1. Renal Denervation Next Steps
Considerations for Trial Design in Moderate Hypertension
David E. Kandzari, MD, FACC, FSCAI
Chief Scientific Officer
Director, Interventional Cardiology
Piedmont Heart Institute
Atlanta, Georgia

2. Disclosure
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below
Affiliation/Financial Relationship Company
Grant/Research Support Abbott Vascular, Boston Scientific, Medtronic CardioVascular, Biotronik, Thoratec
Consulting Fees/Honoraria Boston Scientific Corporation, Medtronic CardioVascular, Micell Technologies
Major Stock Shareholder/Equity None
Royalty Income None
Ownership/Founder None
Intellectual Property Rights None
Other Financial Benefit None

3. Actions following SYMPLICITY HTN 3
Conducted hundreds of analyses on HTN-3 and prior clinical data
Identified The Key Areas for Next Trial Design
Discussions with Physician Advisors, Payers, & Regulators
Initiated Multiple new
Pre-Clinical Studies to
Test Hypotheses

4. SYMPLICITY HTN 3: Confounding Factors
Drug Changes and Variable Patient Adherence
Study Population
Procedural experience and variability

5. Procedure
Issue:
Incomplete renal denervation and procedural variability significantly impact blood pressure reductions
Alternative:
Symplicity Spyral™
Expand procedure to include renal artery branches

6. NE Concentration (pg/mg)
Combined Branch & Main Artery Treatment: Effective in Reducing Renal NE in Normotensive Pigs I V Y Y2 N 12 12 12 12
500
400
200
300
100
71% * † ‡
83%
92%
91%
NE Concentration (pg/mg)
Control
Main
Branch
Branch + Main
One-way ANOVA with Tukey’s *P=
†P<
‡P<
§P<
Melder et al. TCT 2014.
Branch + Main x2
Treatment

7. Medications
Issue:
Medication changes and variable adherence were potential confounders in SYMPLICITY HTN-3.
Many patients changed medications during HTN-3.
Drug adherence not measured, but likely a key uncontrolled variable.
The mechanisms of action of antihypertensive drugs and RDN overlap, with unknown effect on impact of RDN on BP.
Alternative:
Consider Pharma model: Obtain off-meds data
Standardize drug regimen
Measure drug adherence

8. Study Population Issue:
The population studied in HTN-3 differed from other SYMPLICITY studies.
Severe resistant HTN on 5 medications including a diuretic with ≥3 at maximal tolerated dose
US Study
Large African American cohort
Obese (average BMI ~35)
Large variability in control group BP response in HTN-3 by geographic area and by ethnic group
Alternative:
Change enrollment BP criteria
Not focused on maximum-tolerated meds & severe trHTN
Avoid changing patient behavior and medication patterns

9. 2013 ESH/ESC Hypertension Guidelines: Co-Morbidity Risk Matrix
Other Risk Factors, Asymptomatic Organ Damage or Disease
Blood Pressure (mmHg)
High Normal
SBP 130–139 or DBP 85–89
Grade 1 HT
SBP 140–159 or DBP 90–99
Grade 2 HT
SBP 160–179 or DBP 100–109
Grade 3 HT
SBP ≥180 or DBP ≥110
No other RF
Low risk
Moderate risk
High risk
1–2 RF
Moderate to high risk
≥3 RF
Low to Moderate risk
OD, CKD stage 3 or diabetes
High to Very high risk
Symptomatic CVD, CKD stage ≥4 or diabetes with OD/RFs
Very high risk
BP=blood pressure; CKD=chronic kidney disease; CV=cardiovascular; CVD=cardiovascular disease; DBP=diastolic blood pressure; HT=hypertension; OD=organ damage; RF=risk factor; SBP=systolic blood pressure.
Mancia G, et al. Eur Heart J. 2013;34:

10. Spyral HTN Global Clinical Program
HTN-3 Factor Identified
Alternative
Spyral™ Catheter
Combined Main + Branch VesselTreatment
Med Standardization
Off-Meds
No Max Dose Titration
Focus on ABPM
Less Severe Hypertension
Fewer Prescribed Meds
Procedural
Medications
Study Population

11. SPYRAL HTN Global Clinical Program*
Off Meds
On Meds
RDN
Sham 3M 6M
Titrate Meds
Phase A
Phase B
*Pending appropriate regulatory body review

12. Summary
The Spyral HTN Global Clinical Trial program is intended to address the confounding factors identified in SYMPLICITY HTN-3.
The on- and off-antihypertensive studies will allow better understanding of the impact of medication on renal denervation.
The Spyral HTN clinical program is being actively discussed with global regulatory bodies.