Invasive treatment of Resistant HT

17889 M

Renal Denervation

Carotid Baroreceptor Stimulation

A-V Fistula

Brain Stem Stimulation

Total Sympathectomy

Splanchnicectomy

Is efficacious in reducing high BP? No conclusive answer

RDN Trials in Resistant HT

Is safe? No safety issues during a 3 years follow-up

A series of earlier, observational

studies and registries

(+ +)

4 Randomized, controlled

studies

HTN -2 (+), DENER HTN (+)

Prague 15 (-), Oslo (-)

1 Randomized, blind, sham

controlled study

HTN -3 (-)

Treatment strategies in hypertensive patients with

resistant hypertension

2013 ESH/ESC Hypertension Guidelines

What have we learned from HTN 3 and

other RDN clinical/pre clinical trials?

Procedural aspects

Degree of optimal denervation

Distribution of lesions

Study population

Appropriate population

BP response to RDN: Huge variability and heterogeneity

Potential confounders

Design of the study

Medication stability

Medication adherence

office BP as end point

Impact of Number of Ablations on BP

19679 M Kandzari et al., Eur Heart J 2015; 36: 219

≥ 8 ≥ 9 ≥ 10 ≥ 11 ≥ 12 ≥ 13 ≥ 14 ≥ 15 ≥ 16

0

-5

-10

-15

-20

-25

-30

P value for trend= 0.16

RDN Sham

P 0.47 0.33 0.06 <0.05 0.002 0.02 0.16 0.23 0.7

SBP change (mmHg)

≥ 8 ≥ 9 ≥ 10 ≥ 11 ≥ 12 ≥ 13 ≥ 14 ≥ 15 ≥ 16

0

-5

-10

-15

-20

-25

-30

-35

P value for trend= 0.01

RDN Sham

P 0.54 0.27 0.07 0.04 0.07 0.03 0.06 0.18 0.43

Office Ambulatory

Number of ablations Number of ablations

Our View of Renal Nerve Distribution Has Changed

Renal nerves may have a positional bias on radial distance from arterial lumen: distal nerves are closer

Current concept—nonuniform radial distribution

Distal Proximal

Prior concept—uniform radial distribution

Distal Proximal

Sakakura K et al. JACC. 2014;64:634–643

Procedural aspects: Distribution of lesions

6530 G Hypertension 2015; 65: 393-400

Revised Definition of Resistant Hypertension

15862 M

Failure to reach BP targets despite use of ≥ 3 drugs

(including a diuretic) at adequate doses in patients

in whom pseudoresistant hypertension is excluded

and a mineralocorticoid receptor antagonist

(antialdosterone agent) has been tested

Ambulatory 24-hour Average Blood Pressure (BP) Changes

6533 G Rosa J et al., Hypertension 2015; 65: 407-413

Baseline

6 Month

60

80

100

120

140

160

180

200

RDN PHAR RDN PHAR

Blo

od

pre

ssu

re (

mm

Hg)

24h SBP Difference in change

-0.5 (-6.1; 5.2)

p = 0.87

24h DBP Difference in change

-1.1 (-4.3; 2.0)

p = 0.48

Change from baseline

-8.6 (-11.8; -5.3)

p < 0.001

Change from baseline

-8.1 (-12.7; -3.4)

p = 0.001

Change from baseline

-5.7 (-7.9; -3.4)

p < 0.001

Change from baseline

-4.5 (-6.8; -2.3)

p < 0.001

6726 G

Ambulatory 24-h Systolic Average Blood Pressure Changes

Rosa et al., Hypertension 2016; 67: 397-403

60

80

100

120

140

160

180

200

BP

(m

mH

g)

RDN

n = 51

PHAR

n = 50

Complete

RDN

n = 44

Spironolactone

added & continued

n = 19 Baseline 12 months

Difference in change

1.9 (-4.2; 8.0)

p = 0.54

Change from baseline

-6.4 (-10.1; -2.7)

p = 0.001

Change from baseline

-8.2 (-13.2; -3.3)

p = 0.001

Difference in change

8.7 (0.4; 17.1)

p = 0.04

Change from baseline

-6.3 (-10.4; -2.1)

p = 0.004

Change from baseline

-15.0 (-24.0; -6.0)

p = 0.003

Meta-analysis of Controlled Studies

6337 G Davis MI et al., JACC 2013; 62: 231-41

Increase in BP Decrease in BP

Catheters Used for Renal Denervation

6338 G Davis MI et al., JACC 2013; 62: 231-41

Decrease in BP Increase in BP

Selection of Trials

6745 G Zhang et al., Blood Press Monit 2016

Characteristics of the Randomized Trials Included

6746 G Zhang et al., Blood Press Monit 2016

Forest Plot of Outcomes of Patients Treated with RDN and Medicine

Office SBP Change at 6 Months

6748 G Zhang et al., Blood Press Monit 2016

6749 G Zhang et al., Blood Press Monit 2016

Forest Plot of Outcomes of Patients Treated with RDN and Medicine

Office DBP Change at 6 Months

6750 G Zhang et al., Blood Press Monit 2016

Forest Plot of Outcomes of Patients Treated with RDN and Medicine

Ambulatory SBP Change at 6 Months

Office and 24h SBP Reduction by Renal Denervation at 6, 12 and 24 Months

(Global Symplicity Registry, n° of ablations 13.3 ± 4.0)

19862 M Mahfoud, Böhm, Narkiewicz, Ruilope, Schlaich, Schmieder, Williams, Mancia, ESH Meeting, 2015

Office SBP 24h SBP

(mm

Hg

)

Severe resistant HTN OSBP > 160, ABPM > 135

and 3+ meds

(N = 681)

Less severe HTN OSBP 150-180, ABPM 140-170

and DBP > 90

(N = 213)

-25

-20

-15

-10

-5

0

-25

-20

-15

-10

-5

0

-25

-20

-15

-10

-5

0

-25

-20

-15

-10

-5

0

Severe resistant HTN OSBP > 160, ABPM > 135

and 3+ meds

(N = 681)

Less severe HTN OSBP 150-180, ABPM 140-170

and DBP > 90

(N = 213)

(mm

Hg

)

-22.0 -22.4 -21.3

-12.8

-16.7 -17.3

-8.5

-11.0 -11.0

-7.4

-10.9 -10.7

Baseline OSBP 181 ± 18

P < 0.0001

Baseline OSBP 165 ± 8

P < 0.0001

Baseline ABP 161 ± 16

P < 0.0001

Baseline ABP 154 ± 8

P < 0.0001

Change at 6 months

Change at 1 year

Change at 2 years

RDN potential effects beyond BP lowering (if any)

Risk

Factors

Intermediate

Surrogates

Cardio-Renal

Disease

Hypertension

Arrhythmias

Glucose Impairment

Sleep Apnea

LVH

Arterial Stiffness

Albuminuria

Renal hemodynamics

Heart Failure

Chronic Kidney Disease

RDN Ukena C, et al. Int J Cardiol 2013

Brandt MC, et al. J Am Coll Cardiol. 2012;59:901-909

Mahfoud F, et al. Circulation. 2011; 123:1940-1946

Mahfoud F, et al. Hypertension. 2012;60:419-424.

Mahfoud F, et al. Eur Heart J 2014

Tsioufis C, et al, JHH 2014

Tsioufis et al, JH 2014

6715 G

Change in Daytime Ambulatory and Office BP to RDN

by Quartile of Starting Daytime Ambulatory SBP

Sharp et al., Clin Res Cardiol 2015; doi:10.1007/s00392-015-0959-4

-0.4 -1.8

-15.2

-5.3 -6.5

-3.8

-22.3

-10.9

-14.5

-6.4

-22.9

-9.0

-22.1

-13.3

-30.3

-12.4

-35

-30

-25

-20

-15

-10

-5

0

Daytime ASBP

Ch

an

ge

(mm

Hg)

Daytime ADBP Office SBP Office DBP

Quartile 1

(mean 143 mmHg)

Quartile 2

(mean 162 mmHg)

Quartile 3

(mean 176 mmHg)

Quartile 4

(mean 199 mmHg)

Starting daytime ASBP

6734 G

Blood Pressure Changes in Patients with Available ABPM

Before and After Renal Denervation

Ott et al., J Am Coll Cardiol 2013; 62: 1880-1886

Office BP 24-h ABPM

-20

-15

-10

-5

0

Ch

an

ge

in B

P (

mm

Hg)

aft

er R

DN

3 months 6 months 6 months

Change in SBP

Change in DBP

p=0.012

p=0.003

p<0.001

p<0.001

p<0.001

p<0.001

6756 G Desch et al., Hypertension 2015; 65: 1202-1208

Change in 24-h Systolic Blood Pressure

Intention-To-Treat cohort Per-Protocol cohort

Volume

Overload

SNS Activation Structural

vascular

changes

Pathophysiological Profile of Resistant Hypertension

Effects of RDN on Mean BP Changes According to Baroreflex Sensitivity

6333 G Zuern CS et al., JACC 2013; 62: 2124-30

Ch

an

ge

in B

P 6

mon

ths

aft

er R

DN

(m

mH

g)

Mean SBP on ABPM

Mean DBP on ABPM

p=0.003

Baroreflex sensitivity at baseline

-25

-20

-15

-10

-5

0

5 All patients

(n = 50)

Lowest tertile

(n = 17)

Middle tertile

(n = 16)

Highest tertile

(n = 17)

p=0.022

ANOVA SBP p=0.023

ANOVA DBP p=0.128

12-month Change in Office HR and SBP according to Office HR Tertiles at Baseline and

12-month Change in 24-h HR and SBP according to 24-h HR Tertiles at Baseline

6743 G Mahfoud, Böhm, Narkiewicz, Ruilope, Schlaich, Schmieder, Williams, Mancia, ESH Meeting, 2015

Office HR Office SBP

Ch

an

ge

(bp

m)

-10

-8

-6

-4

-2

0

2

4

6

-16

-12

-8

-4

0

-6

-4

-2

0

2

4

6

-10

-8

-6

-4

-2

0

Ch

an

ge

(mm

Hg

)

According to

Office HR

Tertiles

According to

24-h HR

Tertiles

Ch

an

ge

(bp

m)

Ch

an

ge

(mm

Hg

)

24-h HR 24-h SBP

5.1

3.8

1.8

-3.0

-8.2

0.5

-5.7

-8.4 -7.6

-11.3

-14.5

-12.3

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P = 0.002

P < 0.001

P = 0.003

P < 0.001

Baseline HR < 63 63-74 > 74 < 63 63-74 > 74

Baseline HR < 61 61-70 > 70 < 61 61-70 > 70

Office, Ambulatory and Beat-to-beat BP and MSNA in Normotensive (NT),

Non-resistant Hypertensive (HT) and Resistant Hypertensive (RHT) Patients

19863 M Grassi, Seravalle, Brambilla, Pini, Alimento, Facchetti, Spaziani, Cuspidi, Mancia, Int J Cardiol 2014; 177: 1020

0

40

80

120

160

200

mmHg

NT HT RHT NT HT RHT

Office BP Ambulatory BP Beat-to-beat BP

0

40

80

120

160

200

0

40

80

120

160

200

mmHg mmHg ** **

** **

** **

** **

** **

**

* **

**

S

D

S

D

S

D

MSNA

bs/100hb

0

25

50

75

100

NT HT RHT

*

** **

6724 G

Blood Pressure Values in Resistant and Pseudo-resistant HT

T T

Grassi G, Mancia G et al., unpublished data

Early Sympathetic Activation in the Prehypertensive State

6482 G Seravalle G et al., J Hypertension 2015

MSNA MSNAc

0

10

20

30

40

50

Optimal Normal High-normal

(bs/min)

** **

0

10

20

30

40

50

60

70

Optimal Normal High-normal

(bs/100 hb)

** **

Office, Ambulatory, and Beat-to-beat (Finapres) SBP and DBP

Before and 15 Days, 1, 3 and 6 Months after Bilateral Renal Denervation

19723 M Grassi, Seravalle, Brambilla, Trabattoni, Cuspidi, Corso, Pieruzzi, Genovesi, Stella, Facchetti, Spaziani, Bartorelli, Mancia,

Hypertension 2015; 65: 1209-1216

4 0

6 5

9 0

1 1 5

1 4 0

4 0

6 5

9 0

1 1 5

1 4 0

Office

Time

Baseline 15 days 1 month 3 months 6 months

Ambulatory Beat-to-beat

SB

P (

mm

Hg

) D

BP

(m

mH

g)

8 0

1 2 0

1 6 0

2 0 0

2 4 0

8 0

1 2 0

1 6 0

2 0 0

2 4 0

8 0

1 2 0

1 6 0

2 0 0

2 4 0

4 0

6 5

9 0

1 1 5

1 4 0

Time

Baseline 15 days 1 month 3 months 6 months

Time

Baseline 15 days 1 month 3 months 6 months

*

*

** * * ** * * **

*

* ** * * ** * * **

MSNA and Spontaneous Baroreflex Control of MSNA

Before and 15 Days, 1, 3 and 6 Months after Bilateral Renal Denervation

19724 M Grassi, Seravalle, Brambilla, Trabattoni, Cuspidi, Corso, Pieruzzi, Genovesi, Stella, Facchetti, Spaziani, Bartorelli, Mancia,

Hypertension 2015; 65: 1209-1216

BRS

- 5

- 4

- 3

- 2

- 1

0

Baseline 15 days 1 month 3 months 6 months

Time

* * (a

.u.)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

MSNA

Time

Baseline 15 days 1 month 3 months 6 months

*

*

(bs/

100

hb

)

MSNA Responses to RDN in Patients with a SBP Response after 6 Months Above or Below the Median Value

SBP Responses to RDN in Patients with a MSNA Response after 6 Months Above or Below the Median Value

19845 M Grassi, Seravalle, Brambilla, Trabattoni, Cuspidi, Corso, Pieruzzi, Genovesi, Stella, Facchetti, Spaziani, Bartorelli, Mancia,

Hypertension 2015; 65: 1209-1216

S

BP

(m

mH

g)

S

BP

(m

mH

g)

** Above m.v.

M

SN

A (

bs/

100

hb

)

M

SN

A (

bs/

100

hb

)

According to changes in SBP (above or below median value [m.v.])

According to changes in MSNA (above or below median value [m.v.])

Below m.v. Above m.v. Below m.v.

Above m.v. Below m.v. Above m.v. Below m.v.

-30

-25

-20

-15

-10

-5

0

-30

-25

-20

-15

-10

-5

0

-30

-25

-20

-15

-10

-5

0

-30

-25

-20

-15

-10

-5

0

** ns

ns

6741 G Grassi G et al, Abstract ESH 2016

“Residual” Sympathetic Activation in treated HT

20

40

60

80

MS

NA

(b

s/100 h

b)

NT HT-U HT-T

(ACEI)

HT-T

(ARB)

HT-T

(ACEI/CA)

RHT-U RHT-RD

1)Pharmacological treatment unsatisfactory

2)Renal denervation remains worthy of continuing investigation

3)Future trials to be done against best drug therapy (rather than

sham procedures)

4)Control of variables such as treatment changes/adherence to

treatment/denervation effectiveness fundamental

5)How much of the risk is reversible?Need to go beyond

assessment of BP reduction into outcome data

True Res HT-renal Denervation/Where are we?

20082 M