beginQ4 2013

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

• Efficacy Endpoint – Reduction of SBP and DBP (Office Based and ABPM) at six months post procedure compared to baseline

• Safety Endpoint – Acute Safety

• Renal artery dissection or perforation during the procedure that requires stenting or surgery

• Renal artery infarction or embolus• Cerebrovascular Accident (CVA) at time of procedure• Myocardial infarction at time of procedure• Sudden cardiac death at time of procedure

– Long-term Safety • Renal stenosis requiring an intervention documented by angiography• Absence of flow limiting stenosis in the renal artery at six (6) months

measured by duplex ultrasound core laboratory

SBP=Systolic Blood Pressure; DBP=Diastolic Blood Pressure; ABPB=Ambulatory Blood Pressure Monitoring; PMS=Post Market Study.

REDUCE-HTN PMSStudy Endpoints

REDUCE-HTN Case Bipolar RF Technology on a Balloon for the treatment of smaller arteries

Small diameter renal arteries and accessory renal arteries treated withthe Vessix™ system

RF=RadiofrequencyImages of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.

REDUCE-HTN Case Bipolar RF Technology on a Balloon for the treatment of smaller arteries

RF=Radiofrequency

Right accessory renal artery pre treatment

Distal balloon placemetn – 5mm Proximal balloon placement – 5mm

Images of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.

REDUCE-HTN Case Continued Patency, No spasm

RF=RadiofrequencyImages of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.

Right accessory renal artery pre treatment

Right accessory renal artery post treatment

P<.0001 for each timepoint vs baseline.Error bars represent 95% confidence bounds.

Significant Office Blood Pressure Reductions Over Time

BP=blood pressure

1 Month (N=142) 3 Months (N=144) 6 Months (N=142)

-12

-10

-8

-6

-4

-2

0

-10.0

-8.2

-10.3

Change in Office Systolic BP Change in Office Diastolic BP

Mea

n BP

Cha

nge

from

Bas

elin

e (m

mH

g)

Sievert, H. CRT 2014.* Vessix™ is an investigational device and not available for sale in the US.

Mean reduction in office-based BP was 24.7/10.3 mmHg at 6 months (P<.0001)

P<.0005 for each timepoint vs baseline.Error bars represent 95% confidence bounds.

Significant Office Blood Pressure Reductions for Patients with Treated Accessory Renal Arteries (n=24)

BP=blood pressure

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

mH

g)

Sievert, H. CRT 2014.* Vessix™ is an investigational device and not available for sale in the US.

Most Bets Are Won and Lost on the First Tee

• My shoulder hurts.• I was up all night.• I haven’t played in a

long time.• I never played this

course before.• I need extra strokes.

Results of Clinical Studies are Highly Dependent on Their Protocols

The SYMPLICITY HTN-3 Clinical TrialMedtronic is sponsoring a clinical trial that will involve more than 500 patients at up to 90 hospitals in the United States. The purpose of this study is to provide additional information about a medical device intended to help treat high blood pressure in people whose blood pressure is not controlled despite treatment with multiple blood pressure medications.

The study is "Controlled", meaning some of the patients will be treated with the device (the "Treatment Group") and some will NOT be treated with the device (the "Control Group"), and the results of the two groups will be compared.

This study is "Randomized" meaning that patients who are confirmed to be eligible will be randomly assigned to one of two groups. Each patient has a 2 to 1 chance of being assigned to the treatment group. This means you are twice as likely to be in the treatment group rather than the control group. At 6 months, those who were in the control group and remain eligible may be able to have the treatment if they wish.

This study is also "Blinded" meaning that patients will not be told which group they are assigned to, and certain procedures will be followed to prevent patients from knowing which group they are in. This study design is necessary to properly evaluate the safety and effectiveness of the investigational device and procedure.

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Superiority Margin

• A superiority by a margin tests that the treatment mean is better than the reference mean by more than the superiority margin.

• Most clinical trials designed to demonstrate superiority assume the margin is zero. That is, the goal is to prove that any significant difference exists.

• SYMPLICITY HTN-3 was designed to demonstrate that RDN was much better than control. Therefore, chose to perform a more stringent and rigorous comparison and selected a superiority margin of 5 mm Hg.

Courtesy I Patrick Kay, MD PhD

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Illustrative examples of endpoint scenarios, either meeting or not meeting the set assumptions for the primary endpoint (PE)

Primary Efficacy Endpoint Assumptions

150 5 10

Does Not Meet

Meets PE

Does Not Meet

Relative drop in office systolic blood pressure

between treatment and control

Courtesy I Patrick Kay, MD PhD

SYMPLICITY HTN-3 fails to meet primary efficacy endpoint

Thursday, 09 Jan 2014 12:24

Symplicity HTN2 vs 3

Symplicity 2• 190 assessed• 106 patients enrolled• Enrollment one year• 24 Centers• Average enrollment/center

4 patients

Symplicity 3• 1000+ assessed• 535 patients enrolled• Enrollment 2+ years• 89 centers• Average enrollment/center

6 patients

Primary Endpoint: 6-Month Office BP

-32

1

-12

0

-50

-40

-30

-20

-10

0

10

RDN (n=49) Control (n=51)

∆ 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

40

Systolic

Diastolic

Systolic Diastolic

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

Symplicity HTN-2

Why Did HTN-3 Fail to Meet Primary Endpoint?

• Do not know.• Control group not truly refractory?• Insufficient drop in BP in treated group?

– Operators inexperienced?– Treated patients stopped their meds?

• Endpoint too ambitious?• Maybe we will know in 2½ weeks.

Pneumococcal Pneumonia Study 1942

• Untreated pneumococcal pneumonia carried 80% mortality.

• Treated with Penicillin, expected mortality 20%.

• Using these numbers as results, a 10 patient study (5 treated, 5 placebo) would be positive in favor of PCN at p < .0000001

Hypothetical study for FDA approval of PCN for Pneumococcal Pneumonia Indication 1942

• 500 patient RCT drug vs. placebo.• Cannot consent placebo patients, because they have heard

about “wonder drug.”• Penicillin supplies preferentially shipped to soldiers in

Europe.• Patients (placebo and control) obtain their own PCN on the

black market, but not in time for early treatment.• 50% mortality in both groups.• Conclusion: no benefit from PCN for pneumococcal

pneumonia.• Result: PCN never approved for this indication.

How Do We Avoid Repeat of HTN-3 Debacle?

• Smaller study– Bigger is not necessarily better.– HTN-2 was positive at .0001 level with only 100 patients.

• No sham procedure.– Unethical in my opinion.– No rationale to include it.– Seriously hampers patient enrollment.

• More careful patient selection and monitoring.– Assure patients in both groups are truly refractory.– Make sure treated patients do not stop their medications.

• Test for superiority as opposed to superiority margin.

Summary

• Renal denervation is an effective treatment for refractory hypertension.

• To date, every study with every system has achieved systolic BP reductions of 20-30 mmHg at six to 12 months.

• Why HTN-3 did not reach its primary endpoint remains a mystery until all of the data is presented.

• Future studies should have a simpler design:– As with penicillin for pneumococcal pneumonia, we do not

need a 500 patient RCT to prove effectiveness.– A 100 patient RCT is already overkill.

Thank you