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Hypertrophy Arrhythmia Oxygen Consumption Vasoconstriction Atherosclerosis Insulin Resistance Renal Sympathetic Activation: Afferent Nerves Kidney as Origin of Central Sympathetic D

Renal Denervation: Fact or

Fiction

A/Prof Michael Nguyen

Cathlab Director Fremantle Hospital

Australia

Hypertrophy Arrhythmia Oxygen Consumption

Vasoconstriction

Atherosclerosis

Insulin

Resistance

Renal Sympathetic Activation: Afferent Nerves

Kidney as Origin of Central Sympathetic Drive

Renal Afferent Nerves

↑ Renin Release  RAAS activation

↑ Sodium Retention

↓ Renal Blood Flow

Sleep Disturbances

2

Renal sympathetic activity, assessed with renal norepinephrine spillover measurements in

patients with untreated essential hypertension, expressed in relation to age

DiBona G F , and Esler M Am J Physiol Regul Integr Comp Physiol 2010;298:R245-R253

• Nerves arise from T10-L2

• The nerves arborize around the artery and primarily lie within the adventitia

• Sympathetic Outflow > HT

Renal Nerve Anatomy

Vessel Lumen

Media

Adventitia

Renal Nerves

4

4

Renal Nerve Anatomy Allows a

Initial Cohort – Reported in the Lancet, 2009:

-First-in-man, non-randomized

-Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a

diuretic; eGFR ≥ 45 mL/min)

- 12-month data

\

Expanded Cohort* – This Report (Symplicity HTN-1):

-Expanded cohort of patients (n=153)

Symplicity HTN-1: BP Reductions through

3 years

BP change

(mmHg)

P<0.01 for ∆ from BL for all time points

*Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

Symplicity HTN-1: Percentage Responders

• Purpose: To demonstrate the effectiveness of catheter-based renal

denervation for reducing blood pressure in patients with uncontrolled

hypertension in a prospective, randomized, controlled, clinical trial

vs control

designated hypertension centers of excellence)

9

Symplicity HTN-2

Symplicity HTN-2 Investigators Lancet 2010;376:1903-1909

Lancet 2010;376:1903-1909

Symplicity HTN-2 Trial

Inclusion Criteria:

– Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus)

– Stable drug regimen of 3+ more anti-HTN medications

– Age 18-85 years

Exclusion Criteria:

– Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention

– eGFR < 45 mL/min/1.73m 2 (MDRD formula) – Type 1 diabetes mellitus

– Contraindication to MRI – Stenotic valvular heart disease for which reduction of BP would be hazardous – MI, unstable angina, or CVA in the prior 6 months

Symplicity HTN-2 Investigators Lancet 2010;376:1903-1909

EnligHTN™ Renal Denervation System EnligHTN™ Renal Denervation System

Terumo Iberis Catheter

Vessix Vascular V2

• RF electrodes and thermistors on

balloon

• 4-8 gold electrode pairs

• 30 sec inflation/ treatment per renal

artery

ReCor Medical Paradise

Non-focussed high-frequency ultrasound

Low pressure balloon with cooled fluid

Frictional heating of soft tissues

Uniform circumferential denervation

Mercator Bullfrog

• Balloon-sheathed microneedle

• Injection into adventitial tissues

• Guanethidine given locally induces

direct and immune-mediated

autonomic denervation

Kona Medical

• Low-intensity, focussed ultrasound

• Nerves are particularly sensitive to mechanical vibration and heat

• Ultrasound or MRI-guided: elastography, temperature mapping

Renal Denervation in Patients with Uncontrolled Hypertension: Results

of the SYMPLICITY HTN 3 Trial

Deepak L Bhatt, M.D., M.P.H., David E Kandzari, M.D., William W O’Neill, M.D., Ralph D'Agostino, Ph.D., John

M Flack, M.D., M.P.H., Barry T Katzen, M.D., Martin B Leon, M.D., Minglei Liu, Ph.D., Laura Mauri, M.D., M.Sc., Manuela Negoita, M.D., Sidney A Cohen, M.D., Ph.D., Suzanne Oparil, M.D., Krishna Rocha-Singh, M.D.,

Raymond R Townsend, M.D., George L Bakris, M.D.,

for the SYMPLICITY HTN-3 Investigators

Trial Objectives

• SYMPLICITY HTN-3 is the first prospective, multi-center, randomized, blinded, sham controlled study to evaluate both the safety and efficacy of percutaneous renal artery denervation in patients with severe treatment-resistant

Key Inclusion Criteria

• Age ≥18 and ≤80 years at time of randomization

• Stable medication regimen including full tolerated

different classes, including a diuretic (with no changes for a minimum of 2 weeks prior to screening) and no expected changes for at least 6 months

• Office SBP ≥160 mm Hg based on an average of 3 blood pressure readings measured at both an initial and a

confirmatory screening visit

• Written informed consent

Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

SYMPLICITY HTN-3 Trial Design

Eligible subjects randomized

Home BP &

HTN med confirmation

Home BP &

HTN med confirmation

Primary endpoint

2 weeks

2 weeks

Sham Procedure

Renal Denervation

1 M

1 M 3 M

3 M 6 M

6 M 12-60 M

• Patients, BP assessors, and study personnel

all blinded to treatment status

• No changes in medications for 6 M

2 weeks

Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

Patient Disposition

1441 subjects assessed for eligibility

Excluded:

• 880 not eligible for randomization

• 26 eligible but not randomized because randomization cap was reached

Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

Baseline Hypertensive Therapy

Characteristic mean ± SD or %

Renal Denervation

(N=364)

Sham Procedure (N=171 )

No of antihypertensive medications 5.1 ± 1.4 5.2 ± 1.4 Angiotensin-converting enzyme inhibitors

% at max tolerated dose

49.2 45.9

41.5 37.4 Angiotensin receptor blockers

% at max tolerated dose

50.0 49.5

53.2 51.5

Calcium channel blockers

% at max tolerated dose

69.8 57.1

73.1 63.7

Diuretics

% at max tolerated dose

99.7 96.4

100 97.7

Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

Safety Event Rate

Safety Measures (%) Renal

Denervation (N=364)

Sham Procedure (N=171)

Difference (95% CI) P

6-Month Composite Safety 4.0 5.8 -1.9 (-6.0, 2.2) 0.37

Myocardial infarction 1.7 1.8 0.0 (-2.4, 2.3) 1.00

Serum creatinine elevation >50% 1.4 0.6 0.8 (-0.8, 2.5) 0.67 Embolic event resulting in end-organ

damage

0.3 0 0.3 (-0.3, 0.8) 1.00

Vascular complication requiring treatment 0.3 0 0.3 (-0.3, 0.8) 1.00 Hypertensive crisis/emergency 2.6 5.3 -2.7 (-6.4, 1.0) 0.13

Hospitalization for new onset heart failure 2.6 1.8 0.8 (-1.8, 3.4) 0.76 Hospitalization for atrial fibrillation 1.4 0.6 0.8 (-0.8, 2.5) 0.67 New renal artery stenosis >70% 0.3 0 0.3 (-0.3, 0.9) 1.00

Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

Primary Efficacy Endpoint

Δ = -14.1±23.9 P<0.001

Δ = -11.7±25.9 P<0.001

Powered Secondary Efficacy

Endpoint

Δ = -6.8±15.1 P<0.001

Δ = -4.8±17.3 P<0.001

Change in Office SBP by Tertile

P=0.13 P=0.29

Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

Results: Prespecified Subgroup

Analyses

*

* P value for superiority with margin of 5 mm Hg Bhatt DL, Kandzari DE, O’Neill WW, et al Bakris GL N Engl J Med 2014

Trademarks may be registered and are the property of their respective owners A reminder that this is a discussion of SYMPLICITY trial results and their implications for the

future of RDN Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography Always refer to the Instructions for Use

®

Comparison of HTN-2 and HTN-3 Trial Designs

HTN-2 (N = 106)

HTN-3 (N = 535)

Stable 3+ drug regimen with no changes ≥2

Trademarks may be registered and are the property of their respective owners A reminder that this is a discussion of SYMPLICITY trial results and their implications for the

future of RDN Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography Always refer to the Instructions for Use

®

HTN-3: Procedural Experience

a) 5X more operators vs HTN-1 b) Greater heterogeneity of operator experience vs HTN-1 and HTN-2 c) Case proctoring was different and not comparable

HTN-1 HTN-3

No of procedures per operator 6.0 3.3

No of procedures per site 8.6 4.7

12 Month Results EAR

• At 6 months, patients in the sham-control group (n=171) were offered renal denervation, but only if they still met the initial inclusion criteria for the trial

• 101 ultimately underwent the procedure (crossover group) and the other 70 did not (non-crossover group)

• Through 12 months, there was no difference between the 3 groups in the rate of the composite safety endpoint (death, new-onset end-stage renal disease, embolic events resulting

in end-organ damage, vascular complications, renal artery

reintervention, and hypertensive emergency/crisis): 6.8% in the original renal denervation group, 5.3% in the crossover group, and 7.2% in the non-crossover group

Average BP reductions at 1 year

Consecutive patients treated

in real world population

Rest of GSR N~3500

* Limited to resistant hypertension only

231 international sites in 37 countries Min 10% randomly assigned to 100% monitoring

Change in Office Systolic BP for

All Patients and Subgroups

-10.0

12.9

-2.0

-18.9 -11.9

N=96 N=94

N=751

*P<0.0001 for both 3 and 6 month change from baseline

†P=0.14 at 3 months and P=0.0006 at 6 months

Is Renal Denervation Dead?

Issues that need to be addressed

• Is there a way to quantify procedural success?

– In Simplicty 3 on 19/364 had complete 4 quadrant circumferential ablation

– Where do the renal nerves lie – studies suggesting they are concentrated more distally

Issues to be addressed

• Physician behaviour at question?

– 40% of patients in both arms had drug alterations despite protocol requesting drug consistency for 6 months

Issues that need to be addressed

• Technology still lacks significant preclinical

science

– Technology driven by early Clinical Trials

– We need to invest research into identifying

subgroups that will have most benefit (may be small group)