1. 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

2. 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.

3. “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

4. 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

5. Symplicity HTN-2 Design
Lancet. 2010;376:
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: 5 5

6. 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: 6

7. 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 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: 7 7

8. 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

9. 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: 9

10. 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)

11. 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

12. 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

13. 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

14. Distribution of Office SBP for RDN Group
% Patients

15. Distribution of Office SBP For Crossover Group
% Patients

16. 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

17. 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

18. 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”.

19. 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

20. 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