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Renale Denervierung – Ein fehlgeschlagenes Therapiekonzept? Priv.-Doz. Dr.med. Dr. phil. Thomas Weiss 3. Medizinische Abteilung für Kardiologie Wilhelminenspital,

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Präsentation zum Thema: "Renale Denervierung – Ein fehlgeschlagenes Therapiekonzept? Priv.-Doz. Dr.med. Dr. phil. Thomas Weiss 3. Medizinische Abteilung für Kardiologie Wilhelminenspital,"—  Präsentation transkript:

1 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

2 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

3 Hypertension – a major public health burden EPIDEMIOLOGIE HYPERTONIE Eur Heart J. (2007) 28, 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, Lancet Jan 15-21;365(9455:217-23

4 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 Eur Heart J. (2007) 28,

5 THERAPIE EMPFEHLUNG Eur Heart J. (2007) 28, Therapiestart: Welches Präparat? Thiazid-Diuretika Calciumantagonisten (CA) ACE-Hemmer (ACEI) Angiotensinrezeptorblocker (ARB) (Betablocker (BB) – Nicht bei MetS oder hohem DM Risiko.)

6 THERAPIE EMPFEHLUNG Eur Heart J. (2007) 28, Welche Kombination? BP Crush Studie (Amelior)

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

8 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 RENALE DENERVATION

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

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

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

12 1952 Effektive Blutdruckkonntrolle - Hohe Mortalität CHIRURGISCHE DENERVATION

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

14 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

15 Procedure Overview RENALE DENERVATION Katheterbasiert

16 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 RENALE DENERVATION Präklinische Studien

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

18 First in Man Cohort: 45 patients, EU, Australia Non-Randomised First patient enrolled: June, month initial report in The Lancet, 2009 Expanded Cohort* (this report): 153 patients, EU, Australia, USA Non-Randomised 36-month follow-up *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) Office SBP 160 mmHg Stable drug regimen of 3+ more anti-HTN medications eGFR 45 mL/min/1.73m 2 Key Inclusion Criteria Symplicity HTN-1 Eckdaten

19 DemographicsAge (yr) 57 ± 11 Gender (female) (%) 39 Race (noncaucasian) (%) 5 ComorbiditiesDiabetes mellitus type 2 (%) 31 CAD (%) 22 Hyperlipidemia (%) 68 eGFR (mL/min/1.73m 2 ) 83 ± 20 Blood pressureBaseline 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.) Symplicity HTN-1 Population

20 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.) Symplicity HTN-1 Procedural Data

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

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

23 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.) Symplicity HTN-1 Safety Record

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

25 RDN Improves Glucose Metabolism and Insulin Resistance *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 Timepoint Fasting Glucose (mg/dl) Insulin (mU/l) C-peptide (µg/l)HOMA-IR Baseline (n = 25)118 ± ± ± ± month (n = 21)113 ± ± 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 ± ± ± 1.4 Renale Denervation Glucose Metabolism

26 0 Minutes 60 Minutes120 Minutes Glucose Concentration (mg/dl) 3 Months (n = 15) * * * *Significant reduction (p <0.05) compared with baseline Months (n = 7) * * * Baseline (n = 25) Oral Glucose Tolerance Test (75 g) Mahfoud et al. Deutsche Gesellschaft Für Kardiologie: Jahrestagung Mannheim. April RDN Improves Glucose Metabolism and OGTT Renale Denervation Glucose Metabolism

27 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 Conclusions

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30 40-year-old white female with a longstanding history of hypertension, hypercholesterolemia, obesity and a positive family history of CAD Baseline1 Month3 Months6 Months Office BP171/109138/90147/95131/81 24-hr ABPM150/94-117/69- Serum Cr (mg/dL) 0.6 Medications Diuretic–Furosemide Diuretic–HCTZ Diuretic–Spironolactone ARB–Valsartan BB–Metoprolol CCB–Verapamil Vasodilator–Minoxidil A2B–Guanfacine … BB–Metoprolol … BB–Metoprolol … BB–Metoprolol … Rocha-Singh. TCT Renale Denervation Wunderheilung

31 (n=143)(n=148)(n=144)(n=130)(n=107)(n=59)(n=24)(n=24)* Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) 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 Symplicity HTN-1 Zeit bis zum Effekt

32 Blaufox et al. N Engl J Med. 1969;280(2):62–66. 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 NIERENFUNKTION nach DENERVATION

33 Combined group (n=76)6 month Post-RDN 12 months Post-RDN 18 months Post-RDN 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 Change67.1% (51/76)42.1% (32/76)34.2% (25/73) Indeterminate5.3% (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 Medication Changes Post-Renal Denervation in Pooled Group Symplicity HTN-2 Results – Medication

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

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

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

37 Backup Slides

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

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

40 Related changes in underlying physiology Baseline1 Month Office BP(mmHg)161/107141/90 Renal NE spillover(ng/min) Left kidney % Right kidney % Total body NE spillover(ng/min) % Plasma renin(μg/l/hr) % Renal plasma flow(ml/min) % LV mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m 2 ) from baseline to 12 months Consistent with expected effects of denervation Schlaich et al. NEJM. 2009;36(9): Renale Denervation Proof of Principle

41 Renal Norepinephrine Spillover: 10 Cases Example Case Left: 75% reduction Right: 85% reduction Esler et al. J Htn. 2009;27(Suppl. 4):s167. Schlaich et al. J Htn. 2009;27(Suppl. 4):s154. Mean total renal norepinephrine spillover 47%, p = (95% CI: 28–65%) Mean total body NE spillover 28%, p = (95% CI: 4–52%) Renal NA Spillover (ng/min) Baseline30-Day Post Right Denervation 30-Day Post Left Denervation Right Kidney Left Kidney 85% 75% Renale Denervation Proof of Principle

42 Symplicity HTN-1: Response Rate Among 1-Month Non-responders (n=45)* ( n=45) (n=17) *Non-responder defined as a SBP reduction of <10 mmHg ( n=44) ( n=39) ( n=8)(n=45) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

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


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