Percutaneous Renal Denervation: A New Promise in the Treatment of RHT?

BAD KROZINGEN Prof. T. Zeller, MD Bad Krozingen, Germany Percutaneous Renal Denervation: A New Promise in the Treatment of RHT?

Potential conflicts of interest Speaker s name: Thomas Zeller X I have the following potential conflicts of interest to report: X Research contracts X Consulting Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other(s)

Resistant hypertension Resistant Hypertension Definition BP > 140/90 mmhg, despite treatment with 3 drug classes including a diuretic (ESH / ESC) AHA Statement Circulation 2008;117:e510ff

Renal Injury Induces Activation of Sensory Efferent Signals CNS Integration Smooth muscle migration Vasoconstriction Atherosclerosis Hypertrophy Arrhythmias Ischemia Heart Failure Renal ischemia Stroke volume Adenosine Renal Afferent Nerves Renin release Systemic sympathetic gain Na+ retention Hypervolemia Wall stiffness Decreased RBF Proteinuria BNP resistance BNP=brain natriuretic peptide; CNS=central nervous system; RAAS=renal-angiotensin-aldosterone system; RBF=renal blood flow. Adapted from Schlaich MP et al. Hypertension. 2009;54:1195-1201.

Conceptual Basis for Renal Denervation Neurohormones BP Disrupt the renal nerves, break the cycle Simultaneously reduce both efferent and afferent effects BP=blood pressure. Adapted from Schlaich MP et al. Hypertension. 2009;54:1195-1201.

The Renal Denervation Procedure 4-8 focal treatments are delivered 120 seconds per treatment 5 mm between locations Stable, unique locations Circumferential coverage The catheter is pulled, rotated, and new location and prior treatment site are assessed

The Symplicity TM Renal Denervation System* Clinical Trial Program Staged Evaluation in Hypertension First-in-man 1 Symplicity HTN-1 2 Series of pilot studies *device not approved for use in the US Symplicity HTN-2 3 EU/AU randomized clinical trial USA Symplicity HTN-3 4 US randomized clinical trial (ongoing) EU/AU Other Areas of Research: 4 Insulin resistance, HF/cardiorenal, OSA, more HF=heart failure; OSA=obstructive sleep apnea. 1. Krum H et al. Lancet. 2009;373:1275-1281; 2. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917; 3. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909; 4. Data on file, Medtronic, Inc.

The Symplicity HTN-1 Trial: Study Design Design Multicenter, international, nonrandomized, open-label, proof-of-concept study Population 153 patients with treatment-resistant hypertension Treatment Endovascular catheter-based renal denervation using the Symplicity Catheter System* plus baseline antihypertensive medications Duration 36 months (assessments at 1, 3, 6, 12, 18, 24, and 36 months) Outcome measures Primary efficacy measure: Change in office BP Primary safety measures: Physical examination, blood chemistries, anatomic assessment of renal vasculature Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Symplicity HTN-1 Trial Key Inclusion/Exclusion Criteria Inclusion criteria >18 years Office SBP 160 mm Hg 3 antihypertensive medications (including 1 diuretic) Exclusion criteria egfr <45 ml/min/1.73 m 2 Type 1 diabetes mellitus Known secondary cause of hypertension (other than OSA or CKD) Significant renovascular abnormalities CKD=chronic kidney disease; egfr=estimated glomerular filtration rate; OSA=obstructive sleep apnea; SBP=systolic blood pressure. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Symplicity HTN-1 Trial Demographics of Treated Patients Demographics Mean age ± SD (years) 57 ± 11 Gender (% female) 39 Race (% noncaucasian) 5 Comorbidities Type 2 diabetes mellitus (%) 31 Coronary artery disease (%) 22 Hyperlipidemia (%) 68 Mean egfr ± SD (ml/min/1.73 m 2 ) 83 ± 20 BP Mean baseline BP ± SD (mm Hg) 176/98 ± 17/15 Mean number of antihypertensive medications ± SD 5.1 ± 1.4 Diuretics (%) 95 Aldosterone blockers (%) 22 ACE inhibitors or angiotensin receptor blockers (%) 91 Direct renin inhibitors (%) 14 β-blockers (%) 82 Calcium channel blockers (%) 75 Centrally acting sympatholytics (%) 33 Vasodilators (%) 19 α-1 blockers (%) 19 BP=blood pressure; egfr=estimated glomerular filtration rate. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Procedural safety Symplicity HTN-1: Acute Safety No catheter or generator malfunctions No major complications Minor complications in 4 of 153 patients: 1 renal artery dissection during catheter delivery (prior to RF energy delivery); no sequelae 3 access site complications (pseudoaneurysm/hematoma); treated without sequelae First 20 patients had short-term (14-30 days) follow-up angiography No evidence of renal artery stenosis or other abnormalities RF=radio frequency. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Symplicity HTN-1 Trial: Change in Office Blood Pressure Through 36 Months BP change (mmhg) P<0.01 for from BL for all time points

Change in Office Blood Pressure for 24 Patients with 36 Month Follow-up BP change (mmhg) P<0.01 for from BL for all time points Caution: The Symplicity Catheter System is an Investigational Device. Limited by U.S. law to investigational use. For OMA distribution only. 2012 Medtronic, Inc. All rights reserved. 10047134DOC_1A 03/2012

% Patients Distribution of SBP Change at BL, 1, 12, 24, and 36 Months (N=150) (N=143) (N=130) (N=59) (N=24) Caution: The Symplicity Catheter System is an Investigational Device. Limited by U.S. law to investigational use. For OMA distribution only. 2012 Medtronic, Inc. All rights reserved. 10047134DOC_1A 03/2012

Chronic Safety Out to 3 Years One progression of a pre-existing stenosis unrelated to RF treatment (stented without further sequelae) One new moderate stenosis which was not hemodynamically relevant and no treatment 3 deaths within the follow-up period; all unrelated to the device or therapy No hypotensive events that required hospitalization There was no significant change in mean electrolytes or egfr Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Conclusions The magnitude of clinical response is significant and sustained through 3 years The treatment effect was consistent across subgroups (age, diabetes status, and baseline renal function) No late adverse events were seen Caution: The Symplicity Catheter System is an Investigational Device. Limited by U.S. law to investigational use. For OMA distribution only. 2012 Medtronic, Inc. All rights reserved. 10047134DOC_1A 03/2012

Symplicity HTN-2: Study Design Multicenter, Randomized, Prospective Trial Renal denervation with previous treatment (n=52) Patients with resistant hypertension Randomization Primary endpoint: Change in seated office SBP at 6 months Maintain previous treatment alone (n=54) SBP=systolic blood pressure. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2 Trial Key Inclusion/Exclusion Criteria * Inclusion criteria 18-85 years of age Elevated office SBP 160 mm Hg (or 150 mm Hg for type 2 diabetics) Documented compliance with 3 antihypertensive medications Exclusion criteria egfr <45 ml/min/1.73m 2 Type 1 diabetes mellitus Contraindications to MRI Substantial stenotic valvular heart disease Pregnancy or planned pregnancy during the study Myocardial infarction, unstable angina, or cerebrovascular accident in the previous 6 months Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention *Inclusion/exclusion criteria in the trial settings were stringent and conservative in order to ensure a homogenous population in clinical practice, individual patient characteristics and physician judgment should guide patient selection. egfr=estimated glomerular filtration rate; MRI=magnetic resonance imaging. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Patient Disposition Assessed for Eligibility (n=190) Screening Randomized (n=106) Excluded During Screening, Prior to Randomization (n=84) BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) Ineligible anatomy (n=30; 16%) Declined participation (n=10; 5%) Other exclusion criteria discovered after consent (n=8; 4%) 6-month Primary End-Point Allocated to RDN N=52 Treated N=49 Analyzable Allocated to Control N=54 Control N=51 Analyzable Crossover N=46 (2 LTFU) 12-month Post- Randomization 12-month post-rdn N=47 Per protocol, 6-mo Post RDN (Crossover) N=35 Not-per-protocol*, 6-mo Post RDN (Crossover) N=9 * Crossed-over with ineligible BP (<160 mmhg)

Symplicity HTN-2 Trial: BP and Antihypertensive Medication Use at Baseline Symplicity RDN Group (n=52) 1 Control Group (n=54) 1 P 2 BP Mean baseline SBP ± SD (mm Hg) 178 ± 18 178 ± 16.97 Antihypertensive Use Mean baseline DBP ± SD (mm Hg) 97 ± 16 98 ± 17.80 Mean number of antihypertensive medications ± SD 5.2 ± 1.5 5.3 ± 1.8.75 Diuretics (%) 89 91.76 Aldosterone blockers (%) 17 17 >.99 ACE inhibitors, angiotensin receptor blockers (%) 96 94 >.99 Direct renin inhibitors (%) 15 19.80 β-blockers (%) 83 69.12 Calcium channel blockers (%) 79 83.62 Centrally acting sympatholytics (%) 52 52 >.99 Vasodilators (%) 15 17 >.99 α-1 blockers (%) 33 19.12 BP=blood pressure; DBP=diastolic blood pressure; RDN=renal denervation; SBP=systolic blood pressure. 1. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909; 2. Data on file, Medtronic, Inc.

Change in Office Blood Pressure (mm Hg) 10 5 6-mo post-rdn* 6-mo post randomization 6-mo Crossover 12- mo post randomization 12-mo post-rdn* Crossover 6-mo post-rdn* 0-5 -10-15 -20-12 +7 +1-10 -8 RDN SBP RDN DBP Cross over SBP Cross over DBP -25-30 -35-32 -28-24 * P<0.001 for SBP and DBP change from baseline P=0.026 for SBP change from baseline

% Patients Distribution of Office SBP for RDN Group 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 180 mm Hg 160-179 mm Hg 140-159 mm Hg <140 mm Hg 0% RDN Baseline RDN 6-month RDN 12-month

Symplicity HTN-2 Trial: 6-Month Home BP 2 0 22/12 mm Hg difference between Symplicity RDN and control groups (P<.0001) DBP=diastolic blood pressure; RDN=renal denervation; SBP=systolic blood pressure. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Patients (%) Symplicity HTN-2: Goal Achievement 100 80 Renal denervation group Control group (n=41, 84%) 60 (n=24, 47%) P<.0001 for all between-group comparisons 40 (n=18, 35%) (n=19, 39%) 20 (n=5, 10%) (n=3, 6%) 0 No Decrease in SBP 10 mm Hg Decrease in SBP SBP <140 mm Hg at 6 Months SBP=systolic blood pressure. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Medication Changes at 6 and 12 Months Post-Renal Denervation RDN (n=47) 6 month 12 months Decrease (# Meds or Dose) 20.9% (9/43) 27.9% (12/43) Increase (# Meds or Dose) 11.6% (5/43) 18.6% (8/43) Crossover (n=35) 6 months post-rdn Decrease (# Meds or Dose) 18.2% (6/33) Increase (# Meds or Dose) 15.2% (5/33) Physicians were allowed to make changes to medications Once the 6 month primary endpoint was reached* *Further analysis of Medications is ongoing

Symplicity HTN-2 Trial: Short-Term Procedural Safety No serious device- or procedure-related adverse events Minor complications in 5 of 52 patients: 1 access-site complication (femoral artery pseudoaneurysm); treated with manual compression 1 post-procedural drop in BP 1 urinary tract infection 1 extended hospital admission for assessment of parasthesias 1 case of back pain; treated with pain medication and resolved after 1 month BP=blood pressure. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2 Trial: Chronic Safety 43 renal denervation patients underwent CTA, MRA, or duplex evaluation at 6 months No new vascular abnormalities or stenoses at any site of RF delivery 1 possible progression of a preexisting stenosis unrelated to RF treatment; no further therapy warranted Serious Adverse Events at 6 Months Requiring Hospital Admission Composite Cardiovascular Events Symplicity RDN Group (n=49) Control Group (n=51) Hypertensive event unrelated to nonadherence to medication 3 2 Other cardiovascular events 0 0 Other Serious Adverse Events Transient ischemic attack 1 2 Hypertensive crisis after abruptly stopping clonidine 1 0 Hypotensive episode resulting in reduction of medications 1 0 Coronary stent for angina 1 1 Temporary nausea/edema 1 0 CTA=computed tomography angiography; MRA=magnetic resonance angiography; RDN=renal denervation; RF=radiofrequency. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2: Renal Function No Significant Differences in Renal Function Observed at 6 Months Renal Function (baseline-6m) Symplicity RDN Group Control Group Difference (95% CI) P Mean egfr ± SD (ml/min/1.73m 2 ) 0.2 ± 11 (n=49) 0.9 ± 12 (n=51) -0.7 (-5.4, 3.9).76 Mean serum creatinine ± SD (μmol/l) 0.2 ± 17.6 (n=49) -1.1 ± 10.3 (n=51) 1.3 (-4.5, 7.0).67 Mean cystatin-c ± SD (mg/l) 0.1 ± 0.2 (n=37) 0.0 ± 0.1 (n=40) 0.0 (0.0, 0.1).31 egfr=estimated glomerular filtration rate; RDN=renal denervation. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2: Conclusions Symplicity HTN-2 supports and extends the results of previous uncontrolled evaluations of renal denervation Renal denervation led to a reduction in BP of 10 mm Hg in 84% of treated patients At 6 months, an SBP reduction of 32 mm Hg was observed among renal denervation patients, compared with a 1 mm Hg increase in control patients (P<.0001) Procedure was conducted without major adverse effects No evidence of renal artery stenosis No evidence of aneurysmal dilatation No changes in measured renal function BP=blood pressure; SBP=systolic blood pressure. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-3 Trial Overview Design Multicenter (90 sites in the United States), prospective, randomized, blinded, controlled study Population 530 patients with treatment-resistant hypertension Treatment Treatment group (endovascular catheter-based renal denervation with the Symplicity Catheter System* plus baseline antihypertensive medications) Control group (sham procedure ** plus baseline antihypertensive medications) Primary Outcome Measures Change in office SBP from baseline to 6 months Safety **The renal angiogram also acts as the sham procedure for patients in the control group. SBP=systolic blood pressure. Data on file, Medtronic, Inc.

Symplicity HTN-3 Trial Key Inclusion/Exclusion Criteria* Inclusion criteria 18-80 Years of age Elevated office SBP ( 160 mm Hg) Stable medication regimen, including full doses of 3 antihypertensive medications of different classes, of which one must be a diuretic No planned medication changes for 6 months Exclusion criteria Renal artery anatomy that is ineligible for treatment ABPM 24-hour average SBP <135 mm Hg egfr <45 ml/min/1.73m 2 >1 In-patient hospitalization for a hypertensive crisis within the past year Type 1 diabetes mellitus *Not comprehensive; full listing of inclusion/exclusion criteria will be available in the Symplicity HTN-3 protocol. ABPM=ambulatory blood pressure; egfr=estimated glomerular filtration rate; SBP=systolic blood pressure. Data on file, Medtronic, Inc.

Objectives: Assess procedural and long term safety of renal denervation Evaluate effectiveness of renal denervation on clinical outcomes Establish procedural benchmarking and physician practice patterns Evaluate the effect of geographical variations in patients and procedural characteristics on clinical outcomes Perform Quality of Life analysis First enrollment February 2 nd, 2012 Scope: Over 200 sites world wide; at least 5,000 patients Prospective, single-arm, open-label In accordance with Instructions For Use Geographies with commercial availability of Medtronic Symplicity Renal Denervation System* *device not approved for use in the US

What s Next?

New renal denervation systems unveiled at EuroPCR Two new denervation systems were launched at EuroPCR (Paris, 15 18 May 2012). St. Jude Medical announced the launch of the EnligHTN system Covidien unveiled its OneShot system

EnligHTN (St. Jude Medical) The first multi-electrode ablation technology for renal denervation Basket design Each placement of the ablation catheter allows a consistent and predictable pattern of four ablations in 90-second intervals Minimal catheter repositioning may result in a reduction of dye and fluoroscopic (X-ray) exposure

EnligHTN (St. Jude Medical) The EnligHTN I trial (primary investigator Stephen Worthley) on patients with resistant hypertension Preliminary data presented at EuroPCR Average baseline blood pressure despite being on multiple medications: 176/96mmHg 30 days average BP: 148/87mmHg Reduction in systolic BP <140 mmhg: 41% of patients

OneShot system (Covedian) The OneShot device received CE mark clearance in 02-2012 Irrigated, radiofrequency-based balloon catheter Spiral configuration of electrodes allows a single application of radiofrequency inside the artery The irrigated catheter cools the arterial surface with a saline solution Covidien is working on a lower-profile catheter (7F) The system will start being commercialised in the end of 2012

RAPID Trial The first patient in the post-ce mark clinical trial, RAPID (Rapid renal sympathetic denervation for resistant hypertension using the OneShot Ablation System) was enrolled at Middleheim Hospital in Antwerp, Belgium, by Stefan Verheye. This trial will enroll subjects throughout Europe and at a site in New Zealand.

Thermocool System Cool Flow Pump Stockert RF Generator 7FR Thermocool Catheter CONFIDENTIAL Biosense Webster, Inc. 2012 Thermocool Irrigated RD Catheter 7FR 3.5mm tip electrode 4 electrodes Saline irrigation 110cm long 39

Cooled (Irrigated) Tip Ablation Definition: Active cooling of the electrode tip by infusion of liquid Purpose: To decrease the risk of coagulum formation To spar the tip electrode/tissue interface To maintain the advantages of a small tip electrode

Placeholder Pre-Clinical Work 16 Animals 8 With each catheter type Survived for 7 Days Looked at norepi levels and histology 5 lesions per artery 15 Watts 30, 60, 120 second burns CONFIDENTIAL Biosense Webster, Inc. 2011

7 day Renal Norepinephrine Levels in Treated and Control Arteries 1000 1200 Thermocool (irrigated) 800 600 400 200 #32053 #32054 #32060 #32065 1000 800 600 400 200 32499 32501 32507 32316 0 Control Treated 0 Control Treated Two minutes 30 seconds and 1 minute 700 1000 Celsius (nonirrigated) 600 500 400 300 200 100 0 Control Treated #32056 #32057 #32058 #32061 800 600 400 200 0 Control Treated 32498 32500 32505 32312

Placeholder Human Clinical Data Single Center trial (Relief) - Praque First 10 patients about to be published Follow up(m) No major adverse events 4-6 ablations per artery 10-20W for 30 seconds N Range Mean Median N Range Mean Median 1 9-85 to -10-37.3-38.5 9-33 to -14-15.3-17 3 6-94 to -8-45.3-41 6-51 to -5-16 -13 9 6-50 to -19-30 -25.5 6-13 to 0-8 -9.5 CONFIDENTIAL Biosense Webster, Inc. 2011

Ultrasound Catheter (Cardiosonic)

Results Animal Study

Results Animal Study There was clear thermal effect in the artery tissue, mainly presented in the adventitia. Theral effect resulted in collagen condensation in the media and adventitia with necrosis of the vasa-vasorum and nerves. In most sections, the endothelium was left without any damage.

Summary RDN of refractory hypertension seems to be effective in a relevant patient population using different devices RDN in other indications is still experimental Besides radiofrequency other technologies will be available soon (cooling, ultrasound, local drug delivery)