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11/21/2017

Hypertension:
Guidelines and Updates
Hypertension 2017: Where are We Now?
VuMedi Webinar, November 21, 2017
William C. Cushman, MD
Professor, Preventive Medicine, Medicine, Physiology
University of Tennessee Health Science Center
Chief, Preventive Medicine, Memphis VA Medical Center
Memphis, Tennessee

Presenter Disclosure Information
William C. Cushman, MD, FACP, FASH, FAHA
FINANCIAL DISCLOSURE:
Institutional Grant: Lilly
Uncompensated Consulting: Takeda, Novartis
I was a member of JNCs 7 & 8, but not the 2017 ACC/AHA HTN Guidelines
The content does not necessarily represent the official views of the SPRINT
or ACCORD Steering Committees, the NIH, the VA, or the U.S. government

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

11/21/2017

Publication Information
This slide set is adapted from the 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
Published on November 13, 2017, available at: Hypertension and Journal of the
American College of Cardiology.
The full-text guidelines are also available on the following websites: AHA
(professional.heart.org) and ACC (www.acc.org)

Blood Pressure (BP) and Cardiovascular Disease (CVD) Risk
Diastolic Blood Pressure (DBP)

Age at risk:
80-89 years

128

70-79 years

60-69 years

50-59 years

40-49 years

8
4
2
1

120

140

160

IHD Mortality
(Floating Absolute Risk and 95% CI)

Systolic Blood Pressure (SBP)
256

256

Age at risk:
80-89 years

128

70-79 years

60-69 years

50-59 years

40-49 years

8
4
2
1

180

Usual SBP (mm Hg)

100

110

Usual DBP (mm Hg)

Lewington et al. Lancet. 2002;360:1903-1913.

Diastolic BP Goal Trials
Several trials used DBP goal ~90 mm Hg and demonstrated consistent reduction of
CVD events
1. VA Cooperative Study
- Entry: DBP 90-129 mm Hg
- Goal: DBP <90 mm Hg
2. Hypertension Detection and Follow-up Program (HDFP)
- Entry: DBP ≥90 mm Hg
- Goal: DBP ≤90 mm Hg and at least 10 mm Hg ↓
3. Australian National Blood Pressure (ANBP) Trial
- Entry: DBP 95 to <110 mm Hg
- Goal: DBP ≤90 mm Hg initially, then after 1 year, lowered to ≤80 mm Hg
4. STOP-Hypertension Trial
- Entry: SBP 180-230 mm Hg + DBP ≥90 mm Hg, or DBP 105-120 mm Hg irrespective of SBP
- Goal: BP <160/95 mm Hg
HOT Trial
- no further benefit (or harm) to DBP <85 or <80 mm Hg

11/21/2017

Major Randomized Trials Testing SBP Goals in General
(Older) Populations Prior to SPRINT
Age
Number
Entry SBP
Goal SBP
Achieved SBP
Stroke 
CVD 
Mortality 

SHEP

Syst-Eur

HYVET

JATOS

VALISH

>60
4,736
160-219
<148
142
36%
32%
ns

>60
4,695
160-219
<150
151
42%
31%
ns

>80
3,845
160-199
<150
144
ns
34%
21%

65-85
4,418
>160
<140
136
ns
ns
ns

70-84
3,260
>160
<140
137
ns
ns
ns

SBP = systolic blood pressure; CVD = cardiovascular disease

Systolic BP Intervention Trial (SPRINT)
Year 1
Mean SBP
136.2 mm Hg

Average SBP
(During Follow-up)

SBP goal <140 mm Hg

Standard

Standard: 134.6 mm Hg
Delta: 13.5 mm Hg

Mean SBP
121.4 mm Hg

Intensive

Intensive: 121.5 mm Hg

SBP goal <120 mm Hg
Average number of
antihypertensive
medications

Number of
participants

SPRINT Primary Outcome (CVD)
Cumulative Hazard
Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)
The SPRINT Research Group. N Engl J Med. 2015;373:2103-16
Primary
Outcome

Standard
(319 events)

Hazard
Ratio

P value

0.75

<0.001

25% reduction
P<0.001

Intensive

Components

(243 events)
All MI

During Trial (median follow-up = 3.26 years)
Number Needed to Treat (NNT)
to prevent a primary outcome = 61

0.83

0.19

Non-MI ACS 1.00

0.99

All Stroke

0.89

0.50

0.62

0.002

0.57

0.005

Number
AllofHF
Participants
CVD Death

11/21/2017

Hazard ratios and 95%CIs
for major CVD associated
with more intensive
reductions in SBP
42 trials, n=144,220
Most of the trials included
significant numbers of participants
with diabetes mellitus

Bundy JD, et al. JAMA Cardiol.
2017;2:775-81

Changes in BP Categories from JNC7 to
the New Guideline
DBP

JNC7

2017 ACC/AHA

<120
120–129

SBP
and
and

<80
<80

Normal BP
Prehypertension

Normal BP
Elevated BP

130–139
140–159
≥160

or
or
or

80–89
90-99
≥100

Prehypertension
Stage 1 hypertension
Stage 2 hypertension

Stage 1 hypertension
Stage 2 hypertension
Stage 2 hypertension

The categorization of BP should be based on the average of ≥ 2 readings on ≥ 2 occasions following a
standardized protocol.
Adults with SBP and DBP in two categories are designated into the higher category.

Changes in BP Categories from JNC7 to
the New Guideline
DBP

JNC7

<120
120–129
130–139

SBP
and
and
or

<80
<80
80–89

Normal BP
Prehypertension
Prehypertension

2017 ACC/AHA
Normal BP
Elevated BP
Stage 1 hypertension

140–159
≥160

or
or

90-99
≥100

Stage 1 hypertension
Stage 2 hypertension

Stage 2 hypertension
Stage 2 hypertension

The 2017 ACC/AHA guideline definition of hypertension:
SBP ≥ 130 mm Hg or
DBP ≥ 80 mm Hg

11/21/2017

Distribution of US adults into BP Categories –
NHANES 2011-2014
Prevalence of hypertension: 45.6%

Normal BP

Elevated BP

Muntner et. al., Journal of the American College of Cardiology 2017 (in press)
Muntner, et. al., Circulation 2017 (in press)

Prevalence of Hypertension –
2017 ACC/AHA and JN7 Guidelines
Prevalence of hypertension, %

50%

Number of US adults with hypertension, millions
120

45.6%

40%
31.9%

103.3

13.7%

90
72.2

30%

31.1, M

60
20%
30

10%
0%

JNC7 guideline
2017 ACC/AHA guideline

Muntner et. al., Journal of the American College of Cardiology 2017 (in press)
Muntner, et. al., Circulation 2017 (in press)

BP Measurement Methodology in SPRINT
• Similar to what has been used in virtually all HTN outcome
trials defining the recommended BP thresholds and goals
in guidelines.
• Similar to what has been recommended for clinical
practice by virtually all HTN guidelines around the world
for decades, including all JNCs, ASH/ISH, VA/DoD,
ESH/ESC, UK/NICE, Canadian/CHEP, Australian, ...

11/21/2017

BP Measurement in SPRINT
(Automated)
• Visit BP was the average of 3 seated office BP measurements
obtained using an automated measurement device: Omron
907XL.
• Appropriate cuff size was determined by arm circumference.
• Participant was seated with back supported and arm bared and
supported at heart level.
• Device was set to delay 5 minutes and then take/average 3 BP
measurements, during which time participant refrained from
talking.

Cushman, et al. Hypertension. 2016;67:263-5

Accurate Measurement of BP in the Office

COR
I

LOE
C-EO

Recommendation for Accurate Measurement of BP in the Office
For diagnosis and management of high BP, proper methods are
recommended for accurate measurement and documentation of BP.

Out-of-Office and Self-Monitoring of BP
COR

LOE

Recommendation for Out-of-Office and Self-Monitoring of BP

ASR

Out-of-office BP measurements are recommended to confirm the
diagnosis of hypertension and for titration of BP-lowering medication,
in conjunction with telehealth counseling or clinical interventions.

SR indicates systematic review.

11/21/2017

BP Treatment Threshold and the Use of CVD Risk Estimation to Guide Drug Treatment of
Hypertension
COR

LOE
SBP: A

I
DBP:
C-EO

C-LD

Recommendations for BP Treatment Threshold and Use of Risk Estimation* to
Guide Drug Treatment of Hypertension
Use of BP-lowering medications is recommended for secondary prevention of
recurrent CVD events in patients with clinical CVD and an average SBP of 130 mm
Hg or higher or an average DBP of 80 mm Hg or higher, and for primary prevention in
adults with an estimated 10-year ASCVD risk of 10% or higher and an average SBP
130 mm Hg or higher or an average DBP 80 mm Hg or higher.

Use of BP-lowering medication is recommended for primary prevention of CVD in
adults with no history of CVD and with an estimated 10-year ASCVD risk <10% and an
SBP of 140 mm Hg or higher or a DBP of 90 mm Hg or higher.

*ACC/AHA Pooled Cohort Equations (http://tools.acc.org/ASCVD-Risk-Estimator/) to
estimate 10-year risk of atherosclerotic CVD (ASCVD).

ACC/AHA POOLED COHORT EQUATIONS
To estimate the 10-year risk of atherosclerotic CVD

http://tools.acc.org/ASCVD-Risk-Estimator/

BP THRESHOLDS AND RECOMMENDATIONS
FOR TREATMENT AND FOLLOW UP
BP thresholds and recommendations for treatment and follow-up

Normal BP
(BP <120/80
mm Hg)

Elevated BP
(BP 120-129/<80
mm Hg)

Promote optimal
lifestyle habits
(Class I)

Non-pharm-acologic
therapy
(Class I)

Stage 1 Hypertension
(BP 130-139/80-89 mm Hg)

Clinical CVD or estimated
10 y ASCVD risk ≥ 10%

No
Reassess in 1 y
(Class IIa)

Reassess in
3-6 mo
(Class I)

Stage 2 Hypertension
(BP >140/90 mm Hg)

Non-pharmacologic
therapy
(Class I)

Reassess in
3-6 mo
(Class I)

Yes
Non-pharmacologic therapy
and BP lowering medication
(Class I)

Non-pharmacologic therapy
and BP lowering medication
(Class I)

Reassess in 1
mo
(Class 1)

11/21/2017

Thank you!

11/21/2017

Hypertension 2017: Where are we now?

BP Targets in Patients with and without
Chronic Kidney Disease.
Clive Rosendorff, MD, PhD, DScMed,
FACC, FAHA, FRCP.

Professor of Medicine (Cardiology), Icahn School of
Medicine at Mount Sinai, New York, NY, USA
and
James J. Peters VA Medical Center, Bronx, NY, USA

Disclosures
I was a member of the SPRINT Intervention Committee
I have no other disclosures relating to the subject
matter of this presentation.

Lower Is Better:
12.7 million person years
IHD Rates by SBP, DBP, and Age

IHD Mortality
(Floating Absolute Risk, 95% CI)

SBP

DBP

256

Age at Risk (y)
80–89

128

70–79

60–69

50–59

40–49

120

140

160

180

Usual SBP (mm Hg)

100

110

Usual DBP (mm Hg)

IHD = ischemic heart disease; CI = confidence interval.
Lewington et al. Lancet. 2002;360:1903-1913.

11/21/2017

Impact of Pre-Hypertension on CV Risk

Cumulative
Incidence of CV
Events(%)

Lower Blood Pressure is Better
16
14
12
10
8
6
4
2
0

Men

130-139 or 85-89
120-129 or 80-84
Normal BP
(< 120/80)

Cumulative
Incidence of CV
Events (%)

Women

130–139 or 85–89

8
6
4

120-129 0r 80-84

2
0

Normal BP
(< 120/80)
2

Years
Normal BP: < 120/80 mm Hg; Pre-hypertension: 120–139 or 80–89 mm Hg.
Vasan RS et al. N Engl J Med. 2001;345:1291-1297.

Progression Rate of Coronary Artery Disease
According to JNC 7 BP Categories

Δ in Atheroma Volume (mm3)

30 -

P<.001 by ANCOVA
P<.001

25 20

15 10 50–5 P=.01

–10 –15 -

P=.039

–20 Normal
<120/80

Prehypertension
120-139/80-89

Hypertension
≥140/90

JNC 7 Categories
Sipahi I et al. J Am Coll Cardiol. 2006;48:833-838.

500

400

Total
Organ 300
Blood
Flow
(ml/min) 200

0
0

100

150

200

S.B.P. (mmHg)
Rosendorff, In “Hypertension, A Companion to Braunwald’s Heart Disease”
Ed. Black & Elliott, Elsevier 2013; 253-261

11/21/2017

Achieved B.P. and the Rate of Decline in Renal Function.

Khosla et al. Med Clin N Am 2009;93:697-715

Selected Baseline Characteristics of the SPRINT Population
CHARACTERISTIC

INTENSIVE
TREATMENT (N=4678)

STANDARD
TREATMENT (N=4683)

Criterion for increased CV risk – no. (%)
Age ≥75 yr

1317 (28.2)

1319 (28.2)

Chronic kidney
disease

1330 (28.4)

1316 (28.1)

Cardiovascular
disease

940 (20.1)

937 (20)

Framingham
R.S.≥15%

2870 (61.4)

2867 (61.2)

Estimated GFR –

ml/min/1.73m2

All

71.8±20.7

71.7±20.5

eGFR ≥60

81.3±15.5

81.1±15.5

eGFR <60

47.8±9.5

47.9±9.5

11/21/2017

Systolic BP During Follow-up

Year 1
Mean SBP
136.2 mm Hg

Standard

Mean SBP
121.4 mm Hg

Intensive

SPRINT Primary Outcome
MI, ACS, stroke, HF, CV death
Hazard Ratio = 0.75 (95% CI: 0.64 to 0.89)

Standard
(319 events)

Intensive
(243 events)
Median follow-up = 3.26 years)
Number Needed to Treat (NNT) to
prevent a primary outcome = 61

Number of
Participants

SPRINT - All-cause Mortality
Cumulative Hazard
Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)

During Trial (median follow-up =
3.26 years)

Number Needed to Treat
(NNT) to Prevent a death = 90

Standard
(210 deaths)

Intensive
(155 deaths)

Include NNT

11/21/2017

SPRINT Primary Outcome and its Components
Event Rates and Hazard Ratios
Intensive

Standard

No. of
Events

Rate,
%/year

No. of
Events

Rate,
%/year

HR (95% CI)

P value

Primary Outcome

243

1.65

319

2.19

0.75 (0.64,
0.89)

<0.001

All MI

0.65

116

0.78

0.83 (0.64,
1.09)

0.19

Non-MI ACS

0.27

1.00 (0.64,
1.55)

0.99

All Stroke

0.41

0.47

0.89 (0.63,
1.25)

0.50

All HF

0.41

100

0.67

0.62 (0.45,
0.84)

0.002

CVD Death

0.25

0.43

0.57 (0.38,
0.85)

0.005

Primary Outcome Experience in the Six Pre-specified
Subgroups of Interest

*Treatment by subgroup interaction

It is a fool who is blown about
with every wind of criticism
Samuel Johnson 1709-1784

CRITICISMS
1. Unacceptable incidence of adverse events
2. “I would not apply these findings to my elderly, frail patients”
3. The absolute risk reduction is small
4. No benefit in preventing stroke
5. We do not measure blood pressure with the same care as in SPRINT

11/21/2017

It is a fool who is blown about
with every wind of criticism
Samuel Johnson 1709-1784

CRITICISMS

1. Unacceptable incidence of adverse events
2. “I would not apply these findings to my elderly, frail patients”
3. The absolute risk reduction is small
4. No benefit in preventing stroke

5. We do not measure blood pressure with the same care as in SPRINT

Adverse Events
1.Patients without CKD at Baseline: ≥30% reduction in
eGFR:
Standard: 0.35%/y
Intensive: 1.21%/y P<0.001 (?RAS blockers)
2. Other
Intensive
%

Standard
%

Hypotension

2.4

1.4

1.67

0.001

Syncope

2.3

1.7

1.33

0.05

Hyponatremia

3.8

2.1

1.76

<0.001

Hypokalemia

2.4

1.6

1.50

0.006

It is a fool who is blown about
with every wind of criticism
Samuel Johnson 1709-1784

CRITICISMS
1. Unacceptable incidence of adverse events

2. “I would not apply these findings to my elderly, frail patients”
3. The absolute risk reduction is small
4. No benefit in preventing stroke
5. We do not measure blood pressure with the same care as in SPRINT

11/21/2017

SPRINT
Primary Outcome
in Subjects >75 years,
by Baseline Frailty Status

Williamson et al.
JAMA 2016,
doi:10.1001/jama.2016.7050

It is a fool who is blown about
with every wind of criticism
Samuel Johnson 1709-1784

CRITICISMS
1. Unacceptable incidence of adverse events
2. “I would not apply these findings to my elderly, frail patients”

3. The absolute risk reduction is small
4. No benefit in preventing stroke
5. We do not measure blood pressure with the same care as in SPRINT

Generalizability of SPRINT Results to the U.S. Adult Population, and
Potential Impact on Outcomes.

CV
Events
%/y

Mortality
%/y

Stroke
%/y

Standard

2.19

1.40

0.47

Intensive

1.65

1.03

0.41

Difference

0.54

0.37

0.06

90,700

62,200

10,100

Fewer
events
p.a.

Bress et al. J Am Coll Cardiol. 2016;67(5):463-472.

11/21/2017

It is a fool who is blown about
with every wind of criticism
Samuel Johnson 1709-1784

CRITICISMS
1. Unacceptable incidence of adverse events
2. “I would not apply these findings to my elderly, frail patients”
3. The absolute risk reduction is small

4. No benefit in preventing stroke
5. We do not measure blood pressure with the same care as in SPRINT

ACCORD - STROKE
Nonfatal Stroke
Total Stroke
20

HR = 0.63
95% CI (0.41-0.96)
P=0.03

Patients with Events (%)

HR = 0.59
95% CI (0.39-0.89)
P=0.01

0
0

Years Post-Randomization

Why were Stroke Outcomes in ACCORD and
SPRINT Different?
An Hypotheses

ACCORD stroke K-M curves started to diverge at about 3.5
years. SPRINT was stopped before that (median follow-up
3.26 years). The SPRINT 11% RRR for stroke might have
increased to significant levels with more time.

11/21/2017

It is a fool who is blown about
with every wind of criticism
Samuel Johnson 1709-1784

5. We do not usually measure blood pressure with the same care as in

SPRINT.

“The doctor will now measure your blood pressure”

BP MEASUREMENT
1. Patient sits in a quiet room for
5 minutes.

2. Automated BP measurement
system.
3. Mean of 3 measurements.

11/21/2017

Categories of BP in Adults

BP Category

SBP

Normal

<120 mm Hg

and

DBP
<80 mm Hg

Elevated

120-129 mm Hg

and

<80 mm Hg

Stage 1

130-139 mm Hg

80-89 mm Hg

Stage 2

≥140 mm Hg

≥90 mm Hg

Hypertension

Whelton PK et al. 2017 High Blood Pressure Clinical Practice Guideline

Summary
• The 130/80 mm Hg cutoff for the diagnosis of hypertension and
for the goal of anti-hypertensive treatment is reasonable.
• However, physicians should be aware that a SBP target of
<120 mm Hg has been shown to reduce cardiovascular events
and mortality.
• BP is a continuous variable, so “lower is better”, as long as
patients are carefully monitored for symptoms or signs of
intolerance.
• Management should, therefore, be individualized.

Non-Pharmacological Treatment
of Hypertension
Marcos Rothstein, MD
Professor of Medicine
Department of Medicine ~ Division of Nephrology

“Haemastaticks”
(1733)

Stephen Hales
(1677-1761)

Medicine
Nephrology

Percentage of Patients (%)

Failure of Current Multidrug Approach
to Successfully Treat Hypertension

61%
53%

50%
41%
29%

34%
16%

Hypertension Control in Treated Hypertensive Patients
Kearney PM, et al. J Hypertens. 2004; 22:11-19.
Medicine
Nephrology

Forms of Human HTN with
Neurogenic Component
• Essential HTN
• Obesity-renal HTN
• Renal HTN
• HTN associated with
obstructive sleep apnea
• Preeclampsia
Medicine
Nephrology

Consequences of Chronic Elevated
Central Sympathetic Drive
Hypertrophy
↑ Arrhythmia
↑ Oxygen
Consumption

Vasoconstriction

Insulin
Resistance

Dyspnea,
Sleep
Disturbances

Renal
Sympathetic
Efferent Nerves

↑ pCO2
Sensitivity

↑ Renin Release
↑ Sodium Retention
↓ Renal Blood Flow

Recruitment of
Splanchnic venous
Blood pools
Medicine
Nephrology

Congestion

Sympathetic
drive is elevated
in multiple types
of hypertension

Sympathetic Activity per Minute

Central Sympathetic Drive in
Hypertension
†
‡
§

*
†

*
†
‡

*
‡
§
¶

†
‡
§
#

Baseline activity
(normotensives)

s-MSNA=single-unit efferent sympathetic nerve activity.
LV H=left v entricular hypertrophy.
*P<0.05 Compared with borderline hypertension.
†P<0.05 Compared with white coat hypertension.
‡P<0.05 Compared with normal pressure.
§P<0.05 Compared with high-normal pressure.
¶ P<0.05 Compared with essential hypertension–stage 1 .
#P<0.05 Compared with essential hypertension–stage 2/3.
Adapted from Smith P, et al. Am J Hypertens. 2004; 17:217-222.

Medicine
Nephrology

Baroreflex Activation Therapy (BAT)
Continuously Modulates the Autonomic Nervous System
Carotid Baroreceptor Stimulation

Brain

Autonomic Nervous System
Inhibited Sympathetic Activity
Enhanced Parasympathetic Activity

Heart

↓ HR

Vessels

Kidneys

↑ Vasodilation
↓ Stiffness

↑ Diuresis
↓ Renin
secretion
Medicine
Nephrology

The CVRx Rheos System

Programming
System

Baroreflex Activation
Leads

Implantable Pulse
Generator
Medicine
Nephrology

BP Pre/Post Implant
St. Louis Patient #2
Pre

SBP

DBP

MAP

202 ± 21

108 ± 9

134 ± 11

79 ± 7

Device RX
NA

6 Mths

153 ± 15

80 ± 13

101 ± 13

64 ± 8

Amps = 8
Freq = 30 pps
Width = 480

8 Yrs*

130 ± 10

70 ± 6

90 ± 6

68 ± 5

Amps = 7
Freq = 50 pps
Width = 120

*Drug Rx – Maxide 75/50 mgs QD

Medicine
Nephrology

Change in Antihypertensive
Therapeutic Index Over Time
1 Year

2 Years

3 Years

*p value = 0.05
**p value < 0.001

Medicine
Nephrology

Moving Forward:
Miniaturization to Reduce Procedure Invasiveness
1st Generation Lead

New Generation Lead

Medicine
Nephrology

Vascular Dynamics Mobius Device

Medicine
Nephrology

Renal Nerves as a Therapeutic Target

Medicine
Nephrology

Techniques
RFA
Internal

Non-Invasive

Cryoblation
Pharmacological sympathetic blockade

Medicine
Nephrology

Denervation Catheter Designs

Medicine
Nephrology

Staged Clinical Evaluation
First-in-Man ✓
Symplicity HTN-1
Series of Pilot studies ✓

Symplicity HTN-2 ✓
EU/AU Randomized Clinical Trial

USA

EU/AU

Symplicity HTN-3
US Randomized Clinical Trial

Other Areas of Research:
Insulin Resistance, HF/Cardiorenal,
Sleep Apnea, More

Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.
Medicine
Nephrology

BP change
(mmHg)

BP Lowering Effect of
SYMPLICITY HTN trials

Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917; Symplicity HTN-2 Investigators. Lancet.
2010;376:1903-1909 ; Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014;370:1393-1401
.
Medicine
Nephrology

What Does This Mean?
• Renal Denervation does not work
• Wrong mouse trap
 Next generation RF devices
 Chemical
 Ultrasound

• Wrong population of pt’s
 Too extreme
Medicine
Nephrology

Simplicity HTN3: Exploring an Unexpected
Result
• Inadequate operator technique
• Misunderstood renal nerve anatomy
• Suboptimal catheter design

Medicine
Nephrology

Procedural Variability
Correlation with # of ablations
Correlation with 4-quadrant ablation pattern

Inferior

Superior

Posterior

Crosssection of
artery
4-quadrant ablation pattern
Medicine
Nephrology

Relationship Between SBP Changes and Number of
Ablations Attempted for Denervation Group at 6 Months

Error bars = ± 1 SE
Baseline SBP
(mm Hg)

180

181

180

182

183

186

188

185

Number of ablations remains significant after adjustment for baseline blood pressure
Medicine
Nephrology

Areas of Speculation on the Causes of the
SYMPLICITY HTN-3 Efficacy Results..
Heterogeneity of U.S.
Operator Experience
Patient
Demographics

Medication
Changes or
Adherence

Catheter
Design

Hawthorne
Effect

Trial Design/
Conduct

Placebo Effect
RTM

S. Salmon, CRT 2014
Medicine
Nephrology

Ongoing Studies
Recruiting Patients
• SPYRAL HTN-ON MED Study
• SPYRAL HTN-OFF MED Study
• Renal Sympathetic Denervation in Metabolic Syndrome
(Metabolic Syndrome Study)
• Renal Denervation Using the Vessix Renal Denervation System
for the Treatment of Hypertension (REDUCE HTN:REINFORCE)
• TrAnsCatHeter Intravascular Ultrasound Energy deliVery for
rEnal Denervation (ACHIEVE)
https://clinicaltrials.gov/ct2/results?term=renal+denervation&pg=2

Medicine
Nephrology

Ongoing Studies
Recruiting Patients
•

Renal Denervation using the KONA External Ultrasound device

•

Renal Denervation in Patients with Chronic Heart Failure and
Resynchronization therapy

•

Renal Denervation in Patients with Heart Failure Secondary to Chagas
Disease

•

Renal Denervation in Patients with Heart Failure and Severe Left
Ventricular Dysfunction

•

A Feasibility Study to Evaluate the Effect of Concomitant Renal
Denervation and Cardiac Ablation on AF Recurrence

•

Renal Denervation in Patients Undergoing VT Ablation: Combined
Renal Denervation and VT Ablation vs Simply VT Ablation
https://clinicaltrials.gov/ct2/results?term=renal+denervation&pg=2
Medicine
Nephrology

Medtronic Spyral Catheter

Medicine
Nephrology

SPYRAL HTN
Global Clinical Trial Program
First Phase Includes
Two Parallel Trials
20 Sites Globally

SPYRAL HTN-OFF MED
•100 patients
•Sham RCT (1:1)
•Main body and branch ablation
•No specific medication requirement
•Focus on ABPM change at 3 months

•QOL data to be measured
SPYRAL HTN-ON MED
•100 patients
•Sham RCT (1:1)
•Main body and branch ablation
•No max tolerated dose
•Focus on ABPM change at 3 months
•QOL data to be measured

Second Phase
SPYRAL HTN Pivotal

•Based on OFF/ON trial results
•Cost Effectiveness Data/QOL to
be measured

Medicine
Nephrology

Adventitial Delivery Targets the Renal
Sympathetic Nerves
The Bullfrog MicroInfusion Catheter
•Uses common ballooninflation techniques (2 atm)
•Allows targeted deliver to
renal sympathetic nerve
sheath
•FDA 510(k)-cleared for
delivery to the vessel wall and
perivascular area
Medicine
Nephrology

Paradise: Ultrasound Technology for
Renal Denervation
Paradise RDN System Objective
Cool 0-1mm
Ablate 1-6mm

Paradise Technology Modeling
Paradise Thermal Profile

Ultrasonic Heating

Water Cooling

•

Cool – to protect the renal
artery – from the inside

•

Heat – to ablate the renal
nerves – on the outside

Paradise Thermal Profile Objective:
Protect Renal Arteries & Ablate Renal Nerves
Medicine
Nephrology

Kona Medical Surround Sound® HTN Therapy
Non-Invasive Renal Denervation

Imaging and therapy
ultrasound positioned
beneath patient

External ultrasound energy
guided by ultrasound
image and motion tracking

Ultrasound imaging
used to identify renal
artery

Focused ultrasound energy
administered in treatment
“pattern” to ablate nerves
located outside of artery

Energy field
surrounds artery,
ablates renal nerves

Note: Kona Surround Sound Hypertension Therapy is investigational and not approved for sale
Medicine
Nephrology

Reinnervation Following RDN?
NE content in sheep following RDN and at 5.5 and 11 months

Booth et al, Hypertension 2015
Medicine
Nephrology

Indications for Renal Denervation
Looking to the Future
Indication

Comment

1. Treatment-resistant hypertension
(TRH)

• Poorly defined condition
• TRUE TRH is rare
• Inconsistent evidence that RDN
is better than drugs
• Improved RDN studies ongoing

2. Patients with poor drug compliance

• Improved in long-term BP
control could justify RDN
intervention

3. Systolic HTN in the elderly

• Sympathetic NS is a factor
• Responds well to drugs
• Question about ablation energy
across atherosclerotic vessels
Medicine
Nephrology

Indications for Renal Denervation
Looking to the Future
Indication

4. Hypertension in young adults

Comment
• High sympathetic NS is a hallmark
• Early evidence for LVH, arterial
stiffness, etc
• RDN could potentially improve lifelong natural history of HTN

5. Hypertension related to CKD

• Early evidence the RDN may
reduce rate of decline

6. Atrial fibrillation and heart failure

• These are being studied
independent of hypertension

Medicine
Nephrology

Structural verses Neuro Hormonal
Hypertension
Structural HTN

Neuro-Hormonal HTN

Adapted from Physiology; Berne & Levy
Medicine
Nephrology

Elastic Fibers are Terminally Differentiated
After the age of 50, HTN is principally Structural

Systolic BP

Diastolic BP

Age
Burt. Hypertension 1995;25:313
Medicine
Nephrology

Renal Sympathetic Activity
Declines with Age

Esler et.al., J Cardiovasc Pharmacol, 1986

Medicine
Nephrology

Loss of Aortic Elasticity Increases
Pulse Wave Velocity

Avolio et al; Circ:1983
Medicine
Nephrology

The aorta is meant to buffer each heart beat
The Windkessel Function of the Aorta

Medicine
Nephrology

Reduction of Arterial Volume
with Diuretics
2.4% of total body water is arterial
(42l water in a 70kg adult);
To reduce effective arterial
volume by 1 liter, a diuretic must
remove 25% circulating volume;

Restoring Windkessel with
diuretics inherently activates RAA
and is associated with systemic AE.

adapted by Cevasco M and Dunlap ME
Medicine
Nephrology

Mechanical solutions for structural hypertension:
Immediate BP reduction (-28/-15 mmHg)
186-180

~72

Systolic BP
( mmHg )

Diastolic BP

150-153

~60

( mmHg )

Eliminates the possibility of placebo, sham or Hawthorne effects
Medicine
Nephrology

ROX Coupler Device

Medicine
Nephrology

ROX
Coupler
Device

Medicine
Nephrology

Randomized RH-02: Change in Office BP
Systolic BP
Diastolic BP

Control Group

AV Coupler Group
3 Mo
n=42

6 Mo
n=42

9 Mo
n=38

12 Mo
n=38

24 Mo
n=9

3 Mo
n=33

6 Mo
n=34

Statistically significant at all points
p-values 3, 6, 9 and 12m < 0.0001; 24m <
0.015
Medicine
Nephrology

Electroceutical
(eCoin)

Valencia Technologies Patent US 8805512 B1
Medicine
Nephrology

eCoin for the Rx of HTN

Medicine
Nephrology

Median Nerve Stimulation
• Activates somatic afferent nerve fibers in the
BP control centers of the brain:
• Arcuate and periventricular nuclei of the
hypothalamus
• Ventrolateral periaqueductal gray in the midbrain
• Nucleus tractus solitary
• Caudal ventral lateral medulla
This stimulation will release opioids, GABA and
cause sustained inhibition of sympathetic premotor
neurons, responsible for vasoconstriction
Tjen-A-Looi SC, Li P, et al. AJP, 2007:293(6):H3627-H3635
Medicine
Nephrology

Median Nerve Stimulation
• 30 minute stimulation will release prolonged
transcriptional precursors such as mRNA
preproenkephalin (PPE) for over 72 hrs.

• Long-term effects are seen between 4-8 wks
• Proposed scheme: 30 min sessions weekly at
5-10 pulses/sec.
Li M, Tjen-A-Looi SC, et al. Autonomic Neuroscience 2012:170(0):30-35
Medicine
Nephrology

Medicine
Nephrology

Summary
• Resistant Hypertension is a “Rule-Out”
Diagnosis
• Poor Drug and Diet Adherence and High
Sodium Intake are most common causes

• Device Therapy is still evolving and moving
forward

Medicine
Nephrology

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