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Renale Denervierung – Ein fehlgeschlagenes Therapiekonzept ?

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. Disclosures. Lecture Fees

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Renale Denervierung – Ein fehlgeschlagenes Therapiekonzept ?

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  1. Renale Denervierung– EinfehlgeschlagenesTherapiekonzept? 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

  2. Disclosures • Lecture Fees • Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Medtronic, Menarini, Vifor Pharma • Consultation Fees • Daiichi-Sankyo, Medtronic • Research and EducationalGrants • AustrianScience Fund, Stein Erik Hagen Foundation, Daiichi-Sankyo, Bristol-Myer-Squibb, Boehringer-Ingelheim

  3. EPIDEMIOLOGIE HYPERTONIE Hypertension – „a major public health burden“ • Erstaunlichhohe Prävalenz • Jeder 3. Erwachsene • 1 MilliardeMenschenweltweit→ 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. 2005 Jan 15-21;365(9455:217-23 Eur Heart J. (2007) 28, 1462-1536

  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, 1462-1536

  5. THERAPIE EMPFEHLUNG Therapiestart: Welches Präparat? • Thiazid-Diuretika • Calciumantagonisten (CA) • ACE-Hemmer (ACEI) • Angiotensinrezeptorblocker (ARB) • (Betablocker (BB) – Nicht bei MetS oder hohem DM Risiko.) Eur Heart J. (2007) 28, 1462-1536

  6. THERAPIE EMPFEHLUNG Welche Kombination? BP Crush Studie (Amelior) Eur Heart J. (2007) 28, 1462-1536

  7. THERAPIERESISTENZ • FaktorenderunkontrolliertenHypertonie: • “Physician inertia” • Patientencompliance • Resistente HTN (10-20%) 35% behandelt - nicht imZielbereich 30% unbehandelt 35%behandelt und imZielbereich RenaleDenervation(RDN) = potentielle compliance-unabhängigeTherapie

  8. Renal Sympathetic Connection RENALE DENERVATION • RollederNiere und des SNS in derEntwicklung und Progression der HTN isteindeutigbewiesen • Pharmakotherapiemodifiziert die physiologischenInteraktionen an verschiedenenStellen • Die RDN versucht die Interaktion am Ursprungzuunterbinden

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

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

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

  12. CHIRURGISCHE DENERVATION 1952 EffektiveBlutdruckkonntrolle - HoheMortalität

  13. RENALE DENERVATION Katheterbasiert Die renaleAnatomieerlaubteinenKatheterbasiertenZugang Vessel lumen Media • Ursprung von Th10-L2 • Fasernverlaufentlang Art. renalis • Vorallem in Adventitia • Efferenteand afferenteNervenliegenbeieinander Adventitia Renalnerves

  14. Symplicity™ Renal Denervation System RENALE DENERVATION Katheterbasiert • 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

  15. RENALE DENERVATION Katheterbasiert Procedure Overview

  16. RENALE DENERVATION Präklinische Studien • Extensive präklinische Phase in Schweinemodell(>300 pigs) • Angiographie und histopathologischeAnalysenach 7, 30, 60 und 180 Tagen • KeineStenosenoderLumenreduktion in behandeltenArterien • RF Generator Algorhythmusoptimiert um Gefäßverletzungzuminimieren

  17. 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 PatientenmitverschiedenenIndikationen Trials under way

  18. 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 • Non-Randomised • 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.)

  19. Symplicity HTN-1 Population Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

  20. Symplicity HTN-1 ProceduralData • 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.)

  21. 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.)

  22. Symplicity HTN-2 Results Primary Endpoint (6M post Randomisation) Latest Follow-up (18M post Randomisation) Control (n=51) RDN (n=49) RDN (n=43) ∆ from Baseline to 6 Months (mmHg) ∆ from Baseline to 18 Months (mmHg) Systolic Diastolic 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

  23. 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.)

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

  25. RDN Improves Glucose Metabolism and Insulin Resistance Renale Denervation Glucose Metabolism *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.

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

  27. 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 patientswith treatment-resistant essential hypertension, maybe beyond purely antihypertensive effects. 1. Symplicity HTN-2 Investigators. The Lancet. 2010.

  28. Renale Denervation ”Wunderheilung” Rocha-Singh. TCT 2009.

  29. Symplicity HTN-1 Zeit bis zum Effekt (n=143) (n=148) (n=144) (n=130) (n=107) (n=59) (n=24) (n=24)* • 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.)

  30. NIERENFUNKTION nach DENERVATION Wieist die NierenfunktionohnesympathischeInnervation? • TransplantierteNieren: • KeinesympathischeInnervation • ErhalteneWasser- und Elektrolythasuhaltsfunktion • Die sympathischeKomponentederKontrollederNierenfunktiondienteherals “overdrive”, nichtzurErhaltungder “normalen” Nierenfunktion Blaufox et al. N Engl J Med. 1969;280(2):62–66.

  31. Medication Changes Post-Renal Denervation in Pooled Group Symplicity HTN-2 Results – Medication Physicians were allowed to make changes to medications Once the 6 month primary endpoint was reached

  32. Renale Denervation Vorgangsweise RR an beiden Armen Medikamentenanamnese <3er Kombination oder <160/90 ≥3er Kombination und >160RRsys >150 RRsys und DM Steigerung der Therapie / Kombinationspräparat 1. 24h-Blutdruckmessung 2. Renin-Aldosteron-Spiegel 3. CT-Angio der Nierenarterien 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

  33. Hypertonieamblanz Kontaktdaten Kontakt: 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)

  34. Vielen Dank fürIhreAufmerksamkeit • Efferente Nerven: • SMCs Vasokonstriktion • Reninausschüttung • ??

  35. Backup Slides

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

  37. Renale Denervation Proof of Principle Direct measurement of reduced central sympathetic nerve activity Denervation of Patient with Essential HTN 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.

  38. Renale Denervation Proof of Principle Related changes in underlying physiology 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.

  39. Renal Norepinephrine Spillover: 10 Cases Renale Denervation Proof of Principle • 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 0 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.

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

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

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