Renal Artery Denervation Patient Selection and Results
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Transcript of Renal Artery Denervation Patient Selection and Results
Renal Denervation: Yale Vascular Medicine Experience
Carlos Mena, MD. F.A.C.C., F.S.C.A.IAssistant Professor Department of Internal MedicineMedical Director Vascular Medicine ProgramSection of Cardiovascular MedicineYale University School of Medicine
Definition of resistant HTN
“Resistant hypertension is defined as blood pressure that remains above goal in spite of the concurrent use of 3 anti-hypertensive agents of different classes. Ideally, one of the 3 agents should be a diuretic and all agents should be prescribed at optimal dose amounts.”
AHA Scientific Statement. Hypertension 2008, 51:1403-1419
Kearney et al. Lancet 2005;365:217-23Lloyd-Jones et al. Circulation 2010;121:e46–e215Wolf-Meier et al. JAMA 2003;289:2363–2369Journal of Human Hypertension 2004;18:911-912
More than one quarter of adults in developed societies are affected by hypertension
45% 30MJapan
21% 182MChina
21% 118MIndia
38% 78MLatin America
44% 81MEurope
34% 75MU.S.2
34% 75MU.S.
Global Burden of Hypertension is Substantial and Growing
2000 202525
26
27
28
29
30
400
800
1200
1600
972M
1,560M
26.4%
29.2%
Total Hypertensive Population (M)
Glob
al P
reva
lenc
e (%
)
Year
Kearney PM: Lancet 2005;365:217–223
Hypertension leads to an increased risk of death from stroke and heart disease
2x
4x
8x
Systolic BP / Diastolic BP (mmHg)7
Card
iova
scul
ar M
orta
lity
Risk
CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure.1,2
1Chobanian et al. Hypertension 2003;42:1206-12522Lancet 2002;360:1903-1913
Chronology of Anti-hypertensive Drug Development
1940s 1950s 1960s 1970s 1980s 1990s 2000s
Effectiveness
Side Effects
Peripheral Sympatholytics
Ganglion Blockers
Veratrum Alkaloids
Direct Vasodilators
Thiazide Diuretics
Central Alpha2
Agonists
Non-DHP CCBs
Beta Blockers
Alpha Blockers
DHP CCBs
ACE Inhibitors
ARBs DRIs
Blessing, Leipzig Interventional Course, 2010.
38% of HTN population remain Uncontrolled
9% of HTN population remain resistant
ACE = angiotensin-converting-enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; DHP = dihydropyridine; DRI =direct renin inhibitors
Afferent Nerve Activity:• Systemic Sympathetic Neural Stimulation
• LV Hypertrophy• Systolic Heart Failure• Heart Failure with preserved ejection
fraction (HFpEF)• Arrhythmia
Efferent Nerve Activity:• Renal Artery Vasoconstriction• Sodium and Fluid Retention• Enhanced Renin Release
The Hyperactive Sympathetic Nervous System is a Driver of Hypertension
Doumas et al. Am J Cardiol 2010;105:570-576 Cleveland Clinic Journal of Medicine 2012; 79: 501-10
MDTSymplicity
MDTSpyral
STJ EnligHTN
ReCor Gen-2 Paradise
JNJThermoCool
BSCVessix
CE Mark No No
Catheter Design Catheter with single electrode
Pigtail Catheter 4 electrodes
Basket with four electrodes
Balloon catheter; internal cooling;
Circumferential treatment
Pigtail catheter with 5 electrodes
and cooling
Balloon catheter4-8
electrodes
Balloon No No No No Guidewire No No No
Energy MonopolarRF
MonopolarRF
MonopolarRF Ultrasound Monopolar
RF Bipolar
RF
Power 8W Unknown 8W ~12W Unknown ~1W
Energy Delivery Time 2 min. 1 min. 60 sec 30 sec. Unknown 30 sec.
Total Treatment Time 16-24 min. 2 min. 4 min. 3 min. Unknown 2 min.
Renal Denervation Technologies
None of these devices are available for sale in the US. Medtronic Website, March 2013; The New Medtronic Device, Weil, TRENDS Frankfurt 2013; Worthley, S. EuroPCR 2013; The ReCor Device, Weil, TRENDS Frankfurt 2013; Sievert, Live Case, TRENDS, Frankfort 2013; LINC 2013, Live Case ReCor; J&J Thermocool Bertog, TRENDS Frankfurt 2013.
SymplicityHTN-1
• 50 pts • 12 mo. • BP may
take months to fall
Krum H, et al. Lancet 2009; 373: 1275–81
-14/10 -21/10 -22/11 -24/11 -27/17
SymplicityHTN-2 Results 12 mo
Circ 2012;126:2976
Recent Allegations about RDN
“Small wonder that the cookie is finally crumbling, bigger wonder that it actually took so long. The irrational exuberance for renal denervation in resistant hypertension was entirely driven by
uncontrolled non-randomized observational office-based blood pressure studies.”
F. Messerli
“This is probably the most extreme case I have ever seen of inadvertent bias in measurement
producing – concordantly across several studies – massive overestimation of an effect size”
D. Francis
Forbes 9/10/2013Kirtane, A. TCT 2013.
Clinical Decision Making
Clinical Practice
• Observational registries• Randomized controlled trials• Meta- (or pooled) analyses• Treatment strategy studies
Evidence-based
Medicine
Leon, M. ISET 2014.
• Clinical “judgement”• Patient and physician
expectations• Operator-related issues• Socio-economic factors
Clinical Practice
Other Factors
Clinical Decision Making
Leon, M. ISET 2014.
RDN: What Are The Problems
• Problem Definition• Patient Compliance• Sham – Procedure• Device Related issues
Definition: Resistant HTN
• NHANES 2003-2008 data• N = 5,530• 539 resistant (12.8% of treated hypertensives)
HOWEVER…• Spanish ABPM registry, N = 8,295• Prevalence of office RH = 12.2%• 37.5% normal ABPM (ie, “office resistance”)
How common is resistant HTN?
Persell. Hypertension 2011; 57: 1076-80
De la Sierra. Hypertension 2011; 57: 898-902
• Retrospective study
• 304 patients over 8 years seen at a HTN Center “at least 3 times for at least 6 months”.
• 29 (~10%) remained >140/90 mmHg:
– Higher baseline BP (175/97 vs. 158/89 mmHg)
– More co-morbidity
• Stroke 28% vs. 8%
• CHF 24% vs. 4%
Resistance within a Hypertension Specialist Practice (“Refractory HTN”)
Acelajado, Calhoun et al. J Clin Hypertens 2012; 14: 7-12
Long term prognosis in resistant HTN is better predicted by ABPM
Salles et al. Arch Intern Med 2008; 168: 2340
Adjusted HR 2.11 [1.34-3.34] Adjusted HR 2.0 [1.12-3.55]
N=556, F/U 4.6 years
Howard et al. Heart 2013
Office vs. Ambulatory BP in Open Label Drug TrialsOBP Reductions were 5.6 mm Hg > Ambulatory BP Reductions (p<0.0001)
Study or subgroupOffice Ambulatory
Mean Total Mean Total WeightMean Difference
IV, Random, 95% CIMean Difference
IV, Random, 95% CI
Total (95% CI) 2779 2779 100.0% 5.60 [2.98, 8.22]
Antonicelli (2002)Calhoun (2008)Coca (1997)Coca (2003)De Souza (2010)Finkielman (2005)Mancia (1997)Martina (1994)Middlemost (1992)Mion (2004)Omboni (2001)Oren (1996)Ouzan (2002)Parra Carrillo (2004)Scholze (2011)Spratt (2001)White (2006)
2517.610.426.314
14.2262123122016
35.620.629.222
20.2
24523057
173228184353965501925897717
1615
1312.29.5
22.7169.5181731121312249.9
11.116
10.7
24523057
173228184353965501925897717
1615
4.7%6.0%5.1%6.3%7.1%7.3%7.1%5.4%5.5%6.2%5.9%4.3%4.8%6.6%6.0%4.1%7.6%
12.00 [4.49, 19.51]5.40 [0.30, 10.50]0.90 [-5.82, 7.62]3.60 [-0.81, 8.01]
-2.00 [-4.80, 0.80]4.70 [2.54, 6.86]
8.00 [5.29, 10.71]4.00 [-2.22, 10.22]
-8.00 [-13.89, -2.11]0.00 [-4.56, 4.56]7.00 [1.80, 12.20]
4.00 [-4.44, 12.44]11.60 [4.24, 18.96]10.70 [6.80, 14.60]
18.10 [13.01, 23.19]6.00 [-2.93, 14.93]9.50 [8.58, 10.42]
Ambulatory drop larger
Office drop larger
-20 -10 0 10 20Heterogeneity: Tau2=23.19; Chi2=137.37; df=16; (P<0.00001); I2=88%Test for overall effect: Z=4.19 (P<0.0001)
Office vs. Ambulatory BP in Placebo-treated patients in randomized blinded placebo-controlled drug trialsOBP reductions were 2.9 mmHg > ambulatory pressure reductions (p=0.002)
Study or subgroupOffice Ambulatory
Mean Total Mean Total WeightMean Difference
IV, Random, 95% CIMean Difference
IV, Random, 95% CI
Total (95% CI) 1342 1342 100.0% 2.90 [1.06, 4.74]
Blanchett (1990)Fogari (1997)Guthrie (1996)Lacourcière (1992)Lacourcière (1998)Mancia (1997)Myers (2000)Neutel (1999)Omboni (1998)Staessen (1994)Starmans-Kool (1998)Svensson (2001)Van der Meiracker (1995)Václavík (2011)
33.9-2.1
33
105
-0.45.57
1140
8.1
341016142
10412812326250
233133842
111
5-1.6-2.3
21
0.53
-0.42182
2.64
341016142
10412812326250
233133842
111
4.6%8.2%6.5%5.3%8.3%8.9%8.8%
10.8%8.9%
10.5%2.2%3.2%5.3%8.5%
-2.00 [-8.95, 4.95]5.50 [1.47, 9.53]
0.20 [-4.99, 5.39]1.00 [-5.25, 7.25]2.00 [-1.97, 5.97]9.50 [5.92, 13.80]2.00 [-1.65, 5.65]0.00 [-2.50, 2.50]3.50 [-0.11, 7.11]6.00 [3.35, 8.65]
3.00 [-8.24, 14.24]2.00 [-7.00, 11.00]-2.60 [-8.85, 3.65]
4.10 [0.25, 7.95]
Ambulatory drop larger
Office drop larger
-20 -10 0 10 20Heterogeneity: Tau2=6.50; Chi2=31.99; df=13; (P=0.002); I2=59%Test for overall effect: Z=3.09 (P=0.002)
Howard et al. Heart 2013
Office vs. Ambulatory BP in Active Drug-treated Ptsin randomised blinded placebo-controlled drug trialsSimilar effect on office and ambulatory BP (p=0.45)
Study or subgroupOffice Ambulatory
Mean Total Mean Total WeightMean Difference
IV, Random, 95% CIMean Difference
IV, Random, 95% CI
Total (95% CI) 1342 1342 100.0% -0.88 [-3.18, 1.43]
Blanchett (1990)Fogari (1997)Guthrie (1996)Lacourcière (1992)Lacourcière (1998)Manda (1997)Myers (2000)Neutel (1999)Omboni (1998)Staessen (1994)Starmans-Kool (1998)Svensson (2001)Van der Meiracker (1995)Václavík (2011)
57.7
17.711118
1812.66.51668
126.5
341016142
10412812326250
233133842
111
611.325.2
913
14.515
12.87
105
109.59.8
341016142
10412812326250
233133842
111
5.4%8.1%6.9%6.0%8.1%8.5%8.4%9.5%8.5%9.4%3.0%4.1%6.0%8.2%
-1.00 [-7.95, 5.95]-3.60 [-7.63, 0.43]
-7.50 [-12.69, -2.31]2.00 [-4.25, 8.25]
-2.00 [-5.97, 1.97]-6.50 [-10.08, -2.92]
3.00 [-0.65, 6.65]-0.20 [-2.70, 2.30]-0.50 [-4.11, 3.11]
6.00 [3.35, 8.65]1.00 [-10.24, 12.24]-2.00 [-11.00, 7.00]
2.50 [-3.75, 8.75]-3.30 [-7.15, 0.55]
Ambulatory drop larger
Office drop larger
-20 -10 0 10 20Heterogeneity: Tau2=12.96; Chi2=50.85; df=13; (P<0.00001); I2=74%Test for overall effect: Z=0.75 (P=0.45)
Howard et al. Heart 2013
Compliance: Resistant HTN?
Medication adherence is poor in patients referred to a hypertension service for resistant hypertension
375 referrals = (optimized Rx) = 108 true resistant HTN => 76 “taking all meds”
Analysis by urine LC-MS
Percentage of prescribed drugs taken by non-adherent patients
Adherence to therapy according to drug class
Jung. J Hypertens 2013: epub ahead of print
30% complete non-adherence
Mechanism of Action: RDN Bipolar?
Vessix™ Renal Denervation System Bipolar RF Energy for Renal Denervation
• Localized energy delivery from positive to negative poles; no grounding pad
• No need for cooling• Reduced impact of treatment variability• Low energy of ~1W delivered
• Energy dispersed through the body; terminates in grounding pad
• Cooled via blood flow and/or irrigation• Increased impact of treatment variability• Higher energy required
BipolarRF
MonopolarRF
RF=Radiofrequency
• Renal nerves follow the renal artery to the kidney; only location that renal efferent and afferent nerves travel together
• Catheter-based delivery of low-power RF energy administered at multiple sites, facilitates denervation
• Bilateral denervation is the current standard of care
Sympathetic Nerves
Sympathetic Renal Nerve Anatomy Anatomic Target for Renal Denervation
0 < 2 mm 2 < 4 mm > 4 mm0
10
20
30
40
50
60
70
80
90
10090
100
4031 29
53
23 24
Atherton Virmani Tunstall*
Distance from lumen (mm)
Perc
ent o
f Ner
ves
Virmani, R. TCT 2012Atherton DS. Clin Anat 2012.BSC data on file
*Includes nerve count prior to parsing out plaque /no plaque
Human Renal Nerve Anatomy StudiesSimilar Findings with Varying Methodologies
• Renal Denervation with injury depth of 3-4mm
Vessix Preclinical Studies (Swine) Depth of penetration
• Efficacy comparable to surgical denervation
b.
a.
Lumen
Renal Artery
5mmH&E, 0.38x
Vessix™Treatment, 68°C, 30 sec (n=19)
Surgical Denervation (n=3)
0
50
100
74% NEPI Reduction
77% NEPI Reduction=
Perc
ent r
educ
tion
in N
EPI
BSC data on file. Swine model results not necessarily indicative of clinical performance.
• Histology shows endothelialization at 7 days
• No thrombosis
7 days
Lumen
TunicaMedia
IEL
90 days
• Histology confirms no adverse effect on surrounding tissue
• All treated arteries were patent• No dissections, aneurysms, or changes
in blood or urine chemistry
Vessix Preclinical Studies (Swine) Vascular safety through 90 days
BSC data on file. Swine model results not necessarily indicative of clinical performance.
0
5
10
15
20
25
30
35
40
45
50
10%
28%
Ner
ves (
%) w
ithin
zone
of
trea
tmen
t am
ong
all n
erve
s
Full treatment affected more nerves within the treatment zone (p<0.05) and caused the highest decrease in NEPI levels 14 days post treatment
The group with surgical denervation showed a 75% reduction in NEPI, compared to the endogenous NEPI level of the untreated controls.
-46% NEPIAt 14 days
-78% NEPIAt 14 days
One treatment per artery
n=6 arteries
Full artery length treatment
n=6 arteries
Kidney Norepinephrine Reduction (14d) Following One and Full Artery Treatment in Swine
BSC data on file. Swine model results not necessarily indicative of clinical performance.
Nerves in treatment zone in swine
BSC data on file. Swine model results not necessarily indicative of clinical performance.
0
5
10
15
20
25
30
35
40
23.6
35.8
Tota
l num
ber o
f ner
ves i
n pl
anes
with
trea
ted
zone
sp<0.05
One treatment per artery
N=5
Full artery length treatment
N=5
One treatment per artery
Full artery length treatmet
0%10%20%30%40%50%60%70%80%90%
100%
22 18
3323
2944
16 15
0 1 2 3
% o
f ner
ves
50 µm
50 µm
50 µm
50 µm
Score 0 = Normal Score 1 = Degenerate
Score 2 = Necrotic Score 3 = Chronic
Nerve Morphology at 7 daysFollowing Bipolar RF Treatment in Swine
BSC data on file. Swine model results not necessarily indicative of clinical performance.
Accessory Renal ArteriesUsing the Vessix™ Catheter
RF=RadiofrequencyCase courtesy of Ian Meredith, AM. Results from case studies are not predictive of results in other cases. Results in other cases may vary.
• Small renal and accessory renal arteries were treated with the Vessix™ Catheter in the REDUCE-HTN post market study
• Patients with small or accessory renal arteries were excluded from other trials
Significant Office Blood Pressure Reductions
P≤.0005 for each timepoint vs baseline.Error bars represent 95% confidence bounds.
1 Month 3 Months 6 Months
-25
-20
-15
-10
-5
0
-23.2
-17.8-21.0
-12.6-11.4
-12.3
Change in Office Systolic BP Change in Office Diastolic BP
Mea
n BP
Cha
nge
from
Bas
elin
e (m
mHg
)
Patients with Treated Accessory Renal Arteries (n=24)
Sievert, H. CRT 2014.
Camparison between the Vessix™ and the Symplicity™ System
-30
-25
-20
-15
-10
-5
0
5
-11
-1-4
1
Systolic Diastolic
Redu
ction
in B
P (m
mHg
)
• CardioVascular Center Frankfurt, Sankt Katharinen, Frankfurt, Germany– 15 consecutive patients denervated using the Vessix system– 30 consecutive patients denervated using Symplicity (participating in HTN1 and HTN2 studies)– Primary Endpoint – Office and Ambulatory blood pressure reduction at 6M post denervation
Group Baseline OBP
BaselineAmbulatory
Mean Age (years)
Male(%)
DiabetesMellitus (%)
# of Antihypertensives
Vessix 172/90 mmHg 156/86 mmHg 62.4 ± 8 60 40 5.4 ± 1.6
Symplicity 166/85 mmHg 152/81 mmHg 67.9 ± 9 64 33 5.8 ± 1.5
-30
-25
-20
-15
-10
-5
0
5
-16 -16
-1-6
Systolic Diastolic
Redu
ction
in B
P (m
mHg
)
Vessix(n=14)
Symplicity(n=28)
Office Based BP6M
Ambulatory BP6M
Vessix(n=14)
Symplicity(n=28)
“We can see a propensity for a more pronounced ambulatory BP reduction in the Vessix group”
Jost UL, Bertog S, Ziegler A-K, Gafoor S, Kulow JP, Hofmann I, Vaskelyte L, Sievert H. TRENDS 2014.
Is Sham Necessary????
Arguments on Both Sides
• Unethical (risk without benefit)
• How can there be a placebo effect on objectively measured BP (especially ABPM)?
• Can’t “fake” a painful procedure
• Enrollment deterrent
• Data and durability of effect argues against substantial placebo effect
• Clinicians can “exercise judgment” and BP readings are inaccurate and show regression to the mean
• Data differences between ABPM and Office BP (and even home BP) suggest significant variability and raise doubts regarding effectiveness of RDN
• RDN studies need to be bulletproof in the current environment
No Sham! Pro Sham!
Kirtane, A. TCT 2013.
Evidence-Based MedicineWhat’s the Problem?
Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997
“There is an unsettling truth about the practice of medicine…
…study after study shows that few physicians systematically apply to
everyday treatment the scientific evidence about what works best.”
Leon, M. ISET 2014.
Why Have We Grown More Used tothe Concept of a Sham Control?
The lack of readily measurable surrogates for reduced sympathetic outflow combined with the variability of BP measurements makes us want to be more
rigorous…
Mahfoud, F. Bhatt, D. JACC: Cardiovascular Interventions, October 2013.Kirtane, A. TCT 2013.
What Does Blinding Really Do?
• Patient blinding: can influence adherence and expectations (and interactions with treating physicians)
• Physician blinding (for ascertainment):– Can influence concomitant medications – Can influence ascertainment of blood pressures (office
BP in particular)
• What is debatable: To what real extent is a sham design necessary in order to eliminate these confounders?
• Can study processes (during follow-up / ascertainment) obviate the need for a sham procedure?
Kirtane, A. TCT 2013.
> 1200 Patients planned worldwide
Boston Scientific Renal Denervation Program
REDUCE-HTN Clinical Series
Studies evaluating the Vessix System technologyin the currently defined hypertension space:
• REDUCE-HTN FIM Study
• REDUCE-HTN Post Market Study
• REDUCE-HTN Global Pivotal Study
• REDUCE-HTN Regional Reg. Approval Studies
• REDUCE-HTN EU Post Market Trial
RELIEVE Clinical Series
Includes pre-clinical, clinical and investigator initiated research evaluating the Vessix System technology in additional disease states:
• RELIEVE - End Stage Renal Disease
• RELIEVE - Heart Failure
• RELIEVE - Atrial Fibrillation
• RELIEVE - Diabetes
Vessix™ Global Clinical Program
REDUCE HTN FIM – CE Mark and TGA ApprovalMulticenter, Non-randomized, feasibility N = 18
REDUCE HTN Post Market StudyMulticenter, Non-randomized, post market surveillanceN = 128
Boston Scientific Renal DenervationREDUCE-HTN Clinical Series
Enrollment Complete /In Follow-Up
Year 1
Global Pivotal StudyMulticenter, randomized (2:1), superiorityN = 550
European Post Market TrialMulticenter, Non-randomized, post market N = 500
Planning / Target Enrollment
to begin1H 2014
Regional Regulatory Approval StudiesMulticenter, Non-randomized, prospective, single cohort N = TBD