renal denervation: current evidence and remaining...
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Renal denervation: Current evidence and remaining uncertainties
Michel Azizi
Georges Pompidou European Hospital
Hypertension Unit
ESH excellence Center
Paris Descartes University
Clinical Investigation Center
INSERM CIC9201
Disclosures: Ardian/Medtronic, Cordis, Vessix
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BP Control (<140/90 mmHg) among treated, %
4744
34
42
30
40
50
60
70
4 5 to 54 y 55 to 64 y 65 to 74 y Total
64
59
50
59
30
40
50
60
70
45 to 54 y 55 to 64 y 65 to 74 y Total
Men Women
France, ENNS Survey 2006-2007
Godet-Thobie H et al. BEH 2008;49-50: 478
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Resistant hypertension
1. Estimated Prevalence : 5 to 25% in tertiary Hypertension Clinics
8-12 % in general population
2. Incidence: 0.7 cases per 100 person-years follow-up
3. Associated with TOD and high cardiovascular risk
4. Associated with increased cardiovascular morbidity and mortality
• Prognosis over 3.8 years of median follow-up: • unadjusted CVE rates: RH : 18.0% vs. non-RH: 13.5%, P<0.001• HR: 1.47 (95%CI: 1.33–1.62)
Daugherty SL et al. Circulation 2012, 125:1635Persell SD. Hypertension. 2011;57de la Sierra A et al. Hypertension. 2011;57:898Calhoun et al Circulation 2008;117:e510
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Novel strategiesClinical development stage
1. Vasopeptidase inhibition, safety issues.
2. Dual angiotensin receptor-neprilysin inhibition (ARNI)
3. Aldosterone synthase inhibition
4. DHP-like new MRA
5. Endothelin antagonism
Preclinical development stage
1. Aminopeptidase A inhibition
2. Pro(renin) receptor blockade (handle region peptide)
3. ACE2 inhibition
4. ECE inhibition
5. Dual inhibitors
6. NHE3 inhibitors
7. Rho kinase inhibitors
8. Antisens therapy, siRNA…
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Treatment of resistant hypertension by renal denervation
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Renal Sympathetic efferent and afferent Nerves:Kidney as Recipient of Sympathetic Signals
Kidney as Origin of Central Sympathetic Drive
Renal AfferentNerves
HypertrophyArrhythmiaOxygen ConsumptionHeart Failure
VasoconstrictionAtherosclerosis
InsulinResistance
Renal IschemiaHypoxia AcidosisOxidative stressInflammationEndothelial factorsAdenosine
↑ Renin Release ���� RAAS activationSodium RetentionRightward Shift of Pressure-Natriuresis Curve
↓ Renal Blood Flow
Renal EfferentNerves
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The central sympathetic overdrive in essential Hypertension
Normotensives
High Normals
White Coat
Borderline Htn
Essential Htn – Stage 1
Essential Htn – Stage 2/3
Essential Htn with LVH
Smith et al. AJH 2004; 17:217–222
Central Sympathetic Drive – Assessed by MSNA
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Increased renal sympathetic activity in young and middle -aged untreated hypertensive patients
Di Bona et al. Am J Physiol Regul Integr Comp Physiol 2010; 298: R245.
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• Arise from ~ T10-L2• Follow the renal artery to the kidney• Primarily lie within the adventitia
Vessel
Lumen
Media
Adventitia
Renal
Nerves
Renal Nerves as a Therapeutic Target
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Percutaneous catheter-based transluminal renal ablation by delivery of RF energy
• 40-minute catheter-based procedure
• Selective denervation by delivery of 4 to 6 focal
low power RF energy ablations (5-8W) starting
close to the hilum before renal artery bifurcation
and then every ≈5 mm after pulling back and
rotating the catheter along the length of both renal
arteries.
• Blood flow minimizes surface/endothelial injury
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Focal medial and adventitial fibrosis with minimal intimal thicknening and disruption of the internal elastic lamina
Kippy, R et al. Clin Res Cardiol DOI 10.1007/s00392-011-0346-8
All treated vessels were completely endothelialized after 6 months.
There was no inflammatory cells, renal arterial stenosis or thrombosis
6 months after renal denervation
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Preclinical Data: Renal nerve injury at 6 mo.
Normal nerve Renal nerve injury 6 mo. after RD
Kippy, R et al. Clin Res Cardiol DOI 10.1007/s00392-011-0346-8
•Healing fibrosis causing a thickening of
the surrounding perineurium
•No inflammatory component
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Renal denervation with the Simplicity ®catheter
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Patient 1
-20 -10 0 10 20 30 40 50 60 70 80 90
60
80
100
120
140
160
180
200
Days
One out of four AHTwas stopped becauseof hypotension
BP (m
mH
g)
Effect of renal devervation on BP
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Symplicity HTN -2 Trial
Baseline
Drop-Outs
Registry
Treatment Group
Control Patients
offered treatment
Suboptimal
Anatomy
Registry
Control Group
Primary
Endpoint
6M
6M
12-36M
Anatomical Screening
(MRA, CTA, duplex
or angiogram)
24-hr ABPM
Randomized 1:1
Uncontrolled HTN
SBP ≥ 160 mmHg
(≥ 150 mmHg diabetics)
≥ 3 meds
“Baseline”
2 week observation
Baseline BP measure at end
of baseline period
Symplicity HTN-2 Investigators. The Lancet. 2010.
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Assessed for Eligibility
(n=190)Excluded During Screening,
Prior to Randomization (n=84)
• BP < 160 at Baseline Visit (after 2-weeks of medication
compliance confirmation) (n=36; 19%)
• Ineligible anatomy (n=30; 16%)
• Declined participation (n=10; 5%)
• Other exclusion criteria discovered after consent (n=8; 4%)
Randomized (n=106)
Allocated to RDN
N=52 Treated
N=49 Analyzable
Allocated to Control
N=54 Control
N=51 Analyzable
12-month post-RDN
N=47
Per protocol, 6-mo
Post–RDN, N=35
Patient Disposition
Not-per-protocol*, 6-
mo Post–RDN, N=9
Crossover
N=46
(2 LTFU)
* Crossed-over with ineligible BP (<160 mmHg)
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Baseline Characteristics
RDN
(n=52)
Control
(n=54)p-value
Age 58 ± 12 58 ± 12 0.97
Gender (% female) 35% 50% 0.12
Race (% Caucasian) 98% 96% >0.99
BMI (kg/m2) 31 ± 5 31 ± 5 0.77
Baseline Systolic BP (mmHg) 178 ± 18 178 ± 16 0.97
Baseline Diastolic BP (mmHg) 97 ± 16 98 ± 17 0.80
Type 2 diabetes 40% 28% 0.22
Coronary Artery Disease 19% 7% 0.09
Hypercholesterolemia 52% 52% >0.99
eGFR (MDRD, ml/min/1.73m2) 77 ± 19 86 ± 20 0.013
eGFR 45-60 (% patients) 21% 11% 0.19
Serum Creatinine (mg/dL) 1.0 ± 0.3 0.9 ± 0.2 0.003
Urine Alb/Creat Ratio (mg/g)† 128 ± 363 109 ± 254 0.64
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RDN
(n=52)
Control
(n=54)p-value
Number Anti-HTN medications 5.2 ± 1.5 5.3 ± 1.8 0.75
% patients on HTN meds >5 years 71% 78% 0.51
% percent patients on ≥5 meds. 67% 57% 0.32
% patients on drug class:
ACEi/ARB 96% 94% >0.99
Direct renin inhibitor 15% 19% 0.80
Beta-adrenergic blocker 83% 69% 0.12
Calcium channel blocker 79% 83% 0.62
Diuretic 89% 91% 0.76
Aldosterone antagonist 17% 17% >0.99
Vasodilator 15% 17% >0.99
Alpha-1 adrenergic blocker 33% 19% 0.12
Centrally acting sympatholytic 52% 52% >0.99
Baseline Medications
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BP decrease at 6 months
RDN (n=52) Control (n=54) p
Office BP (mmHg) -32±±±±23/-12±±±±11 (n=49) +1±±±±21/0±±±±10 (n=51) <0.0001
Self BP (mmHg) -20±17/-12±11 (n=32) +2±13/0±7 (n=40) <0.0001
24h-ABPM (mmHg) -11±±±±15/-7±±±±11 (n=20) -3±±±±19/-1±±±±12 (n=25) 0.006/0.014
# Med Dose Decrease (%) 10 (20%) 3 (6%) 0.04
# Med Dose Increase (%) 4 (8%) 6(12%) 0.74
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Distribution of Office SBP for the RDN Group%
Pa
tie
nts
Esler M. et al. Circulation; 126:2976
Pre-
RDN
6
month
12
month
178.3
(18.3)
146.7
(23.3)
150.7
(21.9)
96.1
(15.5)
84.4
(17.0)
87.0
(16.1)
10% of patients did not respond to RDN
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Distribution of office SBP for the crossover group (n= 35)
% P
ati
en
ts
Esler M. ACC 2012
Pre-
RDN
6
month
BP
Change
190.0
(19.6)
166.3
(24.7)
-23.7
(27.5)
99.9
(15.1)
91.5
(14.6)
-8.4
(12.1)
Crossover (n=35)
6 months post-
RDN
Decrease (#
Meds or Dose)
18.2%
(6/33)
Increase (#
Meds or Dose)
15.2%
(5/33)
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Renal Function Over Time
76.9 77.1 78.2
0
10
20
30
40
50
60
70
80
90
BL (N=49) 6 M (N=49) 12 M (N=45)
Crossover
88.8 89.3 85.2
0
10
20
30
40
50
60
70
80
90
BL (N=35) 6 M (N=35) 12 M (N=35)
RDNEsler M. ACC 2012
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Procedural Safety• 38 minute median procedure time
– Average of 4 ablations per artery
• IV narcotics & sedatives used to manage pain during delivery of RF
1. No serious device or procedure related adverse events (n=52)
2. Minor adverse events
• 1 femoral artery pseudoaneurysm treated with manual compression
• 1 post-procedural drop in BP resulting in a reduction in medication
• 1 back pain treated with pain medications & resolved after one month
3. 6-month renal imaging (n=43, 37 Duplex echo, 5 MRI, 5 CT)
• No vascular abnormality at any RF treatment site
• progression of a pre-existing stenosis unrelated to RF treatment
4. 6-month renal function:
• No change
Symplicity HTN-2 Investigators. The Lancet. 2010.
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Change in Office Blood Pressure over 36 months in a cohort study
-19-21 -22
-26 -26
-33 -33 -33
-9 -10 -10
-13 -12
-15 -14
-19
-35
-30
-25
-20
-15
-10
-5
0
1 M (n=143)
3 M (n=148)
6 M (n=144)
12 M (n=130)
18 M (n=107)
24 M (n=59)
30 M (n=24)
36 M (n=24)
Systolic BP
Diastolic BP
BP
cha
nge
(mm
Hg)
P<0.01 for ∆ from BLfor all time points
Sobotka P. ACC 2012
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Evolution of eGFR over 36 months
0
10
20
30
40
50
60
70
80
90
BL (N=143) 3 M (N=131) 6 M (N=141)12 M (N=128)18 M (N=53) 24 M (N=35) 30 M (N=11)
Caution: The Symplicity® Catheter System™ is an Investigational Device. Limited by U.S. law to investigational use. For OMA distribution only. © 2012 Medtronic, Inc. All rights reserved. 10047134DOC_1A 03/2012Sobotka P. ACC 2012
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Critical appraisal of the results of the SIMPLICITY studies
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Impact of non -blinded outcome assessors on estimated intervention effects in RCTs
Hróbjartsson A. BMJ 2012;344:e1119
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Relationship between changes in 24h ambulatory SBP and office SBP in patients treated with AHT
Darusentan study
Symplicity HTN2
Mancia G. J Hypertens 2004; 22:435
A metaanalysis of 44 studies including 5842 patients
67%29%
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BP lowering effects of SNB vs. SRASB in the PHARES study
BP control rates in RH patientsSNB strategy: 58%
SRASB strategy: 20%
Bobrie G et al J Hypertens. 2012; 30(8):1656
Mean difference in dABPSBP: 10 mmHg (95% CI, 7–14 mmHg)
DBP: 4 mmHg (95% CI, 2–7 mmHg)
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Critical Assessment of the Simplicity HTN2 trial1. Internal validity
– Open label
– No ABPM to define resistant hypertension at baseline
– No work-up to exclude secondary hypertension
– No marker/index of primary success
– No assessment of adherence to AHT during the trial
– No standardized AHT (treatment scoring is difficult)
– No masked assessment of the primary endpoint (office BP)
2. List of possible biases– Expectation bias by both patients and doctors
– Performance bias (cointerventions, change in behavior…)
– Evaluation bias (office BP vs. ABPM)
Azizi M et al. Eur J Vasc Endovasc Surg. 2012;43:293.
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Critical appraisal of the renal effects
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Change in eGFR from baseline to 6 weeks by quartile of change in SBP
Mann JE et al. Ann Intern Med. 2009;151:1-10.
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Renal denervation increases glomerular hyperfiltration in the obesity -induced
hypertension in dogs
Lohmeier TE.Hypertension 2012;59:331
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RDN and the kidney: preliminary data in humans
• RDN decreases ultrasound renal resistive index with no change in
eGFR or UAER in patients with RH and baseline eGFR ≥ 45 ml/minMahfoud F et al. Hypertension 2012; 60:419
• RDN preserves renal perfusion in presence of reduced systemic BP:
– decreases renal vascular resistance without changing renal blood flow (MRI) or
GFR suggesting that autoregulation of renal perfusion is maintained
Ott C et al. cJASN 2013
• RDN does not change makers of acute kidney injury (NGAL, KIM-1)Dorr O et al. JACC 2013; 61:479
• RDN reduces safely office BP in pts with RH and stage 3-4 CKDHering D et al. JASN 2012; 23:1250
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Long term safety
Vonend O et al. Lancet 2012; 380: 778Kaltenbach B et al. JACC 2012, Oct 24.
With the increasing use of RDN, such complication may
occur more often: Long term follow-up necessary
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64 y women
During RDN procedure 6 months after RDN
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External validity
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Eligibility for RDN in real-life patients with RH referred to a tertiary hypertension unit during yea r 2011
• 1034 patients hospitalized in 2011
• 200 patients with RH (20%)
− 113 patients with secondary hypertension (57%)
− 87 patients with essential RH (43%)
• 15/1034 patients (1.5%) of all hospitalized patients
eligible for RDN
• 15/87 (17.2%) of patients with essential RH eligible for
RDN
Azizi M. et al. JACC 2012, Oct 25
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Conclusions
• Catheter-based renal denervation in patients with treatment-resistant
essential hypertension, resulted in significant reductions in office BP,
much less marked when using ABPM.
• The technique was applied without major complications in the short
term.
• The technique needs still to be evaluated to :
– assess its efficacy against the best optimal care using predefined and validated
algorhythm of antihypertensive treatments
– Find out a method indicating the primary success of the denervation
– assess its long term safety
Symplicity HTN-2 Investigators. The Lancet. 2010.
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The French DENER -HTN trial
1. Objective :
To assess efficacy, safety and cost-effectiveness of the radiofrequency –based renal denervation (RD, Symplicity catheter,
Medtronic®) in 120 patients with proven resistant hypertension.
2. Methodology :
Multicentre, randomized, controlled, open-label, parallel, superiority trial, comparing RD + standardized optimal antihypertensive treatment (SOAT) vs. SOAT alone with blind assessment of the primary endpoint (ABPM, PROBE design)
3. Total duration of the trial:
27 months (enrollment : 15 months, follow up : 12 months)
Azizi M. The DENERHTN study. http://clinicaltrials.gov/ct2/show/NCT01570777