1. Hope and Hype of Hypertension: Renal Denervation…
Julie Logan, RN, BS
La Jolla, California

2. Julie Logan, RN
I/we have no real or apparent conflicts of interest to report.
Off-Label: Will discuss devices that are not FDA approved but will state accordingly

3. Worldwide Prevalence of Hypertension Is Increasing
Prevalence of Hypertension by World Region
In 2000, 972 million (26%), of the adult population had hypertension
By year 2025, billion (29%) are projected to have hypertension
Most of the expected increase will be in economically developing regions
Established Market Economies
Former Socialist Economies
India
Latin America and
the Caribbean
Middle Eastern Crescent
China
Other Asia and Islands
Sub-Saharan Africa
Number of People With Hypertension (millions)
Kearney PM, et al. Lancet. 2005;365:

4. A Major Global Health Burden
Most commonly diagnosed condition in the US
Astonishing prevalence
74 Million Americans (1 in 3-4 adults)
Shared prevalence among men and women
Single largest contributor to death worldwide
Dramatically increases the risk of heart attack, stroke, heart failure & kidney failure
Estimated cost this year in US = $73.4B

5. Hypertension Is One of the Leading Causes of Cardiovascular Disease
Congestive Heart Failure
Atherosclerosis / LVH
Myocardial Ischemia
Coronary Thrombosis
Myocardial Infarction
Arrhythmias / Loss of Muscle
Ventricular Enlargement
Hypertension
End-stage Heart Disease
LVH = left ventricular hypertrophy; CAD = coronary artery disease.
*Other risk factors also associated with cardiovascular disease include dyslipidemia, smoking, obesity, and diabetes.
Adapted and reproduced with permission from Dzau VJ, et al. Am Heart J. 1991;121:
Dzau VJ. et al. Circulation. 2006;114:

6. Percentage of Patients (%)
Failure of Current Multidrug Approach to Successfully Treat Hypertension
61%
53%
50%
Percentage of Patients (%)
41%
34%
29%
16%
Kearney PM, et al. J Hypertens. 2004; 22:11-19.

7. Cardiovascular Mortality Risk Doubles With Each 20/10 mm Hg Increase in BP*8x 8 7 6 5 4x
CV Mortality Risk 4 3 2x 2
Purpose:
To illustrate graphically that BP is strongly related to CV mortality risk.
Key Points:
A meta-analysis of individual data for 1 million adults without previous vascular disease from 61 prospective observational studies of BP and mortality indicates that the risk for CV mortality doubles with each 20/10 mm Hg increase in BP
The analysis addressed the cause-specific death rate during a 10-year period among people who were initially aged 40, 50, 60, 70, or 80 years. The rise in CV mortality was directly related to higher initial BP in every age group
Over the range of 115/75 mm Hg to 185/115 mm Hg, each 20 mm Hg increase in systolic blood pressure (SBP) or a 10 mm Hg increase in diastolic blood pressure (DBP) doubled the risk of mortality from stroke or ischemic heart disease in individuals aged years
Source:
Lewington S, Clarke R, Qizilbash N, et al, and The Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360: . 1
115/75
135/85
155/95
175/105
SBP/DBP, mm Hg
CV = cardiovascular.
SBP = systolic blood pressure.
DBP = diastolic blood pressure.
*In individuals aged 40 to 69 years (10-year study period), starting at BP 115/75 mm Hg.
Lewington S, et al. Lancet. 2002;360:

8. Consequences of Hypertension
Pre-hypertension
Chronic
Renal
Failure
End-stage
renal disease
Proteinuria
Nephrosclerosis
Atrial
fibrillation
Ventricular arrhythmias
Ventricular
tachycardia/
fibrillation
Established hypertension
DEATH
Left-ventricular
hypertrophy
Systolic/
diastolic
dysfunction
Congestive
heart failure
Coronary
artery
disease
Angina
Myocardial
infarction
Retinopathy
Binswanger lesions
Asymptomatic
Dementia
Transient ischemic attack
Stroke
Oligosymptomatic
Symptomatic
Polysymptomatic or end-stage disease
Adapted from Messerli FH, et al. Lancet. 2007;370:

9. Definition of Resistant Hypertension
Uncontrolled Hypertension
Includes all patients who lack BP control on treatment, including those on inadequate treatment regimens, those with poor adherence, those with undetected secondary hypertension, as well as those with true treatment resistance1
Resistant Hypertension
BP that remains above goal in spite of compliance with full doses of ≥3 antihypertensive medications of different classes; ideally, 1 of the 3 agents should be a diuretic1
The treatment plan must include attention to lifestyle measures2
Includes those patients who achieve BP control but require ≥4 antihypertensive agents to do so1
Resistant
Hypertension
Calhoun DA, et al. Circulation. 2008;117:e510-e526.
Mancia G, et al. Eur Heart J. 2007;28:

10. BP Regulation Is Complex and Involves Many Components
Mosaic Theory of Hypertension, published in 1967
Chemical Factors
Reactivity of Blood Vessels to Hormones
Neurosympathetic Activity
Viscosity of Blood
Vascular Caliber
Cardiac Output
Vascular Wall
Elasticity
Volume Status
Tissue Perfusion
Pressure/Resistance
Key Take Away: Hypertension is influenced by many different factors, each influencing the others.
Over 40 years ago Irvine Page described the “mosaic theory of arterial hypertension” in his attempt to explain the many factors that were intimately involved in regulating BP. He pointed out that the chief virtue of the mosaic theory lies in its ability to visually depict that all the regulatory functions of the circulatory system must work in equilibrium and that the balance can change from minute to minute.
Although this representation is simplistic in its depiction of the mechanisms involved, it serves to show that hypertension is a battle that must be fought on many different fronts.
Reference
Page IH. The mosaic theory of arterial hypertension–its interpretation. Perspect Biol Med. 1967;10(3):
Page IH. Perspect Biol Med. 1967;10(3):

11. Renal Denervation

12. Rational for Renal Sympathectomy
Pts with essential hypertension exhibit increased renal NA spillover into plasma
Increased renal and cardiac NA spillover is consistent with the hemodynamic profile of essential hypertension
Increased heart rate
Increased cardiac output
Renovascular resistence
Essential hypertension has been recognized as a NEUROGENIC phenomenon

13. Renal Nerves and the SNS
Efferent Sympathetics
Afferent Renal Sympathetics
Decreased Renal Blood Flow
Increased Renin Release
Increased Sodium Reabsorption
The kidney is a source of central sympathetic activity, sending signals to the CNS
DiBona GF, et al. Am J Physiol Regul Integr Comp Physiol. 2010;298: R245–R253.
Schlaich MP, et al. Hypertension. 2009;54:

14. Crosstalk Between Renal Nerves and CNS
 Neurohormones
 Blood Pressure
 Vasoconstriction
 Contractility/Rate
Amplifies central, or systemic, sympathetic outflow
Kidney impairment, or dysfunction =  afferent activity
 RBF/GFR
 Na+/Volume
 Renin
Ang II
Aldo
Schlaich MP, et al. Hypertension. 2009;54:

15. Chronic Effect of Increased Sympathetic Nerve Activity
 Neurohormones
 Blood Pressure
Hypertrophy Ischemia
Arrhythmia
Heart Failure
Worsening HF
 Wall Thickness  Compliance
Atherosclerosis
 GFR Ischemia
Kidney Failure
Worsening Kidney Failure
Schlaich MP, et al. Hypertension. 2009;54:

16. Renal Denervation  Neurohormones  Blood Pressure
Disrupt the renal nerves,
break the cycle
Simultaneously reduce both efferent & afferent effects
Adapted from Schlaich MP, et al. Hypertension. 2009;54:

17. To an Interventionalist with a hammer, everything looks like a nail
HYPE?
To an Interventionalist with a hammer, everything looks like a nail

18. .
130-micron diameter needle

19. New Devices Drugs Radiofrequency catheters Radiation
Mercator
Kipprokration Hospital, Athens
Radiation
Best Medical Int.
Ultrasound
Recor Medical
CardioSonic
Sound Interventions
Kona
Other
RoxMedical
CVRX
Radiofrequency catheters
St. Jude Medical
Cordis
Medtronic
Radiofrequency balloons
Covidien – Maya
Vessix Vascular
Nano particles
Apex Nano

20. New Devices Approved in Europe
Radiofrequency catheters
St. Jude Medical- EnligHTN
Medtronic- Symplicity
Radiofrequency balloons
Covidien- OneShot
BSC (Vessix)- V2
Ultrasound
Recor Medical- Paradise
Other
RoxMedical- RoxFlow2W
CVRx- Barostim Neo

21. Show me the “DATA”…

22. OneShot™ Irrigated Balloon Catheter
Single-treatment RF ablation per artery
reduces procedure time
Spiral electrode design offers standardized and reproducible ablation pattern
Integrated irrigation cools the non-treated region of the artery
Low pressure, balloon-based system delivered over a standard 0.014" wire
The OneShot ™ Renal Denervation System is not approved for sale in the United States.  
MKT3004.A / Effective Date: 12/05/2012

23. OneShot™ Irrigated Balloon Catheter
RF is applied in a constant power mode for a pre-set duration
Integrated balloon irrigation pump
2 min. ablation per artery
Safety shutoff in case of:
Out of range impedance
Pressure loss in the balloon
High pressure in the balloon
High temperature
Catheter disconnect
Ground pad disconnect
MKT3032.A / Effective Date: 12/05/2012

24. Baseline Variables n=9 patients enrolled
RHAS First-in-Man Study (Renal Hypertension Ablation System) Study
Baseline Variables n=9 patients enrolled
Mean ± SD or % (n/N)
Age (years)
59.5 ± 15.6
Male gender
55.6% (5/9)
Weight (kg)
83.6 ± 17.1
# anti-hypertensive meds
2.9 ± 0.6
Office SBP at baseline (mmHg)
185.9 ± 17.5
Office DBP at baseline (mmHg)
91.6 ± 13.6

25. RHAS First-in-Man Study (Renal Hypertension Ablation System) Study
Defined as the ability to insert the RHAS balloon in each renal artery and deliver low level radiofrequency energy - 8/9 technical success
Only failure was with first patient: RF generator high-impedance safety shut-off threshold set too low for humansminor re-programming led to no further issue
Median total procedure time: 35 min
Median fluoro time: min
Median contrast volume: ml
No serious adverse events

26. RHAS First-in-Man Study (Renal Hypertension Ablation System) Study

27. EnligHTN™ Multi-Electrode Renal Denervation System

28. EnligHTN™ Ablation Catheter Key Features
Multi-electrode
8 F compatible
Deflectable , atraumatic tip
Common femoral access
Durable electrodes
Easy insertion with guiding catheters
Hemostatic hub and Tuohy Borst
Compatible with St. Jude Medical RF generator

29. EnligHTN™ Multi-Electrode Renal Denervation System
Acute
One Month

30. EnligHTN I
The objective of this first-in-human study is to evaluate the safety and efficacy of the St. Jude Medical EnligHTN multi-electrode renal denervation system in the treatment of patients with resistant hypertension
Safety Marker
All adverse events during the study period
Efficacy Marker
Office BP during the study: according to Standard Joint National Committee VII Guidelines / ESC and ESH Guidelines

31. Inclusion Criteria
Office systolic blood pressure that remains ≥160 mmHg (≥150 mmHg for patient with type 2 diabetes)
Stable use of ≥3 antihypertensive medications concurrently at maximally tolerated doses for a minimum of 14 days prior to enrollment
of which one is a diuretic, or
patient was on diuretic previously but documented to be diuretic intolerant
≥18 and ≤80 years old

32. Exclusion Criteria Prior renal artery intervention
Evidence of renal artery atherosclerosis (defined as a stenotic severity of >30%) in either renal artery
Multiple main renal arteries in either kidney
Main renal arteries are <4 mm in diameter or <20 mm in length
eGFR of <45 mL/min/1.73m2 using Modification of Diet in Renal Disease (MDRD) formula
Type 1 Diabetes Mellitus
Identified secondary cause of hypertension
Hemodynamically significant valvular heart disease

33. Study Design Key Discussion Points:
Inclusion Criteria:
Office BP
Antihypertensive Medications
Anatomical Evaluation
≥ 18 and ≤ 80 years old
Consented
n = 62
Renal Denervation Eligible
n = 47
Not Eligible
n = 15
Observation Arm n = 1*
Denervation Arm
n = 46
Follow-up continued through 6 months
Primary Objectives: Safety (Adverse Events) & Efficacy (Office BP)
Follow-up continued through 24 months
Exclusion Criteria:
Prior renal artery intervention or evidence of renal artery disease (diameter stenosis >30%)
Multiple main renal arteries in either kidney or main renal arteries <4 mm in diameter or <20 mm in length
eGFR of <45 mL/min/1.73m2 (MDRD formula)
Type 1 Diabetes Mellitus or identified secondary cause of hypertension
Hemodynamically significant valvular heart disease
Key Discussion Points:
Here is a diagram of the study design for EnligHTN I.
62 patients were enrolled and gave informed consent
15 of these patients did not meet the inclusion criteria listed in top left box
The remaining 47 went through the denervation procedure with 46 being followed at 1, 3, 6, 12, 18 and 24 month time periods.
The remaining 1 patient was in the observational arm with follow up at the 6 month timeframe
* Exclusion due to renal artery anatomy

34. Safety Results: Procedural & Device
Treatment delivered with:
No renal artery dissections, aneurysms or new stenoses
No flow-limiting renal artery vasospasms
No major vascular access complications
The primary safety outcome was assessment of all Adverse Events
At the three month time point, one serious event (worsening of pre-existing proteinuria) was classified as related to the device/procedure
There have been other minor procedural-related events such as hematoma (5), vasovagal episodes (2), hypotensive episodes (2) and bradycardia (2)

35. EnligHTN I 3 Month Results: Office BP
95% CI

36. Catheter-Based Radiofrequency Renal Nerve Ablation
Standard interventional technique
4-6 two-minute treatments per artery
Proprietary RF Generator
Automated
Low-power
Built-in safety algorithms
RF energy through circumferential cath: 40 minutes on both arteries 36 36

37. Multiple Discrete Treatments Maximize Nerve Coverage Without Applying Circumferential Energy in a Single Segment

38. The Symplicity HTN Clinical Trial Program
Symplicity HTN-1 First-in-Man, and Expanded Cohort (N=153)1,2
Symplicity HTN-2 Randomized, Controlled Trial (N=106)3
= Planned follow up
= Partial cohort reports
= Primary endpoint
Symplicity HTN-3 Randomized, Blinded, Controlled Trial (N~530)4
Purpose:
To provide a brief description of the 3 Symplicity® Renal Denervation System™ clinical trials: Symplicity HTN-1, Symplicity HTN-2, and Symplicity HTN-3.
Key Points:
The Symplicity HTN clinical trial program has been developed and conducted in a methodical manner with long-term follow up and rigorous attention to the safety of participants
Symplicity HTN-1 was initiated as a proof of principal, nonrandomized cohort study (N=45) in patients with treatment-resistant hypertension at 5 Australian and European sites and later expanded to a total of 19 sites in Europe, Australia, and the United States1,2
Symplicity HTN-2 was designed to evaluate the safety and efficacy of catheter-based RDN in patients with treatment-resistant hypertension in a randomized, controlled manner3
Symplicity HTN-3 is a US-based, randomized, blinded, controlled trial commencing this year to further explore the safety and efficacy of RDN4
As the timeline on the slide indicates, patients in each of the 3 studies will be formally followed for a period of 3 years
Sources:
Krum H, Schlaich M, Whitbourn R, et al. Catheter- based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of- principle cohort study. Lancet. 2009;373:
Symplicity HTN-1 Investigators; Krum H, Barman N, Schlaich M, et al. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:
Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:
Data on file, Medtronic.
2015
2006
2010
2011
2012
2013
2014
2016
2007
2008
2009
Shading on bars indicates clinical trial enrollment periods. Enrollment period for HTN-3 is estimated.
Krum H, et al. Lancet. 2009;373:
Symplicity HTN-1 Investigators. Hypertension. 2011;57:
Esler et al. Lancet. 2010;376:
Data on file, Medtronic.

39. Symplicity HTN-2 Design
Lancet. 2010;376:
Purpose: To demonstrate the effectiveness of catheter-based renal denervation (RDN) for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial
Patients: 106 patients with drug-resistant hypertension randomized 1:1 to treatment with RDN vs. control
Clinical Sites: 24 centers in Europe, Australia, & New Zealand
67% were designated hypertension centers of excellence
Primary Endpoint: Office systolic BP change from baseline at 6 months
Symplicity HTN-2 Investigators. Lancet. 2010;376: 39

40. Patient Population Inclusion Criteria: Exclusion Criteria:
Office SBP ≥160 mmHg (≥150 mmHg with type II diabetes mellitus)
Stable drug regimen of 3+ more anti-HTN medications
Age 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
Stenotic valvular heart disease for which reduction of BP would be hazardous
MI, unstable angina, or CVA in the prior 6 months

41. Procedure Detail & Safety
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

42. Primary Endpoint: 6-Month Office BP
∆ from Baseline to
6 Months (mmHg)
Systolic
Diastolic
Diastolic
Systolic
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
Symplicity HTN-2 Investigators. The Lancet 42

43. Office Systolic BP Distribution
Symplicity HTN-2 Investigators. The Lancet 43

44. Time Course of Office BP Change
RDN
∆ from Baseline
(mmHg) † ††
†††
† p< for between-group comparisons
†† p=0.002 for between-group comparisons
††† p=0.005 for between-group comparisons
Two-way repeated measures ANOVA, p=0.001
Control
∆ from Baseline
(mmHg)
Symplicity HTN-2 Investigators. The Lancet 44

45. Office BP in RDN & Crossover Groups
Treated with RDN
RDN
N=47
Baseline
6 month
BP Change
(p-value)
12 months
Systolic BP
178.3 ± 18.2
146.7 ± 23.3
-31.7 ± 23.1
p<0.001
150.7 ± 21.9
-28.1 ± 24.9
Diastolic BP
96.1 ± 15.5
84.4 ± 17.0
-11.7 ± 11.2
87.0 ± 16.1
-9.7 ± 10.6
P<0.001
compliance period
2 week
compliance period
2 week
Treated with RDN at 6-mo Follow-up
Crossover
N=35
No compliance period for Crossover patients prior to 6 month post-RDN BP measurements
compliance period
2 week
Pre-RDN*
6 month
BP Change
(p-value)
Systolic BP
190.0 ± 19.6
166.3 ± 24.7
-23.7 ± 27.5
p<0.001
Diastolic BP
99.9 ± 15.1
91.5 ± 14.6
-8.4 ± 12.1
* At 6 months post-randomization

46. Procedure Safety No vascular abnormalities at any site of RF delivery
One progression of a pre-existing stenosis unrelated to RF treatment (stented without further sequelae)
Two deaths within the follow-up period; both unrelated to the device or therapy
No orthostatic or electrolyte disturbances
No change in renal function (∆ eGFR)

47. Conclusions
BP reduction can be achieved with catheter based renal denervation.
The treatment effect of renal denervation appears to be significant, sustained, and consistent across subgroups
No major adverse effects of renal denervation
Affirms the crucial relevance of the renal sympathetic system in the maintenance of hypertension.