Renal Sympathetic Denervation The Academic View Krishna RochaSingh

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Renal Sympathetic Denervation: The Academic View Krishna Rocha-Singh, M. D. , FACC, FSVM, FSCAI

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

Krishna Rocha-Singh, M. D. • Research – None • Consultant/Advisory Board/Training – Medtronic –

Krishna Rocha-Singh, M. D. • Research – None • Consultant/Advisory Board/Training – Medtronic – ev 3, 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

Ardian Renal Denervation: A Case Study in ‘Bench to Bedside’ • The ‘mechanism of

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

Vessel Lumen Anatomy of Renal Sympathetic Nerves • Approx. 70% of renal nerves are

Vessel Lumen Anatomy of Renal Sympathetic Nerves • Approx. 70% of renal nerves are within 1. 5 mm of the ostium of the human renal artery Media Adventitia Renal Nerves • The 95% of renal nerves are within 2. 5 mm of the vessel lumen Atherton 2011

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

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

2 nd Generation Symplicity™ Catheter Symplicity® Catheter System, Ardian, Inc. , Palo Alto, CA,

2 nd Generation Symplicity™ Catheter Symplicity® Catheter System, Ardian, Inc. , Palo Alto, CA, USA • 6 F 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.

Pre-clinical Animal Work • Safety: – Swine model with angiography, gross pathology, histopathology &

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)

Symplicity HTN I: FIM Study Aims: First-in-man 12 -month evaluation of the safety and

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): 1275 -1281

Symplicity 2 - HTN Trial Design: ‘Defining the Appropriate Patient’ “Baseline” 2 week observation

Symplicity 2 - HTN Trial Design: ‘Defining the Appropriate Patient’ “Baseline” 2 week observation Anatomical Screening (MRA, CTA, duplex or angiogram) 24 -hr ABPM Baseline BP measure at Randomized 1: 1 end of baseline period Control Group Uncontrolled HTN SBP ≥ 160 mm. Hg (≥ 150 mm. Hg diabetics) ≥ 3 meds 6 M Control Patients offered treatment Primary Endpoint Treatment Group Baseline Drop-Outs Registry Clinical. Trials. gov Identifier: NCT 00888433 Suboptimal Anatomy Registry 6 M 12 -36 M

Defining the ‘Appropriate Patient’: Symplicity-2 Trial Patient Disposition Assessed for Eligibility (n=190) Excluded Prior

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) Analyzed (n = 49) Reasons: · Withdrew consent (n=2) · Lost to follow-up (n=1) Analyzed (n = 51) Symplicity HTN-2 Investigators. The Lancet 2010: 376: 1903 -1909.

Renal Sympathetic Denervation: This is a BIG Deal… Moreover… Important ‘collateral’ beneficial biological effects

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

Glucose concentration (mg/dl) Renal Denervation: ‘Collateral’ Benefits 270 Oral Glucose Tolerance Test (75 g)

Glucose concentration (mg/dl) Renal Denervation: ‘Collateral’ Benefits 270 Oral Glucose Tolerance Test (75 g) RDN is associated with improved 250 230 glucose control in diabetic patients with resistant HTN 210 Baseline (n=25) ** 180 * * 150 3 months (n=15) 6 months (n=7) 120 90 ** 0 min *significant reduction (p<0. 05) compared to baseline 60 min 120 min Mahfoud et al. Deutche Gesellschaft Für Kardiologie: Jahrestagung Mannheim. April 2010.

Can Renal Denervation Improve Glucose Metabolism? Timepoint Fasting Glucose (mg/dl) Insulin (m. U/l) C-peptide

Can Renal Denervation Improve Glucose Metabolism? Timepoint Fasting Glucose (mg/dl) Insulin (m. U/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.

Renal Denervation: Questions to be Answered • What is the clinical ‘durability’ RDN? •

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?

Ardian Has Set a High Bar… for the Competition • FIM and RCT trials

Ardian Has Set a High Bar… for the Competition • FIM and RCT trials have established ‘proof-ofconcept’, 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?