RISE, FALL AND RESURRECTION OF RENAL DENERVATION

Michael A. Weber, MD

State University of New York

Downstate College of Medicine

Michael Weber, Disclosures

Research/Trial Commitments and Consulting: Boston Scientific; Medtronics; ReCor; Ablative Solutions, Sanofi

Consulting: Novartis; Arbor; Takeda; Boehringer Ingelheim; Astellas; Johnson & Johnson

Renal Nerves EFFERENT AND AFFERENT FIBERS INFLUENCE MULTIPLE ORGAN SYSTEMS

Hypertrophy Arrhythmia Oxygen consumption

Vasoconstriction atherosclerosis

Insulin resistance

Renal afferent nerves (affect

brain/systemic SNS)

↑ Renin release RAAS activation

↑ Sodium retention

↓ Renal blood flow

Sleep disturbances

Renal efferent Nerves (Govern

Renal BP Effects)

CARDIOVASCULAR CONTINUUM: START THERAPY EARLIER IN HIGH-RISK PATIENTS, SMALL RELATIVE RISK REDUCTIONS TRANSLATE INTO LARGE ABSOLUTE BENEFITS

Zanchetti A. Nat Rev Cardiol. 2010;7:66-7. 1Law MR, et al. BMJ. 2009; 338, 1665–83.

30%

20%

10%

5%

CV risk %

in 10 years

40%

50%

Treatment Benefit:

25% Risk reduction

37.5

22.5

15

7.5

Death

Cardiovascular (CV) continuum:

• A sequence of events beginning with risk

factors, leading to subclinical

(asymptomatic) organ damage

• Untreated, results in clinical

(symptomatic) disease and CV events

(stroke, MI, HF) and death

• Approximate risk is shown as % CV

events expected in 10 years. Risk can be

reduced depending on when treatment is

initiated

• Treatment benefit is calculated to be

approximately 25% reduction of initial

risk1

SYMPATHETIC ACTIVITY IN DIFFERENT HYPERTENSIVE POPULATIONS

Ra

te o

f s

pil

lov

er

of

no

rad

ren

ali

ne

fro

m t

he

kid

ne

ys

to

pla

sm

a (

ng

/min

)

0

100

200

300

400

NormalBP

20-39 40-59 60-79

EssentialHypertension

**

*

Esler M, J Hypertension. 1990

years

Isolated systolic hypertension is the

predominant hypertensive phenotype

in elderly patients

Change in Office BP in Treatment Resistant

Hypertension: Symplicity 2 (Controlled, open-label trial)

-19

-21 -22

-27

-29

-34

-31

-9 -10 -10

-14 -14

-17 -16

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

1 mo (n=143)

3 mo (n=148)

6 mo (n=144)

12 mo (n=132)

24 mo (n=105)

30 mo (n=44)

36 mo (n=34)*

SBP mmHg

DBP mmHg

BP change

(mmHg)

P<0.01 for ∆ from BL

for all time points

Schlaich M, TCT 2012 Reported as mean with 95% confidence intervals

*Number of patients represents data available at time of data-lock

Symplicity 3: RDN vs. Sham in Treatment Resistant HTN

0

50

100

150

200

Denervation Sham

Baseline

6 Months

Δ = -14.1±23.9

P<0.001

Δ = -11.7±25.9

P<0.001

Δ = -2.39 (95% CI, -6.89 to 2.12)

P=0.26*

(N=364) (N=171)

Offic

e S

BP

(m

m H

g)

(N=353) (N=171)

180 mm Hg

166 mm Hg

180 mm Hg

168 mm Hg

*P value for superiority with a 5 mm Hg margin; bars denote standard deviations

Lessons Learned

• Cannot get reliable results when an inconsistent technique is applied to an ill-defined clinical condition

Solution • Optimize catheter designs to ensure full circumferential

effects

• Establish rigorous standards of procedural technique: should we go beyond main renal artery?

• Study carefully defined hypertensive populations

• Use trial designs that effectively measure the effects of treatment on high blood pressure

Caution: The Symplicity™ Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use. Trademarks may be registered and are the

property of their respective owners. For OMA distribution only. © 2014 Medtronic, Inc. All rights reserved. 10139454DOC_1A 3/2014

24h Ambulatory BP Change

-6.8

-9.4

-7.2

-10.3

-8.1

-10.3

-8.7

-10.4

-8.0

-12

-9

-6

-3

0

Syst

olic

Blo

od

Pre

ssu

re C

han

ge

(mm

Hg)

P < 0.001 vs. Baseline

Baseline ABPM 154 ± 18 mmHg

P < 0.001 vs. Baseline

Baseline ABPM 157 ± 18 mmHg

n=104 n=125 n=122 n=965 n=880 n=580 n=353 n=966 n=43

6Mo 1Yr 2Yr 3Yr 3Mo 6Mo 1Yr 2Yr 3Yr 3Mo

Symplicity

SPYRAL™ Symplicity

FLEX™

DENER HTN: The First Successful Controlled Trial of

Renal Denervation in Treatment Resistant Hypertension*

0

Denervation

Control

Daytime ABPM

SB

P C

ha

nge

fro

m B

ase

line

to 6

Mon

ths (

mm

Hg)

–10

–20

Nighttime ABPM

∆: –5.9 mm Hg

(95% CI: –11.3 to –0.5)

p = 0.0329

∆: –6.3 mm Hg

(95% CI: –12.0 to –0.6)

p = 0.0296

Primary endpoint

*It required 1416 referred resistant patients to yield 106 eligible for the trial (1:13) Azizi M et al. The Lancet. 2015 Jan 23. http://dx.doi.org/10.1016/S0140-6736(14)61942–1945.

DENER HTN: Compliance with Drug Therapy Azizi et al. Circulation 2016; 134:847-857

Proportion of poor or

nonadherence according to

drug monitoring in different

cohorts of patients with

apparently resistant

hypertension

Berra E, et al. Hypertension. 2016;68:297-306

NON ADHERENCE TO ANTIHYPRTENSIVE DRUG THERAPY IS WIDESPREAD, DYNAMIC AND DIFFICULT TO DETECT

NON ADHERENCE TO ANTIHYPERTENSIVE MEDICATION IS ASSOCIATED WITH INCREASED MORBIDITY AND MORTALITY

Meta Analysis of 44 studies

N=1,978,919

Only 60% of participants with

hypertension had “good”

adherence (>80%)

Poor adherence to

antihypertensive medications

increased cardiovascular

disease events by 19%

Poor adherence to

antihypertensive medications

increased mortality events by

29%

Chowdhury R, et al. European Heart Journal (2013) 34, 2940–2948.

SPYRAL HTN – OFF MED

BLOOD PRESSURE CHANGE FROM BASELINE TO 3 MONTHS: OFFICE BP

Townsend RR, et al. Lancet. 2017 Aug 25. pii: S0140-6736(17)32281-X. doi: 10.1016/S0140-6736(17)32281-X.

RELATIVE RISK REDUCTION FOR A 10 MMHG FALL IN OFFICE BLOOD PRESSURE

20

17

27 28

13

0

5

10

15

20

25

30

Major CVD CHD Stroke HF Mortality

Rela

tive R

isk R

ed

uc

tio

n

(%)

Source: Ettehad D et al, Lancet. 2016,387:957-967

• Meta analysis of 123

studies

• N= 613,815 patients

• Placebo adjusted

pressure reductions

• Independent of

baseline pressure and

co-morbidity

What do we know, and what can we say, about renal denervation …..in the future….

Given that… this procedure reduces blood pressure in hypertensive patients when used alone or in combination with other therapies, we can propose that:

--- This procedure can be combined with antihypertensive drugs in hypertensive patients whose blood pressures are not adequately reduced despite systematic prescription of drugs alone

--- This procedure can be used in hypertensive patients intolerant of antihypertensive drugs

What do we know, and what can we say, about renal denervation….in the future…. Part 2

It will be critical to explore the value of this procedure in important subgroups of hypertension not fully addressed in initial pivotal trials, including:

---- Patients with isolated or predominant systolic hypertension

---- As a core therapy, the young -- primarily adults aged < 40

Hypertension Guidelines Just Announced

Hypertension is the new egalitarian medical condition we can all share ---

it includes just about everyone !!

2017 ACC/AHA/AAPA/ABC/ACPM/AGS/

APhA/ASH/ASPC/NMA/PCNA

Guideline for the Prevention, Detection,

Evaluation, and Management of High Blood

Pressure in Adults

© American College of Cardiology Foundation and American Heart Association

Categories of BP in Adults*

*Individuals with SBP and DBP in 2 categories should be

designated to the higher BP category.

BP indicates blood pressure (based on an average of ≥2

careful readings obtained on ≥2 occasions, as detailed in

DBP, diastolic blood pressure; and SBP systolic blood

pressure.

BP Category SBP DBP

Normal <120 mm Hg and <80 mm Hg

Elevated 120–129 mm

Hg

and <80 mm Hg

Hypertension

Stage 1 130–139 mm

Hg

or 80–89 mm

Hg

Stage 2 ≥140 mm Hg or ≥90 mm Hg

Blood Pressure Summary (1) Threshold for diagnosis of hypertension is

generally >140/90 mmHg

BUT, it is >130/80 mmHg if: Previous CV/stroke event or procedure

Ischemic heart disease

Diabetes

Chronic kidney disease

Age >65

10% 10 year risk of a CV event

Question: Will 130/80 mmHg soon become the

standard threshold for everyone?

Blood Pressure Summary (2)

The treatment target is

< 130/80 mmHg in ALL patients