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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