The Ardian Catheter Based Approach to Renal Denervation to Treat Refractory HTN: Results of the EU Randomized Clinical Trial Krishna Rocha-Singh, M.D., FACC, FSVM, FSCAI Director, Prairie Vascular Institute Springfield, IL

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

Renal Efferent Nerve Activity Kidney as the Recipient of Sympathetic Signals Renal Efferent Nerves ↑ Renin release  ↑ RAAS activation ↑ Sodium retention ↓ Renal Blood Flow 3 3

What if We Could Disconnect this Circuit? Renal Afferent Nerve Activity The Origin of Central Sympathetic Drive What if We Could Disconnect this Circuit? Hypertrophy Arrhythmia O2 Consumption Heart Failure Vasoconstriction Atherosclerosis Renal Afferent Nerves Insulin Resistance ↑ Renin release  ↑ RAAS activation ↑ Sodium retention ↓ Renal Blood Flow 4

Symplicity HTN-1 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 5 5

Symplicity HTN-2 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: 376:1903-1909 6

Randomized Cross-Over Design 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: NCT00888433 7

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: 376:1903-1909 . 8

Primary Endpoint: 6-Month Office BP ∆ from Baseline to 6 Months (mmHg) Systolic Diastolic Diastolic 33/11 mmHg difference between RDN and Control (p<0.0001) Systolic 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: 376:1903-1909

Procedural Safety RDN can be safely and easily performed through a 6F guide system - 1 CFA PA - No perforations - No change in GFR

RDN…24 Mo Follow-up Renal denervation is a safe and VERY effective percutaneous therapy resulting in a substantial improvement in BP in patients with resistant HTN through 2 yr follow-up in a small cohort TCT 2010

Unresolved Questions and Challenges: Can we predict ‘responders’ and ‘non-responders’? What is the treatment effect’s ‘durability’? ….is it really “a cure”? Can anatomic limitations be overcome? What are the anticipatable other beneficial effects/indications which should be considered?

A Careful and Regimented Clinical Evaluation First-in-Man  Series of Pilot studies  Symplicity HTN-2 Initial Randomized Clinical Trial  Symplicity HTN-3 US PMA Randomized Clinical Trial Lancet Publication 2009 Symplicity HTN-1 n=45 Lancet Publication 2010 n=52 Enrollment to start mid-2011 13