renale denervierung – ein fehlgeschlagenes therapiekonzept? priv.-doz. dr.med. dr. phil. thomas...

Renale Denervierung – Ein fehlgeschlagenes

Therapiekonzept?

Priv.-Doz. Dr.med. Dr. phil. Thomas Weiss

3. Medizinische Abteilung für KardiologieWilhelminenspital, 1160 Wien

CCHR, Oslo University Hospital, Ullevå[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, Bristol-

Myer-Squibb, Boehringer-Ingelheim

Hypertension – „a major public health burden“

EPIDEMIOLOGIEHYPERTONIE

Eur Heart J. (2007) 28, 1462-1536

• 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

THERAPIEEVIDENZ

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

THERAPIEEMPFEHLUNG

Eur Heart J. (2007) 28, 1462-1536

Therapiestart: Welches Präparat?

• Thiazid-Diuretika

• Calciumantagonisten (CA)

• ACE-Hemmer (ACEI)

• Angiotensinrezeptorblocker (ARB)

• (Betablocker (BB) – Nicht bei MetS oder hohem DM Risiko.)

THERAPIEEMPFEHLUNG

Eur Heart J. (2007) 28, 1462-1536

Welche Kombination?

BP Crush Studie (Amelior)

• Faktoren der unkontrollierten Hypertonie:– “Physician inertia”– Patienten compliance– Resistente HTN (10-20%)

Renale Denervation (RDN) = potentielle compliance-unabhängige Therapie

35%behandelt undim Zielbereich

30% unbehandelt

35% behandelt - nicht

im Zielbereich

THERAPIERESISTENZ

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

• ↑ Contractility• ↑ Heart Rate

Afferent Nerves

Schlaich et al. Hypertension. 2009;54(6):1195-1201.

• Vasoconstriction

↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow

EfferentNerves

BloodPressure

9

NIERE UND SNS

• ↑ Contractility• ↑ Heart Rate• Hypertrophy• Arrhythmia• Heart Failure

Afferent Nerves

• Vasoconstriction• Atherosclerosis

↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow↓ Renal Function

EfferentNerves

BloodPressure

10

+ Increase Comorbidities


NIERE UND SNS

Afferent Nerves

• ↑ Contractility• ↑ Heart rate• Hypertrophy• Arrhythmia• Heart Failure


↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow↓ Kidney function

EfferentNerves

BloodPressure

-- Renal Denervation (RDN)--

• ↑ Contractility• ↑ Heart Rate• Hypertrophy• Arrhythmia• Heart Failure


↑ Renin Release RAAS activation↑ Sodium Retention↓ Renal Blood Flow↓ Kidney function

11

- Decrease co-morbidities+ Increase co-morbidities


NIERE UND SNS

1952

Effektive Blutdruckkonntrolle - Hohe Mortalität

CHIRURGISCHEDENERVATION

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

Renalnerves

RENALE DENERVATIONKatheterbasiert

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


Procedure Overview


• 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 DENERVATIONPräklinische Studien

RENALE DENERVATIONKlinische Studien

First-in-Man (AU)

Series of Pilot Studies(EU, US & AU)

Symplicity HTN-2Initial RCT(EU & AU)

SYMPLICITY HTN-3US Pivotal Trial (US)

Global SYMPLICITY Registry

(Approved Regions)

Expand HTN Indication(Approved Regions)

Symplicity HTN-1

Pilot Studies inNew Indications

(Approved Regions)

Trials under way

SYMPLICITY Clinical Trial Program:>5000 Patienten mit verschiedenen Indikationen

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

*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/1.73m2

Key Inclusion Criteria

Symplicity HTN-1Eckdaten

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.)

Symplicity HTN-1Population

• 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


Symplicity HTN-1Procedural Data

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

6M (n=144)

1Y (n=130)

2Y (n=59)

3Y (n=24)

-40

-30

-20

-10

0

10

-22 -26 -33 -33-10 -13 -15 -19

Systolic DiastolicC

ha

ng

e in

Blo

od

Pre

ss

ure

(m

mH

g)

Symplicity HTN-1Treatment Effect

-50

-40

-30

-20

-10

0

10

-32

-12

-50

-40

-30

-20

-10

0

10

-32

1

-12

0

∆ 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

Systolic Diastolic ∆ 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 <0.0001 for ∆ between RDN and Control

RDN (n=49) Control (n=51) RDN (n=43)

Symplicity HTN-2Results

• 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


Symplicity HTN-1Safety Record

The Lancet. Published electronically on Nov 17, 2010.

RENALE DENERVATIONPublikationen

364 Publikationen seit 2009 (HTN-1 Trial)

RDN Improves Glucose Metabolism and Insulin Resistance

*Significant reduction (p <0.05) compared with baselineHOmeostasisModelAssessment-InsulinResistance (HOMA-IR) = (Insulin x Blood Glucose)/405

Mahfoud et al. Deutsche Gesellschaft Für Kardiologie: Jahrestagung Mannheim. April 2010.

TimepointFasting 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

Renale DenervationGlucose Metabolism

0 Minutes 60 Minutes 120 Minutes

Glu

cose

Co

nce

ntr

atio

n (

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.

RDN Improves Glucose Metabolism and OGTT

Renale DenervationGlucose Metabolism

• 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.

Conclusions

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 0.6 0.6 0.6

Medications Diuretic–FurosemideDiuretic–HCTZDiuretic–SpironolactoneARB–ValsartanBB–MetoprololCCB–VerapamilVasodilator–MinoxidilA2B–Guanfacine

…………

BB–Metoprolol………

…………


…………


Rocha-Singh. TCT 2009.

Renale Denervation”Wunderheilung”

(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

Symplicity HTN-1Zeit bis zum Effekt

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

NIERENFUNKTIONnach DENERVATION

Combined group (n=76) 6 monthPost-RDN

12 monthsPost-RDN

18 monthsPost-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 medicationsOnce the 6 month primary endpoint was reached

Medication Changes Post-Renal Denervation in Pooled Group

Symplicity HTN-2Results – Medication

1. RR an beiden Armen2. Medikamentenanamnese

1. 24h-Blutdruckmessung2. Renin-Aldosteron-Spiegel3. CT-Angio der Nierenarterien

Steigerung der Therapie / Kombinationspräparat

<3er Kombinationoder <160/90

≥3er Kombination und >160 RRsys>150 RRsys und DM

NAST R/A >30A >20ng/dL

NAST-Ausschluss und R/A <30

InterventionelleRadiologie Endokrinologie

Ambulanz

Termin für HT Ambulanz bzwFür stationäre Aufnahme zur RD

Renale DenervationVorgangsweise

HypertonieamblanzKontaktdaten

Kontakt:

Priv.-Doz. Dr.med. Dr. phil. Thomas Weiss3. Medizinische Abteilung für KardiologieWilhelminenspital, 1160 Wien

1. Fax Zuweisung: 01/49150 – 2309

2. Telefon:08:00 – 13:00: 01/49150 – Vermittlung08:00 – 13:00: 01/49150 – 2360 – Station D/S08:00 – 13:00: 0650/3939911 (Ordination)

Vielen Dank für Ihre Aufmerksamkeit

Efferente Nerven:- SMCs Vasokonstriktion- Reninausschüttung- ??

Backup Slides

Norepinephrine spillovermeasuring transmitter release from sympathetic nerves to plasma

Muscle sympatheticnerve activity (MSNA)recording postganglionic nerve traffic

Central sympatheticnerve activity

Renal sympatheticnerve activity

Quantifying Human SNS Activity

Renale DenervationProof of Principle

Direct measurement of reduced central sympathetic nerve activity

Denervation of Patient with Essential HTN

Schlaich et al. NEJM. 2009;36(9):932-934.

Baseline

1 month

12 months

MSNA(burst/min)

BP(mmHg)

56 161/107

41 (-27%) 141/90 (-20/-17)

19 (-66%) 127/81 (-34/-26)

Improvement in cardiac baroreflex sensitivity after RDN (7.8 11.7 msec/mmHg)

59-Year-Old Male on 7 HTN Meds


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 (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.


Renal Norepinephrine Spillover: 10 Cases

Example CaseLeft: 75% reductionRight: 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 = 0.023 (95% CI: 28–65%)• Mean total body NE spillover ↓ 28%, p = 0.043 (95% CI: 4–52%)

200

150

100

50

0

Rena

l NA

Spill

over

(ng/

min

)

Baseline 30-Day Post RightDenervation

30-Day Post LeftDenervation

Right Kidney

Left Kidney

85%

75%


Symplicity HTN-1: Response Rate Among 1-MonthNon-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)


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

renale denervierung – ein fehlgeschlagenes therapiekonzept? priv.-doz. dr.med. dr. phil. thomas...

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