1. Catheter-Based Denervation for Resistant Hypertension
Therapeutic Options for Those Previously Without Alternative
David E. Kandzari, MD, FACC, FSCAI
Chief Scientific Officer
Director, Interventional Cardiology
Piedmont Heart Institute
Atlanta, Georgia

2. David E. Kandzari, MD Honoraria: Abbott Vascular
Contracted Research / Grant Support:
Cordis Corporation
Consulting Fees:
Medtronic CoreValve

3. A Major Public Health Burden
Most commonly diagnosed condition in the US
Astonishing prevalence
1 Billion people worldwide - growing to 1.6 Billion by 2025
74 Million Americans (1 in 3-4 adults)
Shared prevalence among men and women
Single largest contributor to death worldwide
Dramatically increases the risk of heart attack, stroke, heart failure & kidney failure
Estimated cost this year in US = $73.4B
Sources: American Heart Association; World Health Organization;
Kearney et al. Lancet. 2005;365(9455):

4. Cardiovascular Mortality Risk Doubles With Each 20/10 mm Hg Increase in BP*8x 8 7 6 5 4x
CV Mortality Risk 4 3 2x 2
Purpose:
To illustrate graphically that BP is strongly related to CV mortality risk.
Key Points:
A meta-analysis of individual data for 1 million adults without previous vascular disease from 61 prospective observational studies of BP and mortality indicates that the risk for CV mortality doubles with each 20/10 mm Hg increase in BP
The analysis addressed the cause-specific death rate during a 10-year period among people who were initially aged 40, 50, 60, 70, or 80 years. The rise in CV mortality was directly related to higher initial BP in every age group
Over the range of 115/75 mm Hg to 185/115 mm Hg, each 20 mm Hg increase in systolic blood pressure (SBP) or a 10 mm Hg increase in diastolic blood pressure (DBP) doubled the risk of mortality from stroke or ischemic heart disease in individuals aged years
Source:
Lewington S, Clarke R, Qizilbash N, et al, and The Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360: . 1
115/75
135/85
155/95
175/105
SBP/DBP, mm Hg
CV = cardiovascular.
SBP = systolic blood pressure.
DBP = diastolic blood pressure.
*In individuals aged 40 to 69 years (10-year study period), starting at BP 115/75 mm Hg.
Lewington S, et al. Lancet. 2002;360:

5. Hypertension: Major Health Burden
1/3
Untreated
Treated & Controlled
Treated & Uncontrolled
1 in 3 adults have hypertension
230 million people in EU5, US, & Japan
1 billion people worldwide
2x cardiovascular mortality for every /10 mmHg BP increase

6. Chronology of Antihypertensive Drug Development
Effectiveness
Tolerability
Over the past 20 years “46 trials and more than 230,000 patients have probably been too many to end up with the current conclusion that what really matters is lowering blood pressure whatever the agents administered”
Alberto Zanchetti Editor, Journal of Hypertension, J Hypertension 2011;29:1-3
1940s
1950
1957
1960s
1970s
1980s
1990s
2007
Direct vasodilators
Alpha blockers
ACE inhibitors
ARBs
DRIs
Peripheral sympatholytics
Ganglion blockers
Veratrum alkaloids
Thiazide diuretics
DHP CCBs
Central alpha2 agonists
Non-DHP CCBs
Beta blockers

7. Drug Resistant Hypertension
Failure to achieve goal BP (<140/90 mmHg) using 3 different drugs with pharmacologically complementary mechanisms, one of which is an appropriately dosed diuretic
All 3 drugs given in near maximal doses
Assumes patient adherence to an adequate and appropriate drug regimen
Reported range is 5-30% of hypertensives, general consensus ~15%
Not the same as resistant HTN, but in major HTN trials 45-82% of patients achieve control on uptitration regimens
Chobanian A et.al. Hypertension 2003; Sarafidis et al. JACC. 2008;52: ; JNC 7 Guidelines

8. Renal Sympathetic Efferent Nerve Activity Kidney as Recipient of Sympathetic Signals
Renal Efferent
Nerves
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow
DiBona, Gerald F. Am. J Physiol Regul Integr Comp Physiol. 289: R633-R641, 2005 9 9

9. Renal Sympathetic Afferent Nerves Kidney as Origin of Central Sympathetic Drive
Vasoconstriction
Atherosclerosis
Hypertrophy
Arrhythmia
Oxygen Consumption
Sleep Disturbances
Insulin
Resistance
Renal Afferent
Nerves
↑ Renin Release  RAAS activation
↑ Sodium Retention
↓ Renal Blood Flow 10 10

10. Dr. Reginald H. Smithwick
Role of Sympathetic System on Resistant Hypertension Early Surgical Precedent
Dr. Reginald H. Smithwick
1952
s: Dr. Reginald H. Smithwick and others develop open surgical sympathectomy for malignant hypertension

11. Survival rate of normal population Age 43
Sympathectomy in Hypertension Effects on Survival with Collateral Morbidity
100
Group 1
Group 2
Group 4
Group 1
Group 2
Group 4
Survival rate of normal population Age 43
Group 3
Group 3 90
Group 1: Patients with persistently elevated BP, minimal/no eyeground changes nor abnormalities in cerebral, cardiac, or renal nerves
Groups 2-4: Patients with increasing amounts of cardiovascular disease 80 70 60
% Survivals 50 40 30 20
Purpose:
To illustrate the decrease in mortality in patients with essential hypertension treated surgically by sympathectomy compared with those who received medical treatment.
Key Points:
In 1953, Smithwick reported the effects of sympathectomy on mortality and survival rates in hypertensive patients who underwent sympathectomy (n=1266) compared with that of control patients (n=467) who were medically treated1
The patients included in the study had persistent hypertension, BP ≥140/90 mm Hg, and the majority had evidence of vascular damage to the target organs of hypertension (either eyes, heart, kidneys, or brain); patients were assigned to 1 of 4 groups based on the severity of hypertensive vascular disease, with Group 4 being the most severe1
As shown in the graph, there was marked improvement in the survival of patients who underwent sympathectomy compared with those who received medical management. For example in group 3, at 7 years there was a 50% improvement in survival in those treated with sympathectomy compared to those receiving medical treatment1
Overall, the mortalities in all 4 surgical groups were significantly lower than in the medical groups; the best survival rates were observed in Groups 2 and 3, which consisted of hypertensive patients with changes in cerebral, cardiac, and/or renal areas; mortality for Group 4 was high regardless of treatment as these patients had severe CV disease1
However, the procedure was associated with many debilitating adverse effects, such as postural hypotension, orthostatic tachycardia, palpitations, intestinal disturbances, and erectile dysfunction attributed to nonspecific sympathetic denervation of the viscera and lower extremity vasculature2
Sources:
Smithwick RH , Thompson JE. Splanchnicectomy for essential hypertension: results in 1,266 cases. JAMA. 1953;152:
Gewirtz JR, Bisognano JD. Catheter-based renal sympathetic denervation: a targeted approach to resistant hypertension. Cardiol J. 2011;18:
Surgical n=1266 10
Medical n=467 1 2 3 4 5 6 7 8 9 10
Time in Years
However, surgical sympathectomy was associated with significant morbidity2
Adapted and reproduced with permission from Smithwick RH, Thompson JE. JAMA. 1953;152:
Gewirtz JR, et al. Cardiol J. 2011;18:

12. Renal Nerves as a Therapeutic Target
Arise from ~ T10-L2
Follow the renal artery to the kidney
Primarily lie within the adventitia
Vessel
Lumen
Media
Adventitia
Renal Nerves 13

13. Symplicity® Catheter System™
Renal Nerves as a Therapeutic Target
Symplicity® Catheter System™
6F catheter access
Articulating tip with RF electrode
Renal nerves lie in adventitia, encircling the renal arteries
4-6 focal 2-minute RF treatments along each renal artery 14

14. Proof of Principle: Therapeutic Renal Denervation and Reduction of Central Sympathetic Nerve Activity
Baseline
MSNA: 46 burst/min
BP: 155/95 mmHg
3 Month Follow-up
MSNA: 33 burst/min (~30%)
BP: 133/78 mmHg (22/17 mmHg)
12 Month Follow-up
MSNA: 21 burst/min (~54%)
BP: 132/75 mmHg (23/20 mmHg)
No impact on flight/fight “epinephrine” response
No blunting of baroreceptor function
Preserve central sympathetic homeostatic mechanisms
Schlaich et al. J Htn. 2009; 27 (suppl 4):s437.

15. The Symplicity HTN Clinical Trial Program
Symplicity HTN-1 First-in-Man, and Expanded Cohort (N=153)1,2
Symplicity HTN-2 Randomized, Controlled Trial (N=106)3
= Planned follow up
= Partial cohort reports
= Primary endpoint
Symplicity HTN-3 Randomized, Blinded, Controlled Trial (N~530)4
Purpose:
To provide a brief description of the 3 Symplicity® Renal Denervation System™ clinical trials: Symplicity HTN-1, Symplicity HTN-2, and Symplicity HTN-3.
Key Points:
The Symplicity HTN clinical trial program has been developed and conducted in a methodical manner with long-term follow up and rigorous attention to the safety of participants
Symplicity HTN-1 was initiated as a proof of principal, nonrandomized cohort study (N=45) in patients with treatment-resistant hypertension at 5 Australian and European sites and later expanded to a total of 19 sites in Europe, Australia, and the United States1,2
Symplicity HTN-2 was designed to evaluate the safety and efficacy of catheter- based RDN in patients with treatment-resistant hypertension in a randomized, controlled manner3
Symplicity HTN-3 is a US-based, randomized, blinded, controlled trial commencing this year to further explore the safety and efficacy of RDN4
As the timeline on the slide indicates, patients in each of the 3 studies will be formally followed for a period of 3 years
Sources:
Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:
Symplicity HTN-1 Investigators; Krum H, Barman N, Schlaich M, et al. Catheter- based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:
Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:
Data on file, Medtronic.
2015
2006
2010
2011
2012
2013
2014
2016
2007
2008
2009
Shading on bars indicates clinical trial enrollment periods. Enrollment period for HTN-3 is estimated.
Krum H, et al. Lancet. 2009;373:
Symplicity HTN-1 Investigators. Hypertension. 2011;57:
Esler et al. Lancet. 2010;376:
Data on file, Medtronic.

16. SYMPLICITY I and Expanded Cohort Baseline Patient Characteristics
Demographics
Age (years)
57 ± 11
Gender (% female)
39%
Race (% non-Caucasian) 5%
Co-morbidities
Diabetes Mellitus II (%)
32%
CAD (%)
24%
Hyperlipidemia (%)
72%
eGFR (mL/min/1.73m2)
81 ± 19
Blood Pressure
Baseline BP (mmHg)
176/98 ± 17/15
Number of anti-HTN meds (mean)
5.0 ± 1.4
ACE/ARB (%)
88%
Beta-blocker (%)
79%
Calcium channel blocker (%)
Vasodilator (%)
19%
Diuretic (%)
96%
Spironolactone (%)
Krum et al. Lancet 2009; Schlaich et al. European Society of Hypertension 2010. 17

17. baseline right kidney
acute post treatment right
30 day post treatment right
baseline left kidney
acute post treatment left
30 day post treatment left

18. Late-Term Safety No RF treatment related vascular complications
One progression of a pre-existing renal artery stenosis (40%80%), possibly related to catheter manipulation, successfully stented
Stable renal function (better than natural history)
3 Month eGFR ∆: ± 13.9 mL/min, p=0.65, n=83
6 month eGFR ∆: ± 13.6 mL/min, p=0.89, n=80
12 Month eGFR ∆ : ± 12.9 mL/min, p=0.11, n=58
No orthostatic hypotension
No electrolyte disturbances
Two deaths within the follow-up period; both unrelated to the device or therapy
Schlaich et al. European Society of Hypertension 2010 19

19. Late-Term Blood Pressure Response
Schlaich et al. European Society of Hypertension 2010; Symplicity HTN-1 Investigators. Hypertension. 2011;57: . 20

22. Primary Endpoint 6-Month Office Blood Pressure
-12
33/11 mmHg
difference between RDN and Control
(P<0.0001)
-32
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:

23. Achieved Office Systolic SBP
84% of RDN patients had ≥ 10 mmHg reduction in SBP
84% of RDN patients had ≥ 10 mmHg reduction in SBP
Change in Medication
Renal Denervation (n=49)
Control (n=51)
# Med Dose Decrease (%)
10 (20%)
4 (8%)
# Med Dose Increase (%)
5 (10%)
Symplicity HTN-2 Investigators. The Lancet 2010: 376:

26. Symplicity HTN-3 Trial Study Design
2 weeks 6M 1M 3M
Home BP &
Med Confirmation
Treatment
2 weeks •
Office
SBP ? 160 mmHg
Primary •
Initial
Screening
Full doses of ? 3
meds
Home BP &
Initial Screening
Confirmatory
Screening
Renal
Angiogram •
ABPM
Endpoint
in past 2 wks
Med Diary •
No plan to change meds
for 6 M
2 weeks
Control
Home BP &
Med Confirmation 1M 3M 12 - 6M
36M
MANDATORY
Patient and Research staff assessing
BP are blinded to treatment status
No changes in medications for 6M 28 28
Clinicaltrials.gov Identifier NCT ;/

27. Future Directions for Research
Chronic activation of renal nerves is common in multiple conditions/disease states1,2
Future research may be warranted in disease states characterized by hyperactive afferent and efferent renal nerves
Vasoconstriction
Atherosclerosis
Sleep disturbances
Sleep Apnea
Afferent Nerves
Hypertrophy
Arrhythmia
Oxygen consumption
Diabetes
Purpose:
To highlight conditions characterized by sympathetic hyperactivation.
Key Points:
Renal afferent nerves influence sympathetic outflow, which leads to1:
Vasoconstriction
Increased heart rate
Increased blood pressure (BP)
Under conditions where sympathetic activity is chronically active, it is associated with a variety of hypertensive conditions including diabetes, kidney failure, heart failure, and sleep apnea1,2
Sources:
Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension. 2009;54:
Blankestijn PJ, Ritz E. Renal denervation: potential impact on hypertension in kidney disease? Nephrol Dial Transplant. 2011; 26:
Heart Failure
Kidney Failure
↑ Renin release  RAAS activation
↑ Sodium retention
↓ Renal blood flow
↓ Kidney function
RAAS = renin-angiotensin-aldosterone system.
Adapted from Schlaich MP, et al. Hypertension. 2009;54:
Blankestijn PJ, et al. Nephrol Dial Transplant. 2011;26:

28. Symplicity HTN-3 Trial Current Status
First patient randomized in October, 2011
Anticipated date of final primary endpoint collection is March 2013
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