1. Renal Sympathetic Denervation: The Academic View
Krishna Rocha-Singh, M.D., FACC, FSVM, FSCAI Associate Clinical Professor of Medicine SIU School of Medicine Springfield, IL

2. Krishna Rocha-Singh, M.D.
Research
None
Consultant/Advisory Board/Training
Medtronic
ev3, Inc.
Minnow
Ardian (expired)
Royalties/Financial Interest
None
VIVA Board Member salary
Medical Director PERC, salary
I will discuss a vascular device which is unavailable in the US

3. Ardian Renal Denervation:
A Case Study in ‘Bench to Bedside’
The ‘mechanism of action’ of the Ardian device been defined in pre-clinical animal models
Important ‘denervation surrogates’ have been defined (NE tissue levels, ‘NE spillover’, MSNA…)
The pre-clinical safety of the ‘mechanism of action’ established

4. Anatomy of Renal Sympathetic Nerves
Vessel
Lumen
Approx. 70% of renal nerves are within 1.5mm of the ostium of the human renal artery
The 95% of renal nerves are within 2.5mm of the vessel lumen
Media
Adventitia
Renal Nerves
Atherton 2011 4 4

5. 1st Generation Symplicity™ Catheter
Used in Symplicity I and II Trials

6. 2nd Generation Symplicity™ Catheter
Symplicity® Catheter System,
Ardian, Inc., Palo Alto, CA, USA
6F compatible
Articulating tip
Designed for renal artery use
Used in US pilot trial
In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use. 6

7. Pre-clinical Animal Work
Safety:
Swine model with angiography, gross pathology, histopathology & clinical pathology at 7, 30, 60 & 180 days
Intact endothelium by 7 days
Vascular healing observed at 30 days, complete in some by 60 days
No renal artery stenosis out to 180 days
Effectiveness: Cath lab procedure is comparable to surgical denervation
Renal
Tissue
Norepinephrine
(pg/mg)

8. Symplicity HTN I: FIM Study Aims:
First-in-man 12-month evaluation of the safety and blood pressure-lowering efficacy of percutaneous renal sympathetic denervation in patients with refractory hypertension
Study Sites:
Melbourne & Newcastle, Australia; Krakow, Poland; & Frankfurt, Germany
Krum et al. Lancet. 2009;373(9671): 8 8

9. Symplicity 2- HTN Trial Design:
‘Defining the Appropriate Patient’
Baseline Drop-Outs
Registry
Treatment Group
Control Patients offered treatment
Suboptimal Anatomy
Control Group
Primary Endpoint 6M
12-36M
Anatomical Screening
(MRA, CTA, duplex or angiogram)
24-hr ABPM
Randomized 1:1
Uncontrolled HTN
SBP ≥ 160 mmHg
(≥ 150 mmHg diabetics)
≥ 3 meds
“Baseline”
2 week observation
Baseline BP measure at end of baseline period
ClinicalTrials.gov Identifier: NCT 9

10. Defining the ‘Appropriate Patient’: Symplicity-2 Trial Patient Disposition
Assessed for Eligibility (n=190)
Excluded Prior to Randomization (n=84)
BP <160 after 2-weeks of compliance confirmation (n=36; 19%)
Ineligible anatomy (n=30; 16%)
Declined participation (n=10; 5%)
Other exclusion criteria discovered after consent (n=8; 4%)
Randomized (n=106)
Allocated to RDN
(n=52)
Allocated to Control
(n = 54)
No Six-Month Primary Endpoint Visit (n = 3)
Reasons:
Withdrew consent (n=1)
Missed visit (n=2)
Withdrew consent (n=2)
Lost to follow-up (n=1)
Analyzed (n = 49)
Analyzed (n = 51)
Symplicity HTN-2 Investigators. The Lancet 2010: 376: . 10

11. Renal Sympathetic Denervation: This is a BIG Deal…
Moreover…
Important ‘collateral’ beneficial biological effects of RDN are emerging: Effect on glucose sensitivity Obstructive sleep apnea? Cardio-renal Syndromes? The substantial reduction of SBP, an established and accepted surrogate, cannot be under-emphasized

12. Renal Denervation: ‘Collateral’ Benefits
0 min
60 min
120 min
Glucose concentration (mg/dl)
3 months (n=15) *
*significant reduction (p<0.05)
compared to baseline
270
6 months (n=7)
Baseline (n=25)
250
230
210
180
150
120 90
Oral Glucose Tolerance Test (75 g)
RDN is associated with improved glucose control in diabetic patients with resistant HTN
Mahfoud et al. Deutche Gesellschaft Für Kardiologie: Jahrestagung Mannheim.  April 2010.

13. Can Renal Denervation Improve Glucose Metabolism?
Timepoint
Fasting Glucose
(mg/dl)
Insulin
(mU/l)
C-peptide
(µg/l)
HOMA-IR
Baseline (n=25)
118 ± 20
22.3 ± 14.8
6.2 ± 3.6
6.2 ± 4.3
1 month (n=21)
113 ± 14
10.9 ± 7.3*
3.2 ± 1.5*
3.0 ± 1.8*
3 months (n=15)
102 ± 12*
8.4 ± 4.8*
3.0 ± 1.1*
2.1 ± 1.3*
6 months (n=7)
99 ± 18*
8.8 ± 4.6
3.1 ± 1.1
2.2 ± 1.4
*significant reduction (p<0.05) compared to baseline
Mahfoud et al. Deutche Gesellschaft Für Kardiologie: Jahrestagung Mannheim.  April 2010. 13

14. Renal Denervation: Questions to be Answered
What is the clinical ‘durability’ RDN?
Will ‘next gen’ catheter designs address its anatomical limitations?
How do we explain the ‘non-responders?
Can its clinical indications be expanded beyond HTN? 14 14

15. Ardian Has Set a High Bar… for the Competition
FIM and RCT trials have established ‘proof-of-concept’, safety and effectiveness in patients with resistant HTN
Many issues will be debated, but the potential for tremendous clinical impact is undeniable
The Symplicity HTN 3 cohort size (?) will be driven by safety issues…not by treatment effect…so how do we get this important innovation ‘on-label’ expeditiously?