Renal Sympathetic Denervation for Treatment of Resistant Hypertension: One-Year Results from the Symplicity HTN-2 Randomized Controlled Trial  Prof Murray Esler Baker IDI Heart and Diabetes Institute, Melbourne On behalf of Henry Krum, Markus Schlaich, Roland Schmieder, Michael Böhm, Paul Sobotka and the Symplicity HTN-2 Investigators 4

Disclaimer Speaker is the Chief Investigator of the multi-centre randomized international trial of therapeutic endovascular renal denervation with the Symplicity catheter in drug-resistant hypertension (HTN-2 trial), and is a recipient of research grant, travel and consultancy funding from Medtronic and Ardian Inc. He holds no stock or shares in either company, or patent rights for renal denervation.

“Renal Denervation Delays or Prevents Development of Many Experimental “Activation of the Renal Sympathetic Nerves in Patients with Essential Hypertension” M Esler, G Lambert, G Jennings J Hypertension 1990;8: S53-S57 (Updated) “Renal Denervation Delays or Prevents Development of Many Experimental Forms of Hypertension” G F DiBona Physiol Rev 1997;77:75-197

Catheter-Based Radiofrequency Renal Nerve Ablation Standard interventional technique 4-6 two-minute treatments per artery Proprietary RF Generator Automated Low-power Built-in safety algorithms Caution: The Symplicity® Catheter System™ is an Investigational Device. Limited by U.S. law to investigational use. 4 4

Symplicity HTN-2 Design Lancet. 2010;376:1903-1909. Purpose: To demonstrate the effectiveness of catheter-based renal denervation (RDN) for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial Patients: 106 patients with drug-resistant hypertension randomized 1:1 to treatment with RDN vs. control Clinical Sites: 24 centers in Europe, Australia, & New Zealand 67% were designated hypertension centers of excellence Primary Endpoint: Office systolic BP change from baseline at 6 months Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. 5 5

Participating Centers: HTN-2 Randomized Controlled Trial Universitätsklinikum des Saarlandes Homburg, Germany (Michael Böhm) CardioVascular Center Frankfurt Frankfurt, Germany (Horst Sievert) Universitätsklinikum Düsseldorf Düsseldorf, Germany (Lars Christian Rump) Universität Erlangen-Nürnberg Erlangen, Germany (Roland Schmieder) Barts and The London London, UK (Mel Lobo) Pauls Stradins Clinical University Hospital Riga, Latvia (Andrejs Erglis) L'Hôpital Européen Georges Pompidou Paris, France (Guillaume Bobrie) John Hunter Hospital Newcastle, Australia (Suku Thambar) Cliniques Universitaires Saint-Luc Brussels, Belgium (Alexandre Persu) Universitaetsklinikum Schleswig-Holstein Lübeck, Germany (Heribert Schunkert) Universität zu Köln Köln, Germany (Uta Hoppe) The Alfred Hospital Melbourne, Australia (Henry Krum) Universität Leipzig – Herzzentrum Leipzig, Germany (Dierk Scheinert) Allgemeines Krankenhaus der Stadt Wien Vienna, Austria (Thomas Binder) Samodzielna Pracownia Hemodynamiczna Warsaw, Poland (Andrzej Januszewicz & Adam Witkowski) Hospital 12 de Octubre Madrid, Spain (Luis Ruilope) St. Vincent’s Hospital Melbourne, Australia (Robert Whitbourn) Universitätsklinikum Essen Essen, Germany (Heike Bruck) Kent and Canterbury Hospital Canterbury, UK (Mark Downes) University Hospital Zurich Zurich, Switzerland (Thomas Lüscher) University of Glasgow Glasgow, UK (Alan Jardine) Auckland City Hospital Auckland, New Zealand (Mark Webster) Herz-Zentrum Bad Krozingen Bad Krozingen, Germany (Thomas Zeller) The John Paul II Hospital Krakow, Poland (Jerzy Sadowski) Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. 6

Patient Population Inclusion Criteria: Exclusion 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 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. Lancet. 2010;376:1903-1909. 7 7

No Six-Month Primary Endpoint Visit (n = 3) Patient Disposition Assessed for Eligibility (n=190) Excluded During Screening, Prior to Randomization (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 (n=8; 4%) Randomized (n=106) Allocated to Renal Denervation (n=52) Allocation Screening Allocated to Control (n = 54) Follow-up 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) Analysis Analyzed (n = 49) Analyzed (n = 51) 8

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) Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. 9

6-month Primary End-Point Patient Disposition Assessed for Eligibility (n=190) Excluded During Screening, Prior to Randomization (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%) Randomized (n=106) Allocated to RDN N=52 Treated N=49 Analyzable 6-month Primary End-Point Screening Allocated to Control N=54 Control N=51 Analyzable 12-month Post- Randomization 12-month post-RDN N=47 Per protocol, 6-mo Post–RDN (Crossover) N=35 Crossover N=46 (2 LTFU) Not-per-protocol*, 6-mo Post–RDN (Crossover) N=9 * Crossed-over with ineligible BP (<160 mmHg)

HTN-2 Baseline Demographics RDN (n=49) Cross-Over (n=35) Office SBP 178.3 ± 18.2 182.8 ± 16.3 Office DBP 96.1 ± 15.5 99.1 ± 17.0 Age 59.0 ± 11.5 58.1 ± 13.0 Gender (% female) 32.7% 60.0% Race (% Caucasian) 98.0% 97.1% BMI 30.8 ± 5.2 31.5 ± 5.3 Type II DM 42.9% 28.6% CAD 18.4% 5.7% Hypercholesterolemia 53.1% 45.7% Heart Rate 75 ± 15 73 ± 15 eGFR (ml/min/1.73m2)* 76.9 ± 19.3 88.8 ± 20.7 Serum Creatinine (mg/dL) 1.03 ± 0.29 0.84 ± 0.21 Cystatin C (mg/L) 0.91 ± 0.25 0.78 ± 0.17 Standard deviations are presented unless otherwise specified *eGFR is calculated per MDRD formula throughout

Office BP in RDN & Crossover Groups Treated with RDN RDN N=47 Baseline 6 month BP Change (p-value) 12 months Systolic BP 178.3 ± 18.2 146.7 ± 23.3 -31.7 ± 23.1 p<0.001 150.7 ± 21.9 -28.1 ± 24.9 Diastolic BP 96.1 ± 15.5 84.4 ± 17.0 -11.7 ± 11.2 87.0 ± 16.1 -9.7 ± 10.6 P<0.001 compliance period 2 week compliance period 2 week Treated with RDN at 6-mo Follow-up Crossover N=35 No compliance period for Crossover patients prior to 6 month post-RDN BP measurements compliance period 2 week Pre-RDN* 6 month BP Change (p-value) Systolic BP 190.0 ± 19.6 166.3 ± 24.7 -23.7 ± 27.5 p<0.001 Diastolic BP 99.9 ± 15.1 91.5 ± 14.6 -8.4 ± 12.1 * At 6 months post-randomization

Change in Office Blood Pressure (mm Hg) 6-mo post randomization 12- mo post randomization 6-mo post-RDN* 6-mo Crossover† 12-mo post-RDN* Crossover 6-mo post-RDN* +7 +1 -8 -10 -12 -24 * P<0.001 for SBP and DBP change from baseline † P=0.026 for SBP change from baseline

Distribution of Office SBP for RDN Group % Patients

Distribution of Office SBP For Crossover Group % Patients

Crossover Procedural Safety One renal artery dissection following guide catheter insertion during angiography. The lesion was stented without further One hospitalization prolonged in a crossover patient due to hypotension following the RDN procedure. IV fluids administered, anti-hypertensive medications decreased and patient discharge without further incident No radiofrequency-related renal artery stenosis or aneurysm occurred in any patient Dissection may have been caused by either the guide catheter or during contrast injection during dye angiography 16

No Material Change in Renal Function in RDN & Crossover Groups Treated at Randomization 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 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 85.2±18.3 Cystatin C (mg/L) 0.78 ± 0.17 0.82±0.16 (n=26) 0.89±0.20

Other Safety 6 to 12 Months Post Randomization Three hypertensive events occurred in 2 patients in the crossover group requiring hospitalization No deaths occurred at any time point during the follow up period for either group No observed changes in eGFR One hypertensive event in crossover patient following intake of contrast in preparation for CT scan for possible diverticulitis. IV anti hypertensive meds were administered, BP controlled and patient discharged with 1 additional oral anti-hypertensive med. This occurred at day 106 post RDN tx 22 days post RDN crossover. CT scan of renal artery to look for any arterial complications – CT scan was negative. Meds were changed upon d/c. A second hypertensive event occurred at day 138 in same patient “hospitalization for persistent severe hypertension”.

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

Conclusions Patients who crossed over to RDN at 6 months had a similar significant drop in BP to that in patients receiving immediate RDN showing that the primary endpoint results are reproducible The natural tendency toward an increase in BP from baseline to 6 months in the crossover group shows the potential cost in delaying treatment with RDN RDN provides safe and sustained reduction of BP to 1 year