Post on 26-Dec-2015
Renal Denervation: Overview
James R. Margolis, MDMiami, FL USA
Disclosure
• Royalties Vessix Vascular/Boston Scientific• Stockholder Boston Scientific
Teaching Points
• Renal denervation is an effective way to lower blood pressure.
• The Symplicity system works, but there is a better way.
• Why HTN 3 was flawed.
More than one quarter of adults in developed societies are affected by hypertension
45% 30M
Japan
21% 182M
China
21% 118M
India
38% 78M
Latin America
44% 81M
Europe
34% 75M
U.S.2
34% 75M
U.S.
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
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
)G
loba
l Pre
vale
nce
(%)
Year
Kearney PM: Lancet 2005;365:217–223
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Hypertension leads to an increased risk of death from stroke and heart disease
2x
4x
8x
Systolic BP / Diastolic BP (mmHg)
Card
iova
scul
ar M
orta
lity
Risk
1Chobanian et al. Hypertension 2003;42:1206-12522Lancet 2002;360:1903-1913
CV mortality risk doubles for every20 mmHg increase in systolic blood pressure
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Systolic BP Reductionand CVD MortalityMeta-analysis of Hypertension Trials
Systolic BP (control - experimental, mm Hg)
Card
iova
scul
ar M
orta
lity
Odd
s Ra
tio
Staessen JA et al. Lancet. 2001;358:1305 -1315.
1.50
1.25
1. 00
0.75
0.50
0.25
-5 0 5 10 15 20 25
P =.003
MIDAS/NICS/VHASUKPDS C vs A
INSIGHTHOT L vs H
HOT M vs HMRC1
MRC2
SHEPHEP
EWPHE
RCT70-80
Syst-Eur
STONE
Syst-ChinaUKPDS L vs H
HOPE
PART2/SCATATMH
STOP1
CAPPP
STOP2/CCBs
STOP2/ACEIs
NORDIL
SBP Reductions as Little as 2 mm Hg Reduce the Risk of
CV Events by Up to 10%
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Courtesy Adam Witkowski, MD PhD
Efferent Nerve Activity:
• Renal Artery Vasoconstriction• Sodium and Fluid Retention• Enhanced Renin Release
Afferent Nerve Activity:• Systemic Sympathetic Neural
Stimulation• LV Hypertrophy• Systolic Heart Failure• Heart Failure with preserved
ejection fraction (HFpEF)• Arrhythmia
The Hyperactive Sympathetic Nervous System is a Driver of Hypertension
HF = Heart Failure; HFpEF= HF with preserved Ejection Fraction; LV = Left Ventricle; RAS = Renin-Angiotensin-Aldosterone
Doumas et al. Am J Cardiol 2010;105:570-576 Cleveland Clinic Journal of Medicine 2012; 79: 501-10
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• Hypertension begets hypertension.• Correction of hypertension resets the
feedback loop.
Feedback Loop
Surgical interruption of the sympathetic nervous system (Sympathectomy)Used to treat hypertension 75 years ago
Smithwick. JAMA. 1953
•Prolonged hospitalization
•Hypotension
Blood pressure levels 10 years after Sympathectomy in 31-year-old patient
Although effective, this procedure led to many adverse events:•Syncope• Impotence•Difficulty walking
103 58
9972
124 88 132
80
Blood Pressure Levels, mm/Hg
Time in YearsOperation
180122
8864
110 78
200
160
120
80
40
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
ACE = angiotensin-converting-enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; DHP = dihydropyridine; DRI =direct renin inhibitors
38% of HTN population remain Uncontrolled
9% of HTN population remain resistant
Medtronic Symplicity System
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Effect of renal sympathetic denervation on muscle sympathetic nerve activity (MSNA) over 12 months of follow-up (FU).
Krum H et al. Circulation 2011;123:209-215Copyright © American Heart Association
Proof of Concept Symplicity HTN-1: Human Feasibility, Safety and Efficacy RegistryChange in Office Blood Pressure Through 36 Months
DBP=diastolic blood pressure; SBP=systolic blood pressure
1 mo (n=141)
3 mo (n=148)
6 mo (n=144)
12 mo (n=132)
24 mo (n=105)
30 mo (n=93)
36 mo (n=88)
-40
-35
-30
-25
-20
-15
-10
-5
0
-19-21 -22
-27-29
-32 -32
-9 -10 -10-14 -14 -15 -14
SBP mmHgDBP mmHg
Krum, H. ESC 2013.
P<0.01 for ∆ from BL all time points
Lancet. 2010;376:1903-1909
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909
• Study design: randomized, controlled, clinical trial• Patients: 106 patients randomized 1:1 to treatment with
renal denervation vs. control• Clinical Sites: 24 centers in Europe, Australia, & New
Zealand
16
Symplicity HTN-2
Primary Endpoint: 6-Month Office BP
-32
1
-12
0
-50
-40
-30
-20
-10
0
10
RDN (n=49) Control (n=51)
∆ from Baseline
to 6 Months (mmHg)
33/11 mmHg difference between RDN and Control
(p<0.0001)
• 84% of RDN patients had ≥ 10 mmHg reduction in SBP• 10% of RDN patients had no reduction in SBP
17
Systolic
Diastolic
Systolic Diastolic
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909
Symplicity HTN-2
Symplicity HTN-2
From presentation by Michael Böhm
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SYMPLICITY HTN-2: BP Reductions Sustained to 3 Years*
Sustained Reductions in the Pooled (RDN and Crossover) Group**
p<0.01 at all time points
∆ fr
om B
asel
ine
to
36 M
onth
s (m
mH
g)
30Mn= 69
24Mn= 69
6Mn= 84
12Mn= 80
18Mn= 74
Systolic
Diastolic
36Mn= 40
Expanded results presented at the Transcatheter Cardiovascular Therapies annual meeting 2013
** Only patients in the RDN group reached the 36 month follow up visit
-50
-40
-30
-20
-10
0
10
-28-26
-31-30
-34-33
-10 -10-12 -11 -13 -14
* Reference: Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension. The Lancet. 2010; 376: 1903–1909.
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Response Rate ≥ 10 mmHg Sustained Through 36 Months
6 Months Post Procedure
12 Months Post Procedure
24 Months Post Procedure
30 Months Post Procedure
36 months Post Procedure
0%
20%
40%
60%
80%
100%
84%79% 80%
87% 85%
63%
52%
76% 77%
RDN Crossover
**
Expanded results presented at the Transcatheter Cardiovascular Therapies annual meeting 2013
** Only patients in the RDN group reached the 36 month follow up visit
* Reference: Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension. The Lancet. 2010; 376: 1903–1909.
MDTSymplicity
MDTSpyral
STJ EnligHTN
COVOneShot
ReCor Gen-2 Paradise
JNJThermoCool
BSCVessix
CE Mark No No
Catheter DesignCatheter with
single electrode
Pigtail Catheter 4 electrodes
Basket with four electrodes
Balloon catheter helical electrode and
cooling
Balloon catheter;
internal cooling; Circumferential
treatment
Pigtail catheter with 5
electrodes and cooling
Balloon catheter
4-8electrodes
Balloon No No No No
Guidewire No No No
Energy MonopolarRF
MonopolarRF
MonopolarRF
MonopolarRF Ultrasound Monopolar
RF Bipolar
RF
Power 8W Unknown 8W 25W ~12W Unknown ~1W
Energy Delivery Time 2 min. 1 min. 60 sec 2 min. 30 sec. Unknown 30 sec.
Total Treatment Time 16-24 min. 2 min. 4 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; Covidien (Maya) Presentation; Ormiston et al. EuroIntv. 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. * Vessix™ is an investigational device and not available for sale in the US.
RF=Radiofrequency;W=Watt
Vessix™ Renal Denervation System* Technology Overview
RF=Radiofrequency; TGA=Therapuetic Goods Administration, AU Regulatory Authority
• Balloon-based technology (4 - 7 mm diameters)
• Helical pattern of bipolar radiofrequency electrodes for uniform treatment
• 30 second treatment time• All electrodes activated simultaneously
• Bipolar energy delivery, ~1 Watt • Temperature-controlled algorithm
ensures energy delivery at 68°C• One button operation• CE-marked and TGA-approved
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 treatment can be tailored to length of the artery landing zone
• Electrodes that are unapposed to vessel wall are automatically deactivated
Vessix™ System RF Balloon Catheter
RF=Radiofrequency
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
> 1200
patients
planned
worldwide
* Vessix™ is an investigational device and not available for sale in the US.
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-UpYear 1
Global Pivotal StudyMulticenter, randomized (2:1), superiorityN = 550
European Post Market TrialMulticenter, Non-randomized, post market N = 500
Planning / Target Enrollment
to beginQ4 2013
Regional Regulatory Approval StudiesMulticenter, Non-randomized, prospective, single cohort N = TBD
• Efficacy Endpoint – Reduction of SBP and DBP (Office Based and ABPM) at six months post procedure compared to baseline
• Safety Endpoint – Acute Safety
• Renal artery dissection or perforation during the procedure that requires stenting or surgery
• Renal artery infarction or embolus• Cerebrovascular Accident (CVA) at time of procedure• Myocardial infarction at time of procedure• Sudden cardiac death at time of procedure
– Long-term Safety • Renal stenosis requiring an intervention documented by angiography• Absence of flow limiting stenosis in the renal artery at six (6) months
measured by duplex ultrasound core laboratory
SBP=Systolic Blood Pressure; DBP=Diastolic Blood Pressure; ABPB=Ambulatory Blood Pressure Monitoring; PMS=Post Market Study.
REDUCE-HTN PMSStudy Endpoints
REDUCE-HTN Case Bipolar RF Technology on a Balloon for the treatment of smaller arteries
Small diameter renal arteries and accessory renal arteries treated withthe Vessix™ system
RF=RadiofrequencyImages of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.
REDUCE-HTN Case Bipolar RF Technology on a Balloon for the treatment of smaller arteries
RF=Radiofrequency
Right accessory renal artery pre treatment
Distal balloon placemetn – 5mm Proximal balloon placement – 5mm
Images of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.
REDUCE-HTN Case Continued Patency, No spasm
RF=RadiofrequencyImages of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.
Right accessory renal artery pre treatment
Right accessory renal artery post treatment
P<.0001 for each timepoint vs baseline.Error bars represent 95% confidence bounds.
Significant Office Blood Pressure Reductions Over Time
BP=blood pressure
1 Month (N=142) 3 Months (N=144) 6 Months (N=142)
-12
-10
-8
-6
-4
-2
0
-10.0
-8.2
-10.3
Change in Office Systolic BP Change in Office Diastolic BP
Mea
n BP
Cha
nge
from
Bas
elin
e (m
mH
g)
Sievert, H. CRT 2014.* Vessix™ is an investigational device and not available for sale in the US.
Mean reduction in office-based BP was 24.7/10.3 mmHg at 6 months (P<.0001)
P<.0005 for each timepoint vs baseline.Error bars represent 95% confidence bounds.
Significant Office Blood Pressure Reductions for Patients with Treated Accessory Renal Arteries (n=24)
BP=blood pressure
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
mH
g)
Sievert, H. CRT 2014.* Vessix™ is an investigational device and not available for sale in the US.
Most Bets Are Won and Lost on the First Tee
• My shoulder hurts.• I was up all night.• I haven’t played in a
long time.• I never played this
course before.• I need extra strokes.
Results of Clinical Studies are Highly Dependent on Their Protocols
The SYMPLICITY HTN-3 Clinical TrialMedtronic is sponsoring a clinical trial that will involve more than 500 patients at up to 90 hospitals in the United States. The purpose of this study is to provide additional information about a medical device intended to help treat high blood pressure in people whose blood pressure is not controlled despite treatment with multiple blood pressure medications.
The study is "Controlled", meaning some of the patients will be treated with the device (the "Treatment Group") and some will NOT be treated with the device (the "Control Group"), and the results of the two groups will be compared.
This study is "Randomized" meaning that patients who are confirmed to be eligible will be randomly assigned to one of two groups. Each patient has a 2 to 1 chance of being assigned to the treatment group. This means you are twice as likely to be in the treatment group rather than the control group. At 6 months, those who were in the control group and remain eligible may be able to have the treatment if they wish.
This study is also "Blinded" meaning that patients will not be told which group they are assigned to, and certain procedures will be followed to prevent patients from knowing which group they are in. This study design is necessary to properly evaluate the safety and effectiveness of the investigational device and procedure.
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Superiority Margin
• A superiority by a margin tests that the treatment mean is better than the reference mean by more than the superiority margin.
• Most clinical trials designed to demonstrate superiority assume the margin is zero. That is, the goal is to prove that any significant difference exists.
• SYMPLICITY HTN-3 was designed to demonstrate that RDN was much better than control. Therefore, chose to perform a more stringent and rigorous comparison and selected a superiority margin of 5 mm Hg.
Courtesy I Patrick Kay, MD PhD
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Illustrative examples of endpoint scenarios, either meeting or not meeting the set assumptions for the primary endpoint (PE)
Primary Efficacy Endpoint Assumptions
150 5 10
Does Not Meet
Meets PE
Does Not Meet
Relative drop in office systolic blood pressure
between treatment and control
Courtesy I Patrick Kay, MD PhD
SYMPLICITY HTN-3 fails to meet primary efficacy endpoint
Thursday, 09 Jan 2014 12:24
Symplicity HTN2 vs 3
Symplicity 2• 190 assessed• 106 patients enrolled• Enrollment one year• 24 Centers• Average enrollment/center
4 patients
Symplicity 3• 1000+ assessed• 535 patients enrolled• Enrollment 2+ years• 89 centers• Average enrollment/center
6 patients
Primary Endpoint: 6-Month Office BP
-32
1
-12
0
-50
-40
-30
-20
-10
0
10
RDN (n=49) Control (n=51)
∆ from Baseline
to 6 Months (mmHg)
33/11 mmHg difference between RDN and Control
(p<0.0001)
• 84% of RDN patients had ≥ 10 mmHg reduction in SBP• 10% of RDN patients had no reduction in SBP
40
Systolic
Diastolic
Systolic Diastolic
Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909
Symplicity HTN-2
Why Did HTN-3 Fail to Meet Primary Endpoint?
• Do not know.• Control group not truly refractory?• Insufficient drop in BP in treated group?
– Operators inexperienced?– Treated patients stopped their meds?
• Endpoint too ambitious?• Maybe we will know in 2½ weeks.
Pneumococcal Pneumonia Study 1942
• Untreated pneumococcal pneumonia carried 80% mortality.
• Treated with Penicillin, expected mortality 20%.
• Using these numbers as results, a 10 patient study (5 treated, 5 placebo) would be positive in favor of PCN at p < .0000001
Hypothetical study for FDA approval of PCN for Pneumococcal Pneumonia Indication 1942
• 500 patient RCT drug vs. placebo.• Cannot consent placebo patients, because they have heard
about “wonder drug.”• Penicillin supplies preferentially shipped to soldiers in
Europe.• Patients (placebo and control) obtain their own PCN on the
black market, but not in time for early treatment.• 50% mortality in both groups.• Conclusion: no benefit from PCN for pneumococcal
pneumonia.• Result: PCN never approved for this indication.
How Do We Avoid Repeat of HTN-3 Debacle?
• Smaller study– Bigger is not necessarily better.– HTN-2 was positive at .0001 level with only 100 patients.
• No sham procedure.– Unethical in my opinion.– No rationale to include it.– Seriously hampers patient enrollment.
• More careful patient selection and monitoring.– Assure patients in both groups are truly refractory.– Make sure treated patients do not stop their medications.
• Test for superiority as opposed to superiority margin.
Summary
• Renal denervation is an effective treatment for refractory hypertension.
• To date, every study with every system has achieved systolic BP reductions of 20-30 mmHg at six to 12 months.
• Why HTN-3 did not reach its primary endpoint remains a mystery until all of the data is presented.
• Future studies should have a simpler design:– As with penicillin for pneumococcal pneumonia, we do not
need a 500 patient RCT to prove effectiveness.– A 100 patient RCT is already overkill.
Thank you