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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