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

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

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, 1.56 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;365:217-223.

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

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;121:1244-1263. Dzau VJ. et al. Circulation. 2006;114:2850-2870.

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.

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 40-69 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;360:1903-1913. . 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;360:1903-1913.

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;370:591-603.

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;28:1462-1536.

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):325-333. Page IH. Perspect Biol Med. 1967;10(3):325-333.

Renal Denervation

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

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;54:1195-1201.

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;54:1195-1201.

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;54:1195-1201.

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;54:1195-1201.

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

. 130-micron diameter needle

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

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

Show me the “DATA”…

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

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

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

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: 7.7 min Median contrast volume: 124 ml No serious adverse events

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

EnligHTN™ Multi-Electrode Renal Denervation System

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

EnligHTN™ Multi-Electrode Renal Denervation System Acute One Month

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

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

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

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

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)

EnligHTN I 3 Month Results: Office BP 95% CI

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

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

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;373:1275-1281. 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;57:911-917. 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;376:1903-1909. 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;373:1275-1281. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917. Esler et al. Lancet. 2010;376:1903-1909. Data on file, Medtronic.

Symplicity HTN-2 Design Lancet. 2010;376:1903-1909. 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;376:1903-1909. 39

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 18-85 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

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

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. 2010. 42

Office Systolic BP Distribution Symplicity HTN-2 Investigators. The Lancet. 2010. 43

Time Course of Office BP Change RDN ∆ from Baseline (mmHg) † †† ††† † p<0.0001 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. 2010. 44

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

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)

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.