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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 [email protected] 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, BristolMyer-Squibb, Boehringer-Ingelheim 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, Lancet. 2005 Jan 15-21;365(9455:217-23 Eur Heart J. (2007) 28, 1462-1536 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 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 THERAPIE EMPFEHLUNG Welche Kombination? BP Crush Studie (Amelior) Eur Heart J. (2007) 28, 1462-1536 THERAPIERESISTENZ 30% unbehandelt 35% behandelt - nicht im Zielbereich • Faktoren der unkontrollierten Hypertonie: – “Physician inertia” – Patienten compliance – Resistente HTN (10-20%) 35% behandelt und im Zielbereich Renale Denervation (RDN) = potentielle compliance-unabhängige Therapie 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 NIERE UND SNS • ↑ Contractility • ↑ Heart Rate • Vasoconstriction Afferent Nerves Efferent Nerves Blood Pressure Schlaich et al. Hypertension. 2009;54(6):1195-1201. ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 9 NIERE UND SNS • Vasoconstriction • Atherosclerosis Afferent Nerves Efferent Nerves Blood Pressure ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Renal Function + Increase Comorbidities Schlaich et al. Hypertension. 2009;54(6):1195-1201. • ↑ Contractility • ↑ Heart Rate • Hypertrophy • Arrhythmia • Heart Failure 10 NIERE UND SNS • Vasoconstriction • Atherosclerosis Afferent Efferent -- Renal Denervation (RDN)-Nerves Nerves Blood Pressure ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function co-morbidities +- Decrease Increase co-morbidities Schlaich et al. Hypertension. 2009;54(6):1195-1201. • ↑ Contractility rate • ↑ Heart Rate • Hypertrophy • Arrhythmia • Heart Failure 11 CHIRURGISCHE DENERVATION 1952 Effektive Blutdruckkonntrolle - Hohe Mortalität RENALE DENERVATION Katheterbasiert Die renale Anatomie erlaubt einen Katheter basierten Zugang Vessel lumen Media • • • • Ursprung von Th10-L2 Fasernverlauf entlang Art. renalis Vor allem in Adventitia Efferente and afferente Nerven liegen beieinander Adventitia Renal nerves 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 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 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) SYMPLICITY Clinical Trial Program: >5000 Patienten mit verschiedenen Indikationen Trials under way Pilot Studies in New Indications (Approved Regions) 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.) Symplicity HTN-1 Population Demographics Comorbidities Blood pressure Age (yr) 57 ± 11 Gender (female) (%) 39 Race (noncaucasian) (%) 5 Diabetes mellitus type 2 (%) 31 CAD (%) 22 Hyperlipidemia (%) 68 eGFR (mL/min/1.73m2) 83 ± 20 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.) 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.) Symplicity HTN-1 Treatment Effect Change in Blood Pressure (mmHg) 10 Systolic Diastolic 0 -22 -10 -26 -13 -33 -15 -33 -19 6M (n=144) 1Y (n=130) 2Y (n=59) 3Y (n=24) -10 -20 -30 -40 • 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.) Symplicity HTN-2 Results Primary Endpoint (6M post Randomisation) 10 RDN (n=49) Control (n=51) 1 0 ∆ from -10 Baseline to 6 Months -20 (mmHg) 0 Systolic Diastolic -12 Diastolic 10 RDN (n=43) 0 ∆ from -10 Baseline to -20 18 Months (mmHg) -12 Diastolic -30 -30 -32 -40 Latest Follow-up (18M post Randomisation) Systolic p <0.0001 for ∆ between RDN and Control -50 Primary Endpoint: • >80% of RDN patients had ≥10 mmHg reduction in SBP • 5 patients had ≤ 5mmHG reduction in SBP -32 -40 Systolic -50 p <0.01 for from baseline 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.) RENALE DENERVATION Publikationen The Lancet. Published electronically on Nov 17, 2010. 364 Publikationen seit 2009 (HTN-1 Trial) Renale Denervation Glucose Metabolism RDN Improves Glucose Metabolism and Insulin Resistance 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 Timepoint *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. Renale Denervation Glucose Metabolism Glucose Concentration (mg/dl) RDN Improves Glucose Metabolism and OGTT 270 Oral Glucose Tolerance Test (75 g) 250 230 210 Baseline (n = 25) ** 3 Months (n = 15) 180 6 Months (n = 7) * * 150 120 90 ** 0 Minutes 60 Minutes 120 Minutes *Significant reduction (p <0.05) compared with baseline Mahfoud et al. Deutsche Gesellschaft Für Kardiologie: Jahrestagung Mannheim. April 2010. 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 - 0.6 0.6 0.6 0.6 Diuretic–Furosemide Diuretic–HCTZ Diuretic–Spironolactone ARB–Valsartan BB–Metoprolol CCB–Verapamil Vasodilator–Minoxidil A2B–Guanfacine … … … … BB–Metoprolol … … … … … … … BB–Metoprolol … … … … … … … BB–Metoprolol … … … Serum Cr (mg/dL) Medications Rocha-Singh. TCT 2009. 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.) NIERENFUNKTION 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. Symplicity HTN-2 Results – Medication Medication Changes Post-Renal Denervation in Pooled Group 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 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 1. RR an beiden Armen 2. Medikamentenanamnese ≥3er Kombination und >160 RRsys >150 RRsys und DM 1. 24h-Blutdruckmessung 2. Renin-Aldosteron-Spiegel 3. CT-Angio der Nierenarterien NAST Interventionelle Radiologie R/A >30 A >20ng/dL Endokrinologie Ambulanz <3er Kombination oder <160/90 Steigerung der Therapie / Kombinationspräparat NAST-Ausschluss und R/A <30 Termin für HT Ambulanz bzw Für stationäre Aufnahme zur RD 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: 08:00 – 13:00: 08:00 – 13:00: 01/49150 – Vermittlung 01/49150 – 2360 – Station D/S 0650/3939911 (Ordination) Vielen Dank für Ihre Aufmerksamkeit Efferente Nerven: - SMCs Vasokonstriktion - Reninausschüttung - ?? Backup Slides Renale Denervation Proof of Principle Quantifying Human SNS Activity Central sympathetic nerve activity Muscle sympathetic nerve activity (MSNA) recording postganglionic nerve traffic Renal sympathetic nerve activity Norepinephrine spillover measuring transmitter release from sympathetic nerves to plasma 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 MSNA (burst/min) BP (mmHg) Baseline 56 161/107 41 (-27%) 141/90 (-20/-17) 19 (-66%) 127/81 (-34/-26) 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. Renale Denervation Proof of Principle Related changes in underlying physiology ∆ Baseline 1 Month 161/107 141/90 Left kidney 72 37 -48% Right kidney 79 20 -75% Office BP (mmHg) Renal NE spillover (ng/min) Total body NE spillover (ng/min) 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. 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%) Example Case Left: 75% reduction Right: 85% reduction 200 Renal NA Spillover (ng/min) • • Left Kidney Right Kidney 150 100 85% 75% 50 0 Baseline Esler et al. J Htn. 2009;27(Suppl. 4):s167. Schlaich et al. J Htn. 2009;27(Suppl. 4):s154. 30-Day Post Right Denervation 30-Day Post Left Denervation Symplicity HTN-1: Response Rate Among 1-Month Non-responders (n=45)* (n=45) (n=45) (n=44) (n=39) (n=17) *Non-responder defined as a SBP reduction of <10 mmHg Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) (n=8) ™ Symplicity RDN System: The First Catheter-Based Therapy for Treatment-Resistant Hypertension