The Return of Renal Denervation

Florian Rader, M.D., M.Sc. Co-Director, Clinic for Hypertrophic Cardiomyopathy and Aortopathies

Assistant Director, Non-invasive Laboratory Hypertension Center of Excellence

Cedars-Sinai Heart Institute

Disclosures: Renal Denervation is investigational and not FDA-approved

PI/Co-PI of Symplicity-HTN-3, Radiance, Reduce-HTN Consultant for MyoKardia, ReCor Medical

Naïve Day 7 Day 60

Viable Nerves Ablated Nerves

Intraluminal renal denervation

Radiofrequency Energy Ultrasound Energy

Overactive SNA in HTN

Normotensive HTN PG Guyenet Nature Reviews Neuroscience, 2006

Age dependency of SNA- conflicting data

Ng et al. Hypertension.1993 Parati G et al., Eur Heart J 2012

Mean age in Simplicity 58 years

Only mild increases

Hypertension

N=9 N=8

N=7 N=8

24y 26y 63y 66y

SNA is increased in obesity

Lambert et al. Hypertension 2007 50:862

SNA is increased in moderate CKD

Grassi et al. Hypertension. 2011;57:846-851

Quartiles of GFR 95 68 48 31

HR NE MSNA

vagal efferents

sympathetic efferents

NE

NE

Ach

EPI

Stress

Renal afferents

Chemoreceptors

Cardiac afferents

NTS

Baroreceptors

Ang II

renin

NE

Muscle afferents

Courtesy of Ron Victor

sympathetic efferents NE

NTS

Renal efferent nerves>>Renal afferent nerves

- Decrease of Renin release - Less tubular Na and H2O

resorption - Increase of renal blood flow

What causes of uncontrolled HTN can be (potentially) addressed by RDN&Co?

• Non-adherence • Physician inertia to intensify antihypertensive

regimen • HTN driven by sympathetic overactivity

– Still learning-Young?, CKD?, OSA?, LVH? • Non-tolerance (or patient’s refusal) of multi-

drug regimens for HTN

Consider what the patient wants not only what physicians think is right!

Symplicity HTN-2 (N=100)

6 month endpoint Denervation group (n-49)

Control group (n=51)

systolic

diastolic

chan

ge fr

om b

asel

ine

[mm

Hg]

p < 0.00001 vs. control

Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09

Symplicity HTN-3 (N=535)

Symplicity HTN-3 Investigators. NEJM 2014;370:1393-401

“Why was Symplicity HTN-3 negative?”

Option #1 RDN does not lower BP: all animal data, our understanding of the sympathetic control of the kidney and all positive trials are wrong

Option #2 HTN-3 had issues

Explanation #1 Inclusion of White-Coat HTN & Large

variability of treatment effect

• ABPM >135/85 for inclusion (>150 in the office) white-coat tendency in the trial by design

• Variability of BP response in Symplicity HTN-3:

– RDN: -14 +/- 24 mmHg – Control: -12 +/- 26 mmHg super-responders, responders, non-responders a statistical nightmare!

Age <65 (RDN: 246; sham: 128) Age >65 (RDN: 104; sham: 41)

RDN better control better

Age predicts response

Symplicity HTN-3 Investigators. NEJM 2014;370:1393-401

Explanation #2 Patient selection

Mean age in Symplicity-HTN 3: 58 years

Hypertension

Explanation #3 Patient selection

control better

Black (RDN: 85; sham: 49) Non-Black (RDN: 264; sham: 120)

RDN better

Race/ethnicity – an adherence issue?

Symplicity HTN-3 Investigators. NEJM 2014;370:1393-401 J Am Soc Hypertens 2015;9(10):769–779

-Black participants on tid and qid drugs had a placebo effect of -26 mmHg!! -This does not explain why the trial was negative, but points out that adherence was a major confounder

Explanation #4 Incomplete denervation

• Operator experience

How would have TAVR or MitraClip faired if most participating centers would have performed one or two TAVRs?

Explanation #5 Incomplete denervation

1. Number of nerves: Proximal>distal

2. Distance from arterial wall: Proximal>distal

1. Distal ablations were discouraged (RAS)

2. Proximal ablation may not have reached nerves

Explanation #5 Incomplete denervation

More ablations greater BP reduction

Kandzari et al. Eur Heart J. 2015 Jan 21;36(4):219-27

Explanation #6… Trial Design Issues

• Confounders: – Compliance not measured (~5 BP meds) – High rate of Central sympatholytics (49% vs.

44%) which increase BP variability and with non-compliance give very labile BP estimates

• Medication changes: – 40% of patients had medication changes prior to

the primary outcome – 69% of those were deemed medically necessary

THE NEW CHAPTER

Optimal care plus RDN (N=106) • Open-label trial of 106 patients randomized stepped

protocolized treatment intensification vs. RDN plus stepped care

• Treatment effect of RDN was 6 mmHg reduction of 24-hour SBP (p=0.03)

Azizi M et al. Lancet 2015; 385: 1957–65

Optimal care plus RDN (N=71) • Sham-controlled trial of 71 patients randomized

stepped protocolized treatment intensification vs. RDN plus stepped care

• In the per-protocol cohort, RDN group had greater ambulatory BP reduction

• Kidney function as estimated by the glomerular filtration rate remained

unchanged at 6 months

Desch et al. Hypertension. 2015;65:1202-1208

SPYRAL OFF-MEDS (N=71)

Townsend RR, et al. Lancet. 2017;390(10108):2160-2170.

Trial design

ASBP = ambulatory systolic blood pressure; DBP = diastolic blood pressure

Townsend RR, et al. Lancet. 2017;390(10108):2160-2170.

24-hour ASBP 24-hour ADBP

Office SBP Office DBP

3-m

onth

cha

nge

in B

P

3-m

onth

cha

nge

in B

P

SPYRAL OFF-MEDS (N=71)

Kandzari DE et al. Lancet. 2018 Jun 9;391(10137):2346-2355

Patients

SPYRAL ON-MEDS (N=75)

Kandzari DE et al Lancet. 2018 May 22. pii: S0140-6736(18)30951-6. doi: 10.1016/S0140-6736(18)30951-6. [Epub ahead of print]

Asleep Awake

Results

SPYRAL ON-MEDS (N=75)

RADIANCE-HTN-SOLO (N=146)

Azizi M, et al. Lancet. 2018. Published online May 23, 2018. http://dx.doi.org/10.1016/S0140-6736(18)31082-1. Accessed May 23, 2018. DAIC [website]. News. February 20, 2012. ReCor medical granted CE mark for transcatheter renal denervation system. https://www.dicardiology.com/content/recor-medical-granted-ce-mark-transcatheter-renal-denervation-system. Accessed May 23, 2018.

N=74

N=72

2 month results

RADIANCE-HTN-SOLO

Unpublished-submitted to ACC 2019

6 month results

• Stepped care if BP >135/85 mmHg at 2 months: 1. amlodipine 5 2. ACEi/ARB 3. HCTZ 12.5->25

• Embargoed results BUT we are HAPPY

Other pending trials

• RADIANCE-HTN TRIO: uncontrolled on triple combination pill, 50% enrolled

• RADIANCE-HTN 2: extension of SOLO for FDA approval

• SPYRAL: pivotal trials are being designed

RDN in summary • Despite the disappointing Symplicity-HTN 3 trial (which

had flaws), new rigorous data demonstrates a significant and clinically meaningful BP reduction in patients with or without medications

• Don’t forget: a sustained 10 mmHg SBP reduction lowers risk of stroke by 30%, MI by 23%, CV mortality by ~25%!

• The magnitude of BP reduction was grossly

overestimated in uncontrolled trials. RDN will not replace medications in most (it does in a few)

• Pivotal trials for FDA approval are currently underway: RADIANCE 2 (start 12/2018)

Staessen JA et al. Lancet 2001; 358: 1305–15

RADIANCE-TRIO: enrolling RADIANCE 2: start in December 2018 PI: Florian Rader Co-PI: Raj Makkar, Suhail Dohad Coordinator: Mo Rashid Mohamad.Rashid@cshs.org Hoonie Kim Hyun-Min.Kim@cshs.org

Parked slides

32

Nifedipine for 2 weeks

Hu et al. Drug Design, Development and Therapy. Volume 11. 3179-3186.