Transcript Symplicity HTN-1

Renal Nerve Denervation
in
Resistant Hypertension
강동경희대학교병원
심장혈관센터
김종진
CASE 1
 M/41
 PMHx
 DM / HTN / Hep / Tb ( - / + / - / - )
 HTN: 1 yrs (not-controlled) + medication for 4 yr
 Medications
 amlodipine 10mg / olmesartan 40mg /
nebivolol 5mg / indapamide 1.5mg
 160/95 mmHg (for 6 months)
 Lab. Findings
 AST/ALT: 41/92 IU/L
 ECG: LVH with strain pattern
 Chest PA: normal
CASE 2
 F/53
 PMHx
 DM / HTN / Hep / Tb ( + / + / - / - )
 HTN: medication for 10 yrs
 Medications
 amlodipine 5mg / losartan 100mg / carvedilol 25mg / indapamide 1.5mg
 160/90 mmHg (for 6 months)
 Lab. Findings
 HbA1C: 8.0%
 ECG: NSR
 Chest PA: mild cardiomegaly
CASE 3

M/56

PMHx
 DM / HTN / Hep / Tb ( - / + / - / - )
 HTN: 15 yrs (not-controlled) + medication for 1 yr
 Medications
 nifedipine oros 60mg / hydrochlorthiazide 25mg / perindopril 8mg /
nebivolol 2.5mg / doxazosin 2mg
 165/85 mmHg (for 7 months)
 Lab. Findings
 Cr 1.4 mg/dL  GFR by MDRD: 52 ml/min/1.73 m2 / Hb 12.7 g/dL
 ECG: biatrial enlargement / LVH with strain pattern
 Chest PA: cardiomegaly
CASE 4
 M/50
 PMHx
 DM / HTN / Hep / Tb ( + / + / - / - )
 HTN: medication for 15 yrs
 Medications
 tenormin 50mg / amlodipine 10mg / olmesartan 40mg
 160/100 mmHg (6 months)
 Lab. Findings
 FBS: 104 mg/dL
 ECG: incomplete RBBB
 Chest PA: no abnormality
CASE 5
 F/69
 PMHx
 DM / HTN / Hep / Tb ( - / + / - / - )
 HTN: medication for 6 months
 Medications
 amlodipine 5mg / omesartan 20mg / indapamide 1.5mg / bisoprolol 5mg
 193/126 mmHg (for 1months)
 Lab. Findings
 ECG: NSR, LVH
 Chest PA: no abnormality
CASE 6
 F/59
 PMHx
 DM / HTN / Hep / Tb ( - / + / - / - )
 HTN: medication for 20yrs
 Medications
 nisoldipine 20mg bid / indapamide 1.5mg qd / diovan 80mg bid /
bisoprolol 5mg bid
 169/95 mmHg (for 2yrs)
 Lab. Findings
 ECG: sinus bradycardia
 Chest PA: no abnormality
Unmet needs in hypertension therapy
Blood pressure lowering
-Goals often not reached
Combination therapy
-Mandatory in most cases
Compliance
-Poor
Organ protection
-Incomplete
Healing
-An illusion?
HYPERTENSION
A MAJOR PUBLIC HEALTH BURDEN
9
A Major Public Health Burden
• Astonishing prevalence
– 1 in 3 adults
– 1 B people worldwide  1.6 B by 2025
• Single largest contributor to death
• Dramatically increases risk of heart attack, stroke,
heart failure, kidney failure & insulin resistance
10
Source: American Heart Association, World Health Organization
Prevalence, Awareness and Therapy
Hypertensives in Hypertensives,kno treated hypertensives controlled * and
Germany
wing that to be aff
treated hyperten
ected
sives
16 millions
12 millions
don´t know
problem: 4 Mio.
8 millions
don´t do
4 Mio.
* = < 140/90 mmHg
do little
6 Mio.
2 millions
Drugs Work, But Not as Well as You May Think
Current approach failing
30%
Untreated
– Physician inertia
35%
Treated but
Uncontrolled
– Patient compliance
– Resistant HTN
35%
Treated &
Controlled
12
Definition of
Resistant Hypertension
• Resistant hypertension
– RR > 140/90 mmHg, despite treatmant with 3 drug classes
including a diuretic
AHA Statement Circulation 2008;117:e510ff
Predictors of resistant hypertension
•Advanced age
•High sodium intake
•Obesity
•Renal condition
•Sleep apnea
•Diabetes
•LVH
AHA Statement Circulation 2008;117:e510ff
For distribution only in markets where the Symplicity renal denervation system is approved. Not for distribution in the USA or Japan.
Trademarks may be registered and are the property of their respective owners. © 2012 Medtronic, Inc. All rights reserved. UC201205566EE
Catheter-Based Renal
Denervation (RDN)
WELL ESTABLISHED
SCIENTIFIC FOUNDATION
20
Renal Sympathetic Connection
• Role of kidneys & sympathetic
nervous system in development &
progression of HTN is well established
• Pharmaceuticals modify physiology at
intermediate steps in pathway
• RDN attempts to break the cycle
at its source
21
Renal Sympathetic Nerve Activity
Kidney as Origin & Recipient of Central Sympathetic Drive
• ↑ Contractility
• ↑ Heart rate
• Vasoconstriction
Afferent
Nerves
Efferent
Nerves
Blood
Pressure
Schlaich et al. Hypertension. 2009;54(6):1195-1201.
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
22
Renal Sympathetic Nerve Activity
Kidney as Origin & Recipient of Central Sympathetic Drive
• Vasoconstriction
• Atherosclerosis
Afferent
Nerves
Efferent
Nerves
Blood
Pressure
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
↓ Kidney function
+ Increase co-morbidities
Schlaich et al. Hypertension. 2009;54(6):1195-1201.
• ↑ Contractility
• ↑ Heart rate
• Hypertrophy
• Arrhythmia
• Heart Failure
23
Disrupts Renal Nerves,
Lowering SNS Activity
• ↑ Contractility
• ↑ Heart rate
• Hypertrophy
• Arrhythmia
• Heart Failure
• Vasoconstrictio
n
• Atherosclerosis
Afferent
Efferent
-- Renal
Denervation
(RDN)-Nerves
Nerves
Blood
Pressure
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
↓ Kidney function
- Decrease
co-morbidities
+
Increase comorbidities
Schlaich et al. Hypertension. 2009;54(6):1195-1201.
24
Proof of Principle
Central Sympathetic
Nerve Activity
Muscle Sympathetic
Nerve Activity (MSNA)
Renal Sympathetic
Nerve Activity
Norepinephrine
Spillover
Reduction of Renal Contribution to Central Sympathetic Drive:
MSNA in Resistant Hypertension Patient
* 59 year old male on 7 HTN meds
Baseline
MSNA
(burst/min)
BP
(mmHg)

56
161/107
1 mo
41 (-27%)

141/90 (-20/-17)
12 mo
19 (-66%)

127/81 (-34/-26)
* Improvement in cardiac baroreflex sensitivity after renal denervation (7.8 11.7 msec/mmHg)
Schlaich et al. NEJM. 2009; 36(9): 932-934.
Proof of Principle:
Related Changes in Underlying Physiology
∆
Baseline
1 mo
161/107
141/90
- left kidney
72
37
-48%
- right kidney
79
20
-75%
Office BP
(mmHg)
Renal NE spillover
(ng/min)
Total body NE spillover
(ng/min)
600
348
-42%
Plasma Renin
(μg/l/hr)
0.3
0.15
-50%
Renal Plasma flow
(ml/min)
719
1126
57%
LV Mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m2) from baseline to 12 months
Schlaich et al. NEJM. 2009; 36(9): 932-934.
Renal Norepinephrine Spillover: 10 cases
• Mean total renal norepinephrine spillover ↓ 47%, p=0.023 (95% CI: 28–65%)
• Mean total body NE spillover ↓ 28%, p=0.043 (95% CI: 4–52%)
Example Case:
Left:
75 % reduction
Right: 85 % reduction
Esler et al. J Htn. 2009;27(suppl 4):s167.
Schlaich et al. J Htn. 2009;27(suppl 4):s154.
ESRD patient (M; 37 yrs) Submitted for publication
Medication at baseline:
Tritace 10 mg
Avapro 300 mg
Zanidip 20 mg
Noten 50 mg
Minoxidil 5 mg
ESRD (FSGS), RRT since 04/2006
Dry Weight: 81 kg
no change in HD regimen
NTx August 2008
Medication at 33 M FU:
Noten 50 mg
Change in BP following bilateral denervation
156
95
Blood Pressure (mmHg)
180
160
140
133
120
100
80
81
60
baseline
3 d FU
30 d FU
90 d FU
33 months
Sobotka Euro-PCR 2011
Renal Denervation
– Summary of Background & Physiology• Trans-catheter Renal Denervation at least
modulates central sympathetic over-drive
• It might be a physiological treatment modality
to treat sympathetic over-drive related disease
– Hypertension
– Sleep disturbances
– Type 2 diabetes mellitus
– ….
Concept Validated by Surgical History
1952
Effective, but significant morbidity
32
A common question …
How will the kidney function without sympathetic control?
• Transplanted kidneys lack innervation
• Yet effectively maintain fluid and electrolyte balance
• Establishes that sympathetic component of control represents
“overdrive” system, rather than foundation of basic renal function
Blaufox et al. N Engl J Med. 1969;280(2):62-66.
33
A SIMPLER, MORE ELEGANT SOLUTION
34
Renal Anatomy
Allows a Catheter-Based Approach
Vessel
Lumen
Media
• Arise from T10-L2
• Follow the renal artery to the
kidney
• Primarily lie within the adventitia
• The only location that renal
efferent & afferent nerves travel
together
Adventitia
Renal
Nerves
35
Symplicity® Catheter System™
• Low profile, electrode tipped catheter
• Delivers RF energy to treatment site
• Proprietary RF generator
- Low power
- Automated
- Built-in safety control algorithms
• Standard interventional technique
• 40-minutes from first to last RF delivery
In the United States: Caution: Investigational Device. Limited by Uni
ted States law to investigational use.
Anatomy of Renal Nerve
Catheter-Based Approach
• Standard interventional technique
• 4-6 two-minute treatments per artery
• Proprietary RF Generator
− Automated
− Low-power
− Built-in safety algorithms
Vascular Safety Predicted by Preclinical Studies
•
•
•
•
Extensive research in >300 swines
Angiography and pathology at 7, 30, 60 & 180 days
No stenosis or luminal reduction seen in treated arteries
RF Generator algorithm optimized to minimize vascular injury
39
Symplicity Catheter Tip Features
Be familiar with the dimensions at the distal end of the catheter
5mm
12mm
Flexible Tip Deflectable
(self-orienting)
Shaft
Symplicity Catheter Handle Features
Orange section of handle rotates shaft, and trigger flexes the catheter tip
Deflect tip by
pulling lever
towards back
of handle
Handle rotator has tactile
“click” every 45 degrees
Dot on rotator gives relative
rotational reference
Straighten tip by
pushing lever
towards front
of handle
Targeting Renal Nerves
• Treat distal to proximal
• 4-6 focal treatments
•
2 min per treatment
• ≥ 5 mm between locations
• Stable, unique locations
• Circumferential coverage
• Common strategy (dependent on renal a
natomy):
• Distal: Inferior and inferolateral locations
• Proximal: Superior and superolateral locations
• Avoid purely lateral treatments (possible electr
ode movement with respiration)
• PULL, ROTATE, ASSESS new location
and prior treatment site
42
Procedure Overview
Areas To Avoid
There is no clinical experience treating near areas of visible disease,
or in vessels with renal artery aneurysms
• Avoid to treat the areas of visible disease
– Such as atherosclerosis, calcification, and fibromuscular dysplasia
Atherosclerosis
(Ostial Stenosis)
Avoid treating
in segment
with stenosis
Calcification
Avoid energy
delivery to area with
visible calcification
Fibromuscular Dysplasia
(FMD)
Avoid treating
in segment
with FMD
Angiographic Appearance – Typical
Typical appearance to expect at one month post-procedure
Pre-Procedure
1 Month Follow-Up
Acute Post-Procedure
SUMMARY
-TECHNIQUE OF RENAL DENERVATION-
• The generation 2 Symplicity catheter facilitates the
procedure and increases procedure safety
•Better catheter navigation
•Less traumatic catheter tip
•Better vessel wall adaption of the tip
• Limitations:
•Hostile aorta
•Bended course of the renal artery trunk
•Short renal artery trunk
•Renal artery diameter < 4mm
•Atherosclerotic plaques or FMD
CLINICAL RESULTS
47
Comprehensive SYMPLICITY Clinical Trial Program
follows over 5000 patients across multiple
indications
This report
First-in-Man (AU)
SYMPLICITY HTN-3
US Pivotal Trial (US)
Series of Pilot Studi
es
(EU, US & AU)
Symplicity HTN-1
Symplicity HTN-2
Initial RCT
(EU & AU)
Global SYMPLICITY
Registry
(Approved Regions)
Expand HTN Indicat
ion
(Approved Regions)
Post-Market Registry
(US)
Pilot Studies in
New Indications
(Approved Regions)
SYMPLICITY HF
Trials under way
Results Recognized for their Importance
Lancet. 2010. published electronically on Nov 17, 2010
49
Symplicity HTN-1
Lancet. 2009;373:1275-1281
Initial Cohort – Reported in the Lancet, 2009:
-First-in-man, non-randomized
-Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs,
including a diuretic; eGFR ≥ 45 mL/min)
- 12-month data
\
Expanded Cohort – This Report (Symplicity HTN-1):
-Expanded cohort of patients (n=153)
-24-month follow-up
Sievert et al. European Society of Cardiology. 2010.
Symplicity HTN-1:
Groundbreaking series of Non-Randomised studies
First in Man Cohort:
• 45 patients, EU, Australia
• Non-Randomised
• First patient enrolled: June, 2007
• 12-month initial report in The Lancet, 2009
Expanded Cohort* (this report):
• 153 patients, EU, Australia, USA
• Non-Randomised
• 36-month follow-up
Key Inclusion Criteria
•
•
•
Office SBP ≥160 mmHg
Stable drug regimen of 3+ more anti-HTN medications
eGFR ≥45 mL/min/1.73m2
*Expanded results presented at the American College of
Cardiology Annual Meeting 2012 (Krum, H.)
Baseline Patient Characteristics
Demographics
Co-morbidities
Blood Pressure
Age (years)
57 ± 11
Gender (% female)
39%
Race (% non-Caucasian)
5%
Diabetes Mellitus II (%)
31%
CAD (%)
22%
Hyperlipidemia (%)
68%
eGFR (mL/min/1.73m2)
83 ± 20
Baseline BP (mmHg)
176/98 ± 17/15
Number of anti-HTN meds (mean)
5.0 ± 1.4
ACE/ARB (%)
90%
Beta-blocker (%)
82%
Calcium channel blocker (%)
75%
Vasodilator (%)
19%
Diuretic (%)
95%
Spironolactone (%)
21%
Sievert et al. European Society of Cardiology. 2010.
Procedure Detail & Safety
• 38 minute median time from first to last ablation
– Average of 4 ablations per artery
• Intravenous narcotics & sedatives used to manage pain
during delivery of RF energy
• No catheter or generator malfunctions
• No major complications
• Minor complications 4/153:
– 1 renal artery dissection during catheter delivery
(prior to RF energy), no sequelae
– 3 access site complications, treated without further
sequelae
Sievert et al. European Society of Cardiology. 2010.
Chronic Safety (Through 3-Year Follow-up)
• 81 patients with 6-month renal CTA, MRA, or Duplex
• No vascular abnormalities at any site of RF delivery
• One progression of a pre-existing stenosis unrelated to RF
treatment (stented without further sequelae)
• Three deaths within the follow-up period; both unrelated
to the device or therapy
• Two hypotensive events that required hospitalization
• Unrelated to device or therapy (sepsis and hypovolemia, each)
• No electrolyte disturbances
• No change in renal function (∆ eGFR)
• 12 Months: -2.9 mL/min/1.73m2 (n.s.)
Sievert et al. European Society of Cardiology. 2010.
Significant, Sustained BP Reduction
10
0
BP change
(mmHg)
Systolic
Diastolic
-20 -10
-24 -11
-25 -11
-23 -11
-26 -14
-32 -14
1M
(n=138)
3M
(n=135)
6M
(n=86)
12 M
(n=64)
18 M
(n=36)
24 M
(n=18)
-10
-20
-30
-40
-50
Sievert et al. European Society of Cardiology. 2010.
Significant, Sustained Blood Pressure
Reductions to at Least 3 Years
Change in Blood Pressure (mmHg)
10
Systolic
Diastolic
0
-22 -10
-26 -13
-33 -15
-33 -19
6M
(n=144)
1Y
(n=130)
2Y
(n=59)
3Y
(n=24)
-10
-20
-30
-40
p <0.01 for  from baseline for all time points
Expanded results presented at the American College of
Cardiology Annual Meeting 2012 (Krum, H.)
Percentage Responders Increases Over Time
Responder was defined as an office SBP reduction ≥10 mmHg
(n=143) (n=148) (n=144) (n=130) (n=107) (n=59)
(n=24)
(n=24)
Expanded results presented at the American College of
Cardiology Annual Meeting 2012 (Krum, H.)
Response Rate Among 1-Month Non-responders
(n=45)
(n=45)
(n=44)
(n=39)
(n=17)
*Non-responder defined as a SBP reduction of <10 mmHg
(n=8)
Expanded results presented at the American College of
Cardiology Annual Meeting 2012 (Krum, H.)
Symplicity HTN-1: SBP Distribution Significantly Improves
After Renal Denervation – Lowering Risk of CV Events
100%
8%
90%
30%
80%
7%
11%
6%
6%
21%
70%
42%
60%
>=180 mmHG
160-179 mmHg
35%
50%
40%
47%
140-159 mmHg
<140 mmHg
65%
30%
20%
36%
40%
41%
10%
0%
5%
Baseline
(n=150)
1 year
(n=132)
2 years
(n=105)
3 years
(n=34*)
Expanded results presented at the Transcatheter Cardiovascular
Therapeutics Annual Meeting 2012 (Schlaich, M.)
Symplicity HTN-2
Lancet. 2010. published electronically on November 17, 2010
•
•
•
Purpose: To demonstrate the effectiveness of catheter-based renal
denervation for reducing blood pressure in patients with uncontrolled
hypertension in a prospective, 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 (67% were
designated hypertension centers of excellence)
Symplicity HTN-2 Investigators. The Lancet. 2010.
Symplicity HTN-2
Inclusion Criteria:
– Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus)
– Stable drug regimen of 3+ more anti-HTN medications
– Age 18-85 years
Exclusion Criteria:
– Hemodynamically or anatomically significant renal artery abnormalities or prior
renal artery intervention
– eGFR < 45 mL/min/1.73m2 (MDRD formula)
– Type 1 diabetes mellitus
– Contraindication to MRI
– Stenotic valvular heart disease for which reduction of BP would be hazardous
– MI, unstable angina, or CVA in the prior 6 months
Symplicity HTN-2 Investigators. The Lancet. 2010.
Symplicity HTN-2: Patient disposition
Assessed for Eligibility
(n=190)
Screening
Randomised (n=106)
6-month P
rimary End
-Point
Allocated to RDN
n=52 Treated
n=49 Analysable
Excluded During Screening,
Prior to Randomisation (n=84)
 BP < 160 at Baseline Visit (after 2-weeks of
medication compliance confirmation) (n=36; 19%)
 Ineligible anatomy (n=30; 16%)
 Declined participation (n=10; 5%)
 Other exclusion criteria discovered after consent
(n=8; 4%)
Allocated to Control
n=54 Control
n=51 Analysable
Crossover
n=46
2 LTFU
12-month Post- 12-month post-RDN
n=47
Randomisation
18-month post-RDN
n=43
* Crossed-over with ineligible BP (<160 mmHg)
Per protocol, 6-mo
Post-RDN (Crossover)
n=35
18-mo Post-RDN
(Crossover)
n=31
Not-per-protocol*, 6mo Post-RDN
(Crossover) n=9
RDN and Control Populations Well-matched,
Severe Treatment Resistant Hypertensives
RDN
Control
p-Value
(n = 52)
(n = 54)
178 ± 18
178 ± 16
0.97
Baseline systolic BP (mmHg)
Baseline diastolic BP (mmHg)
97 ± 16
98 ± 17
0.80
Number anti-HTN medications
0.75
5.2 ± 1.5
5.3 ± 1.8
Age
58 ± 12
58 ± 12
0.97
Gender (female) (%)
35%
50%
0.12
Race (Caucasian) (%)
98%
96%
>0.99
BMI (kg/m2)
31 ± 5
31 ± 5
0.77
Type 2 diabetes
40%
28%
0.22
Coronary artery disease
19%
7%
0.09
Hypercholesterolemia
52%
52%
>0.99
eGFR (MDRD, ml/min/1.73m2)
77 ± 19
86 ± 20
0.013
Serum creatinine (mg/dL)
1.0 ± 0.3
0.9 ± 0.2
0.003
Urine alb/creat ratio (mg/g)*
128 ± 363
109 ± 254
0.64
Cystatin C (mg/L)†
0.9 ± 0.2
0.8 ± 0.2
0.16
n = 42 forrate
RDN and
n = 43 for Control. Wilcoxon rank-sum test for
independent
between-group
comparisons
of UACR.
Heart
(bpm)
75two±
15 samples used
71for±
15
0.23
*
†
n = 39 for RDN and n = 42 for Control.
Expanded results presented at the American College of
Cardiology Annual Meeting 2012 (Esler, M.)
Primary Endpoint: 6-Month Office BP
∆ from
Baseline
to
6 Months
(mmHg)
Systolic
Diastolic
Diastolic
Systolic
•
•
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
Symplicity HTN-2 Investigators. The Lancet. 2010.
Superior to Medical Management,
Reductions Sustained to 12M
Primary Endpoint
(6M post Randomisation)
Latest Follow-up
(12M post Randomisation)
10
RDN (n= 49)
0
∆ from
Baseline
to
6 Months
(mmHg)
Systolic Diastolic
Diastolic
p <0.01 for
Systolic
difference
between RDN
and Control
Primary Endpoint:
• 84% of RDN patients: ≥10 mmHg reductio
n in SBP
• 10% of RDN patients: no reduction in SBP
∆ from -10
Baseline
to
-20
12 Months
(mmHg)
-30
-40
-10
Diastolic
-28
Systolic
p <0.01 for 
-50
from baseline
Latest Follow-up:
•Control crossover (n = 35): -24/-8 mmHg
(Analysis on patients with SBP ≥ 160 mmHg
at 6 M)
Expanded results presented at the American College of
Cardiology Annual Meeting 2012 (Esler, M.)
Superior to Medical Management,
Reductions Sustained to 18M
Primary Endpoint
(6M post Randomisation)
RDN (n = 49)
Control (n = 51)
10
10
1
0
∆ from
-10
Baseline
to
6 Months-20
(mmHg)
-30
-50
0
Systolic Diastolic
-12
Diastolic
-32
-40
Latest Follow-up
(18M post Randomisation)
Systolic
p <0.01 for
difference
between RDN
and Control
Primary Endpoint:
• 84% of RDN patients: ≥10 mmHg reductio
n in SBP
• 10% of RDN patients: no reduction in SBP
RDN (n=43)
0
∆ from -10
Baseline
to
-20
18 Months
(mmHg)
-30
-12
Diastolic
-32
-40
-50
Systolic
p <0.01 for 
from baseline
Control Group Also Benefited
From RDN After Crossover
220
n = 51
183
180
n = 37
191
178
n = 35
n = 49
Systolic BP
(mmHg)
166
147
n = 49
140
n = 33
167
n = 31
162
151
n = 47
145
n = 43
Control
Crossover
RDN
100
Baseline
6M Baseline
6M Post-RDN
6M Post-RDN
12M Post-RDN
12M Post-RDN
18M Post-RDN
18M Post-RDN
Sustained to 18 Months
for RDN, Crossover, and Pooled Groups
RDN Group
10
0
∆ in BP
from
Baseline
(mmHg)
10
Crossover Group
0
-10
-12
-8
-12
-20
-20
-30
-30
-32
-10
-11
n=
47
n=
43
-11
-28
-30
-28
-31
-32
-50
-12
-24
-40
n=
49
-12
-32
-40
-50
-10
-20
-24
-28
18-Month BP Reduction
0
-10
-10
10
-40
n=
35
n=
33
n=
31
-50
n=
43
n=
31
p <0.01 for 
from baseline
n=
74
Systolic
Diastolic
Home & 24 Hour Ambulatory BP
Home BP
Change
BP
(mmHg)
Change
Systolic
(mmHg)
Diastolic
Diastolic
Systolic
24-h ABPM:
• Analysis on technically sufficient (>70% of readings) paired baseline and 6-month
• RDN (n=20): -11/-7 mmHg (SD 15/11; p=0.006 SBP change, p=0.014 for DBP change)
• Control (n=25): -3/ -1 mmHg (SD 19/12; p=0.51 for systolic, p=0.75 for diastolic)
Symplicity HTN-2 Investigators. The Lancet. 2010.
Time Course of Office BP Change
1M
3M
6M
0
RDN
∆ from
Baseline
(mmHg)
-7 ††
-10
-20
-30
-20
-8 †††
†
-24 †
-32 †
Systolic
Diastolic
-40
-50
-12 †
p<0.0001 for between-group comparisons
p=0.002 for between-group comparisons
††† p=0.005 for between-group comparisons
Two-way repeated measures ANOVA, p=0.001
†
††
20
10
Control
∆ from
Baseline
(mmHg)
0
0
1
0
-4
-10
-20
-30
Systolic
Diastolic
Symplicity HTN-2 Investigators. The Lancet. 2010.
-2
0
Procedural Safety
• No serious device or procedure related adverse events (n=52)
• Minor adverse events
• 1 femoral artery pseudoaneurysm treated with manual compression
• 1 post-procedural drop in BP resulting in a reduction in medication
• 1 urinary tract infection
• 1 prolonged hospitalization for evaluation of paraesthesias
• 1 back pain treated with pain medications & resolved after one month
• 6-month renal imaging (n=43)
• No vascular abnormality at any RF treatment site
• 1 MRA indicates possible progression of a pre-existing stenosis unrelat
ed to RF treatment (no further therapy warranted)
Symplicity HTN-2 Investigators. The Lancet. 2010.
Other Safety
RDN
(n=49)
Control
(n=51)
Hypertensive event unrelated to non-adherence to medication
3
2
Other CV events
0
0
Transient ischemic attack
1
2
Hypertensive event after abruptly stopping clonidine
1
0
Hypotensive episode resulting in reduction of medications
1
0
Coronary stent for angina
1
1
Temporary nausea/edema
1
0
Composite CV Events
Other Serious AEs
Symplicity HTN-2 Investigators. The Lancet. 2010.
Renal Function
Δ Renal
Function
Control
Mean ± SD
(n)
Difference
(95% CI)
p-value
(baseline - 6M)
RDN
Mean ± SD
(n)
eGFR (MDRD)
0 ± 11
1 ± 12
-1
(mL/min/1.73m2)
(49)
(51)
(-5, 4)
0.76
Serum Creatinine
0.0 ± 0.2
0.0 ± 0.1
0.0
(mg/dL)
(49)
(51)
(-0.1, 0.1)
Cystatin-C
0.1 ± 0.2
0.0 ± 0.1
0.0
(mg/L)
(37)
(40)
(-0.0, 0.1)
Symplicity HTN-2 Investigators. The Lancet. 2010.
0.66
0.31
Renal Function
100
88.8
eGFR (mL/min/1.73m2)
80
78.2
77.1
76.9
Stage I
85.2
81.2
Stage II
60
Stage III
40
Stage IV
20
ESRD
Stage V
0
n = 49
n = 35
Baseline
n = 49
n = 35
6M post-RDN
n = 45
n = 31
12M post-RDN
RDN
Crossover
Symplicity RDN Safety Record Continues
to be Strong in Expanded Results
RDN
N=47
Treated at Randomisation
Baseline
6 month
12 months
eGFR (ml/min/1.73m2)
76.9 ±19.3 (n= 49)
77.1±18.8 (n=49)
78.2±17.4 (n=45)
Cystatin C (mg/L)
0.91±0.25 (n=38)
0.98±0.36 (n=40)
0.98±0.30 (n=38)
Treated after
6-mo follow-up
Crossover
N=35
Baseline
6 month
12 months
eGFR (ml/min/1.73m2)
88.8 ± 20.7 (n = 35)
89.3±19.5 (n = 35)
85.2±18.3 (n = 35)
Cystatin C (mg/L)
0.78 ± 0.17 (n=27)
0.82±0.16 (n=26)
0.89±0.20 (n=26)
Symplicity HTN-2 Investigators. The Lancet. 2010.
Medication Changes at 6 and 12 Months
Post-Renal Denervation
RDN (n=47)
6 month
12 months
Decrease (# Meds or Dose)
20.9% (9/43)
27.9% (12/43)
Increase (# Meds or Dose)
11.6% (5/43)
18.6% (8/43)
Crossover (n=35)
6 months post-RDN
Decrease (# Meds or Dose)
18.2% (6/33)
Increase (# Meds or Dose)
15.2% (5/33)
Physicians were allowed to make changes to medications
Once the 6 month primary endpoint was reached*
*Further analysis of Medications is ongoing
Impressive Safety Record
•
No device-related SAEs and vascular complications
•
No clinically significant changes to eGFR
•
Two hypotensive events that required hospitalisation
•
One in crossover cohort and 1 in RDN cohort
•
Ten hypertensive events requiring hospitalisation through 18
months post RDN in combined cohort
•
One mild transient acute renal failure
•
Two deaths within the follow-up period
•
All unrelated to the device or therapy
Symplicity HTN-1 Three Year and
Symplicity HTN-2 One Year Summary
• Sustained BP Reductions to Three Years
• First Symplicity HTN-1 patient treated June 2007
• Three year reporting shows no diminishment of effect
and impressive long term safety
• For patients that have completed 3 year follow up, 100%
have been classified as responders (>10 mmHg
reduction), while at 6 months 71% of patients were
classified as responders.
• Superior Results Confirmed in Randomised Study
• Symplicity HTN-2 treatment population shows sustained
treatment effect at 12 month follow-up
• Control cross-over patients also show significant BP
reduction
Only the Symplicity™ renal denervation system has proven
safe, superior and sustained BP reductions
RENAL DENERVATION & INSULIN RESISTANCE
Effects of Renal Denervation on Glucose
Handling in Patients with Resistant HTN
•
•
•
•
•
•
•
Mahfoud et al. European Society of Cardiology. 2010.
25 Treatment, 11 Control
Age 56.9 ± 10 years
BMI 31.4 ± 5.5 kg/m²
Type 2 DM on oral medication, n=15
No patients on insulin treatment
Baseline BP: 178/94 ± 16/13 mmHg
5.6 ± 1.4 antihypertensive meds
Reduction in HOMA Index at 1 & 3 Months
following Renal Denervation
Fasting
Glucose (mg/dl)
Fasting
Insulin (mU/l)
C-peptide (µg/l)
HOMA-IR
Baseline (25)
118 ± 20
20.7 ± 11.8
6.1 ± 3.6
6.1 ± 4.3
1 month (25)
110 ± 14*
12.9 ± 7.3*
3.3 ± 1.5*
3.5 ± 1.8*
3 months (25)
106 ± 12*
11.1 ± 4.8*
3.1 ± 1.1*
2.9 ± 1.3*
Treatment Group
*significant reduction (p<0.05) compared to baseline
HOmeostasisModelAssessment-InsulinResistance (HOMA-IR) = (FPI x FPG)/405
Mahfoud et al. European Society of Cardiology. 2010.
Change in Status:
Diabetes (DM)  Glucose Intolerance (GIT)  Normal
•
Worsening of diabetic status:
(normal  glucose intolerance  diabetes)
- Renal Denervation: 0/25
- Control: 2/11 (18%)
•
Improvement in diabetic status:
(diabetes  glucose intolerance  normal)
- Renal Denervation: 4/25 (16%)
- Control: 0/11
Mahfoud et al. European Society of Cardiology. 2010.
Can Excessive NeuroStimulation
Cause Heart Disease?
• Can excessive sympathetic drive contribute to
– Atrial fibrillation
• High ventricular response to atrial fibrillation
• Low conversion success
– Ventricular tachyarrhythmias
• Electrical Storm
• Long QT pathology
• Can sympathetic drive cause functional ventriular abn
ormalities or systolic or diastolic function?
• Is sympathetic stimulation related to overall
cardiovascular death?
CASE 1
 Medications
 amlodipine 10mg / olmesartan 40mg /
nebivolol 5mg / indapamide 1.5mg
 160/95 mmHg (for 6 months)
 F/U; 2 weeks after RDN
 147/87mmHg at office
 D/C amlodipine
180
160
140
120
100
80
60
40
20
0
SBP
DBP
3/30
4/25
 much improved subjective symptoms
7/27
10/26
CASE 2
 Medications
 amlodipine 5mg / losartan 100mg / carvedilol 25mg /
indapamide 1.5mg
 160/90 mmHg (for 6 months)
 F/U; 1 month after RDN
 116/73mmHg at home
 154/87mmHg at office
 D/C amlodipine
200
180
160
140
120
100
80
60
40
20
0
SBP
DBP
3/14
5/14
8/13
10/15 12/03
CASE 3
 Medications
 nifedipine 60mg / hydrochlorthiazide 25mg / perindopril 8mg
/ nebivolol 2.5mg / doxazosin 2mg
 165/85 mmHg (for 7 months)
 F/U; 2 weeks after RDN
 admission due to suicide
(drug intoxication)
 same medication
 normal BP
180
160
140
120
100
80
60
40
20
0
SBP
DBP
3/15
5/30
7/22
9/25
CASE 4
 Medications
 tenormin 50mg / amlodipine 10mg / olmesartan 40mg
 160/100 mmHg (6 months)
 F/U; 1 month after RDN
 normal BP at home
 160/90mmHg at office
 same medications
200
150
100
SBP
50
DBP
0
10/24
5/2
7/5
1/23
CASE 5
 Medications
 amlodipine 5mg qd / omesartan 20mg qd / indapamide
1.5mg qd / concor 5mg qd
 193/126 mmHg (for 1months)
 F/U; 2wks after RDN
 141/77mmHg at office
 same medications
250
SBP
200
DBP
150
100
50
0
6/4
6/25
9/24
CASE 6
 Medications
 nisoldipine 20mg bid / indapamide 1.5mg qd / diovan 80mg
bid / bisoprolol 5mg bid
 169/95 mmHg (for 2yrs)
 F/U; 1 month after RDN
 occasionally high BP at home
 138/84mmHg at office
 D/C nisodipine
180
160
140
120
100
80
60
40
20
0
SBP
DBP
3/26
6/13 7/5
11/14
2/20
Conclusion
 Renal Sympathetic Nerve Denervation
1. Safe and effective in resistant hypertension
treatment.
2. In the future, will be a promising
interventional procedure for other territories
with hypertension or for diseases with overdrive sympathetic activity.