Invasive treatment of Resistant HT - Capri Cardio · Invasive treatment of Resistant HT 17889 M ......
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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
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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
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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