Renale Denervierung – Ein fehlgeschlagenes Therapiekonzept? Priv.-Doz. Dr.med. Dr. phil. Thomas Weiss 3. Medizinische Abteilung für Kardiologie Wilhelminenspital, 1160 Wien CCHR, Oslo University Hospital, Ullevål thomas.weiss@meduniwien.ac.at

Daiichi-Sankyo, Medtronic Disclosures Lecture Fees Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Medtronic, Menarini, Vifor Pharma Consultation Fees Daiichi-Sankyo, Medtronic Research and Educational Grants Austrian Science Fund, Stein Erik Hagen Foundation, Daiichi-Sankyo, Bristol-Myer-Squibb, Boehringer-Ingelheim Let me first guide you through some of the terms that i will be using through out my presentation. I will start with introducing the concept of the metabolic syndrome, a cluster cardiovascular risk factors, consisting of...

Hypertension – „a major public health burden“ EPIDEMIOLOGIE HYPERTONIE Hypertension – „a major public health burden“ Erstaunlich hohe Prävalenz Jeder 3. Erwachsene 1 Milliarde Menschen weltweit → 1.6 Mrd. bis 2025 “…Single largest contributor to death…” Bedeutender Risikofaktor für eine Reihe an kardiovaskulären Erkrankungen: KHK, Herzinsuffizienz, VH-Flimmern, Insult, pAVK, CNI, Let me first guide you through some of the terms that i will be using through out my presentation. I will start with introducing the concept of the metabolic syndrome, a cluster cardiovascular risk factors, consisting of... Lancet. 2005 Jan 15-21;365(9455:217-23 Eur Heart J. (2007) 28, 1462-1536

Zahlreiche Studien >1 Million Teilnehmern THERAPIE EVIDENZ Zahlreiche Studien >1 Million Teilnehmern Antihypertensive Therapie bringt eine signifikante Reduktion der kardiovaskuläre Morbidität und Mortalität (-40% Insult; -20% CHD) Dieser Effekt gilt für alle Formen der Hypertonie Der Effekt ist unabhängig von Geschlecht oder Ethnie Let me first guide you through some of the terms that i will be using through out my presentation. I will start with introducing the concept of the metabolic syndrome, a cluster cardiovascular risk factors, consisting of... Eur Heart J. (2007) 28, 1462-1536

Therapiestart: Welches Präparat? EMPFEHLUNG Therapiestart: Welches Präparat? Thiazid-Diuretika Calciumantagonisten (CA) ACE-Hemmer (ACEI) Angiotensinrezeptorblocker (ARB) (Betablocker (BB) – Nicht bei MetS oder hohem DM Risiko.) Let me first guide you through some of the terms that i will be using through out my presentation. I will start with introducing the concept of the metabolic syndrome, a cluster cardiovascular risk factors, consisting of... Eur Heart J. (2007) 28, 1462-1536

THERAPIE EMPFEHLUNG Welche Kombination? BP Crush Studie (Amelior) Let me first guide you through some of the terms that i will be using through out my presentation. I will start with introducing the concept of the metabolic syndrome, a cluster cardiovascular risk factors, consisting of... Eur Heart J. (2007) 28, 1462-1536

Renale Denervation (RDN) = potentielle compliance-unabhängige Therapie THERAPIERESISTENZ Faktoren der unkontrollierten Hypertonie: “Physician inertia” Patienten compliance Resistente HTN (10-20%) 35% behandelt - nicht im Zielbereich 30% unbehandelt 35% behandelt und im Zielbereich Renale Denervation (RDN) = potentielle compliance-unabhängige Therapie

Renal Sympathetic Connection RENALE DENERVATION Renal Sympathetic Connection Rolle der Niere und des SNS in der Entwicklung und Progression der HTN ist eindeutig bewiesen Pharmakotherapie modifiziert die physiologischen Interaktionen an verschiedenen Stellen Die RDN versucht die Interaktion am Ursprung zu unterbinden

Blood Pressure Efferent Nerves Afferent Nerves NIERE UND SNS ↑ Contractility ↑ Heart Rate Vasoconstriction Efferent Nerves Afferent Nerves Blood Pressure ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 9 Schlaich et al. Hypertension. 2009;54(6):1195-1201. 9

Blood Pressure Efferent Nerves Afferent Nerves NIERE UND SNS ↑ Contractility ↑ Heart Rate Hypertrophy Arrhythmia Heart Failure Vasoconstriction Atherosclerosis Efferent Nerves Afferent Nerves Blood Pressure ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Renal Function + Increase Comorbidities 10 Schlaich et al. Hypertension. 2009;54(6):1195-1201. 10

-- Renal Denervation (RDN)-- NIERE UND SNS ↑ Contractility ↑ Heart Rate Hypertrophy Arrhythmia Heart Failure Vasoconstriction Atherosclerosis ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function ↑ Contractility ↑ Heart rate Hypertrophy Arrhythmia Heart Failure Vasoconstriction Atherosclerosis ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function Efferent Nerves Afferent Nerves -- Renal Denervation (RDN)-- Blood Pressure + Increase co-morbidities - Decrease co-morbidities 11 Schlaich et al. Hypertension. 2009;54(6):1195-1201. 11

Effektive Blutdruckkonntrolle - Hohe Mortalität CHIRURGISCHE DENERVATION 1952 Effektive Blutdruckkonntrolle - Hohe Mortalität

Die renale Anatomie erlaubt einen Katheter basierten Zugang RENALE DENERVATION Katheterbasiert Die renale Anatomie erlaubt einen Katheter basierten Zugang Vessel lumen Media Adventitia Renal nerves Ursprung von Th10-L2 Fasernverlauf entlang Art. renalis Vor allem in Adventitia Efferente and afferente Nerven liegen beieinander 13

Symplicity™ Renal Denervation System RENALE DENERVATION Katheterbasiert Symplicity™ Renal Denervation System Low-profile, electrode tipped catheter Delivers RF energy to treatment site Proprietary RF generator Low power Automated Built-in safety control algorithms Access via standard interventional technique (6F) Approximately 40 minutes from first to last RF delivery

RENALE DENERVATION Katheterbasiert Procedure Overview

Extensive präklinische Phase in Schweinemodell (>300 pigs) RENALE DENERVATION Präklinische Studien Extensive präklinische Phase in Schweinemodell (>300 pigs) Angiographie und histopathologische Analyse nach 7, 30, 60 und 180 Tagen Keine Stenosen oder Lumenreduktion in behandelten Arterien RF Generator Algorhythmus optimiert um Gefäßverletzung zu minimieren

Global SYMPLICITY Registry RENALE DENERVATION Klinische Studien First-in-Man (AU) Symplicity HTN-1 Series of Pilot Studies (EU, US & AU) Symplicity HTN-2 Initial RCT (EU & AU) SYMPLICITY HTN-3 US Pivotal Trial (US) Global SYMPLICITY Registry (Approved Regions) Expand HTN Indication (Approved Regions) Pilot Studies in New Indications (Approved Regions) SYMPLICITY Clinical Trial Program: >5000 Patienten mit verschiedenen Indikationen Trials under way

Key Inclusion Criteria Symplicity HTN-1 Eckdaten First in Man Cohort: 45 patients, EU, Australia Non-Randomised First patient enrolled: June, 2007 12-month initial report in The Lancet, 2009 Expanded Cohort* (this report): 153 patients, EU, Australia, USA 36-month follow-up Key Inclusion Criteria Office SBP ≥160 mmHg Stable drug regimen of 3+ more anti-HTN medications eGFR ≥45 mL/min/1.73m2 *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) 18

Symplicity HTN-1 Population Demographics Age (yr) 57 ± 11 Gender (female) (%) 39 Race (noncaucasian) (%) 5 Comorbidities Diabetes mellitus type 2 (%) 31 CAD (%) 22 Hyperlipidemia (%) 68 eGFR (mL/min/1.73m2) 83 ± 20 Blood pressure Baseline BP (mmHg) 176/98 ± 17/15 Number of anti-HTN meds (mean) 5.0 ± 1.4 ACE/ARB (%) 90 Beta blocker (%) 82 Calcium channel blocker (%) 75 Vasodilator (%) 19 Diuretic (%) 95 Spironolactone (%) 21 Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) 19

Symplicity HTN-1 Procedural Data 38-minute median time from first to last ablation Average of 4 ablations per artery Intravenous narcotics and sedatives used to manage pain during delivery of RF energy No catheter or generator malfunctions No major complications Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) 20

Symplicity HTN-1 Treatment Effect p <0.01 for  from baseline for all time points, Number of patients represents data available at time of data-lock Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Sobotka, P.) 21

Symplicity HTN-2 Results Primary Endpoint (6M post Randomisation) Latest Follow-up (18M post Randomisation) RDN (n=49) Control (n=51) RDN (n=43) ∆ from Baseline to 6 Months (mmHg) Systolic Diastolic ∆ from Baseline to 18 Months (mmHg) Diastolic Diastolic p <0.0001 for ∆ between RDN and Control Systolic Systolic p <0.01 for  from baseline Primary Endpoint: >80% of RDN patients had ≥10 mmHg reduction in SBP 5 patients had ≤ 5mmHG reduction in SBP

Symplicity HTN-1 Safety Record 81/153 patients with 6-month renal CTA, MRA or duplex No vascular abnormalities at any site of RF delivery 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 not treated There were no clinically significant changes in mean electrolytes or eGFR Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) 23

RENALE DENERVATION Publikationen The Lancet. Published electronically on Nov 17, 2010. 364 Publikationen seit 2009 (HTN-1 Trial)

RDN Improves Glucose Metabolism and Insulin Resistance Renale Denervation Glucose Metabolism RDN Improves Glucose Metabolism and Insulin Resistance Timepoint Fasting Glucose (mg/dl) Insulin (mU/l) C-peptide (µg/l) HOMA-IR Baseline (n = 25) 118 ± 20 22.3 ± 14.8 6.2 ± 3.6 6.2 ± 4.3 1 month (n = 21) 113 ± 14 10.9 ± 7.3* 3.2 ± 1.5* 3.0 ± 1.8* 3 months (n = 15) 102 ± 12* 8.4 ± 4.8* 3.0 ± 1.1* 2.1 ± 1.3* 6 months (n = 7) 99 ± 18* 8.8 ± 4.6 3.1 ± 1.1 2.2 ± 1.4 *Significant reduction (p <0.05) compared with baseline HOmeostasisModelAssessment-InsulinResistance (HOMA-IR) = (Insulin x Blood Glucose)/405 Mahfoud et al. Deutsche Gesellschaft Für Kardiologie: Jahrestagung Mannheim.  April 2010.

RDN Improves Glucose Metabolism and OGTT Renale Denervation Glucose Metabolism RDN Improves Glucose Metabolism and OGTT 0 Minutes 60 Minutes 120 Minutes Glucose Concentration (mg/dl) 3 Months (n = 15) * *Significant reduction (p <0.05) compared with baseline 270 6 Months (n = 7) Baseline (n = 25) 250 230 210 180 150 120 90 Oral Glucose Tolerance Test (75 g) Mahfoud et al. Deutsche Gesellschaft Für Kardiologie: Jahrestagung Mannheim.  April 2010.

The technique was applied without major complications Conclusions Catheter-based RDN, done in a multicentre, randomised trial in patients with treatment-resistant essential hypertension, resulted in significant reductions in BP The technique was applied without major complications This therapeutic innovation, based on the described neural pathophysiology of essential hypertension, affirms the crucial relevance of renal nerves in the maintenance of BP in patients with hypertension Catheter-based RDN is beneficial for patients with treatment-resistant essential hypertension, maybe beyond purely antihypertensive effects. 1. Symplicity HTN-2 Investigators. The Lancet. 2010.

Renale Denervation ”Wunderheilung” 40-year-old white female with a longstanding history of hypertension, hypercholesterolemia, obesity and a positive family history of CAD Baseline 1 Month 3 Months 6 Months Office BP 171/109 138/90 147/95 131/81 24-hr ABPM 150/94 - 117/69 Serum Cr (mg/dL) 0.6 Medications Diuretic–Furosemide Diuretic–HCTZ Diuretic–Spironolactone ARB–Valsartan BB–Metoprolol CCB–Verapamil Vasodilator–Minoxidil A2B–Guanfacine … Rocha-Singh. TCT 2009.

Symplicity HTN-1 Zeit bis zum Effekt Response rate appears not to diminish in time A small number of patients has reached 3Y follow up, all of whom have achieved SBP reduction ≥10 mmHg * Number of patients represents data available at time of data-lock Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

Wie ist die Nierenfunktion ohne sympathische Innervation? nach DENERVATION Wie ist die Nierenfunktion ohne sympathische Innervation? Transplantierte Nieren: Keine sympathische Innervation Erhaltene Wasser- und Elektrolythasuhaltsfunktion Die sympathische Komponente der Kontrolle der Nierenfunktion dient eher als “overdrive”, nicht zur Erhaltung der “normalen” Nierenfunktion Blaufox et al. N Engl J Med. 1969;280(2):62–66.

Medication Changes Post-Renal Denervation in Pooled Group Symplicity HTN-2 Results – Medication Medication Changes Post-Renal Denervation in Pooled Group Combined group (n=76) 6 month Post-RDN 12 months 18 months Decrease (# Meds or Dose) 17.1% (13/76) 23.7% (18/76) 23.3% (17/73) Increase (# Meds or Dose) 10.5% (8/76) 18.4% (14/76) 21.9% (16/73) No Change 67.1% (51/76) 42.1% (32/76) 34.2% (25/73) Indeterminate 5.3% (4/76) 15.8% (12/76) 20.5% (15/73) Physicians were allowed to make changes to medications Once the 6 month primary endpoint was reached

Renale Denervation Vorgangsweise RR an beiden Armen Medikamentenanamnese ≥3er Kombination und >160 RRsys >150 RRsys und DM <3er Kombination oder <160/90 1. 24h-Blutdruckmessung 2. Renin-Aldosteron-Spiegel 3. CT-Angio der Nierenarterien Steigerung der Therapie / Kombinationspräparat NAST R/A >30 A >20ng/dL NAST-Ausschluss und R/A <30 Interventionelle Radiologie Termin für HT Ambulanz bzw Für stationäre Aufnahme zur RD Endokrinologie Ambulanz

Hypertonieamblanz Kontaktdaten Priv.-Doz. Dr.med. Dr. phil. Thomas Weiss 3. Medizinische Abteilung für Kardiologie Wilhelminenspital, 1160 Wien 1. Fax Zuweisung: 01/49150 – 2309 2. Telefon: 08:00 – 13:00: 01/49150 – Vermittlung 08:00 – 13:00: 01/49150 – 2360 – Station D/S 08:00 – 13:00: 0650/3939911 (Ordination)

Vielen Dank für Ihre Aufmerksamkeit Efferente Nerven: SMCs Vasokonstriktion Reninausschüttung ??

Backup Slides

Quantifying Human SNS Activity Renale Denervation Proof of Principle Quantifying Human SNS Activity Central sympathetic nerve activity Muscle sympathetic nerve activity (MSNA) recording postganglionic nerve traffic Norepinephrine spillover measuring transmitter release from sympathetic nerves to plasma Renal sympathetic nerve activity

Direct measurement of reduced central sympathetic nerve activity Renale Denervation Proof of Principle Direct measurement of reduced central sympathetic nerve activity Denervation of Patient with Essential HTN MSNA (burst/min) BP (mmHg) 56  161/107 41 (-27%) 141/90 (-20/-17) 19 (-66%) 127/81 (-34/-26) 59-Year-Old Male on 7 HTN Meds Baseline 1 month 12 months Improvement in cardiac baroreflex sensitivity after RDN (7.8 11.7 msec/mmHg) Schlaich et al. NEJM. 2009;36(9):932-934.

Related changes in underlying physiology Renale Denervation Proof of Principle Related changes in underlying physiology   Baseline 1 Month ∆ Office BP (mmHg) 161/107 141/90 Renal NE spillover (ng/min) Left kidney 72 37 -48% Right kidney 79 20 -75% Total body NE spillover 600 348 -42% Plasma renin (μg/l/hr) 0.3 0.15 -50% Renal plasma flow (ml/min) 719 1126 57% LV mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m2) from baseline to 12 months Consistent with expected effects of denervation Schlaich et al. NEJM. 2009;36(9):932-934.

Renal Norepinephrine Spillover: 10 Cases Renale Denervation Proof of Principle Renal Norepinephrine Spillover: 10 Cases Mean total renal norepinephrine spillover ↓ 47%, p = 0.023 (95% CI: 28–65%) Mean total body NE spillover ↓ 28%, p = 0.043 (95% CI: 4–52%) 200 150 100 50 Example Case Left: 75% reduction Right: 85% reduction Left Kidney Right Kidney Renal NA Spillover (ng/min) 85% 75% Baseline 30-Day Post Right Denervation 30-Day Post Left Denervation Esler et al. J Htn. 2009;27(Suppl. 4):s167. Schlaich et al. J Htn. 2009;27(Suppl. 4):s154. 41

Symplicity HTN-1: Response Rate Among 1-Month Non-responders (n=45)* *Non-responder defined as a SBP reduction of <10 mmHg Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

Symplicity™ RDN System: The First Catheter-Based Therapy for Treatment-Resistant Hypertension