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 david.kandzari@piedmont.org

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

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

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

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

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=0.0003. †P<0.0001. ‡P<0.0001. §P<0.0001. Melder et al. TCT 2014. Branch + Main x2 Treatment

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

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

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;34:2159-219.

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

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

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.