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

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

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

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…

Treatment of resistant hypertension by renal denervation

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

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

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.

• 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

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

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

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

Renal denervation with the Simplicity ®catheter

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

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.

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)

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

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

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

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

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)

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

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.

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

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

Critical appraisal of the results of the SIMPLICITY studies

Impact of non -blinded outcome assessors on estimated intervention effects in RCTs

Hróbjartsson A. BMJ 2012;344:e1119

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%

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)

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.

Critical appraisal of the renal effects

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.

Renal denervation increases glomerular hyperfiltration in the obesity -induced

hypertension in dogs

Lohmeier TE.Hypertension 2012;59:331

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

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

64 y women

During RDN procedure 6 months after RDN

External validity

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

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.

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