Device Therapy Paul A. Sobotka, MD Professor of Medicine/Cardiology The Ohio State University Chief Medical Officer Cibiem, Inc.

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Consulting Fees/Honoraria Royalty Income Ownership/Founder/Salary Ardelyx Inc. Medtronic, Inc. Rox Medical, Inc. Ardian, Inc. Cibiem, Inc.

Renal denervation in less severe treatment resistant hypertension Christian Ott, Felix Mahfoud, Axel Schmid, Tilmann Ditting, Paul A. Sobotka, Roland Veelken, Aline Spies, Christian Ukena, Ulrich Laufs, Michael Uder, Michael Bohm, Roland E. Schmieder Submitted Embargoed

Moderate Hypertension Device therapy for the treatment of hypertension which is NOT proved unresponsive to diet, exercise and medications Device therapy enabling treatment of the persistently non compliant patient Device therapy as an empowering choice for patients to select between treatment with a device and life long poly pharmacy

Background Drug Therapy Proof of safety and efficacy requires stationary background diet, exercise, and drug therapy Resistant hypertension Defines a subgroup of HTN patients who may derive benefit from device intervention In the opinion of many HTN experts, device therapy should be reserved for compliant patients who accept life long poly pharmacy as a treatment strategy and whose physicians are expert in using highest doses of several drugs used in combinations untested and unproven safe and effective

rHTN- Patient Selection? What constitutes failed pharma therapy? 3 drugs, maximal doses (one being a diuretic)? 3 drugs, maximal doses (one being a diuretic), one being spironolactone? Care provided by an HTN expert? Does patient choice matter? Does willful non-compliance with life long poly pharmacy recuse patients from consideration?

Blood Pressure is a lousy way of measuring hypertension Blood pressure is the product of cardiac output, vascular capacitance, compliance, reflection and resistance MI can cure high blood pressure but not hypertension Blood pressure is dynamic; a single measure cannot adequately characterize vascular dynamics when at rest and when under stress.

BP Syndromes Hypertension (mild, moderate, severe) White coat hypertension (hypertension only when in the physicians office) Concealed hypertension (hypertension only when at home) Episodic hypertension (malignant, crisis) Pseudo hypertension (something to do with patient behaviors, or clinical failure to properly measure)

Special case of untreatable hypertension New and novel devices must demonstrate safety and define effectiveness to inform patient choice Special case of untreatable hypertension Above target despite diet/exercise/medication compliance To reduce calculated 10 year CV risk To attenuate or reverse end organ damage Special case of the persistently non compliant patient Universal case of empowering patient choice

Moderate vs Severe HTN The CV risk of hypertension is linear for all bp above 140mmHg Restricting therapy to those with ULTRA hypertension (>160 mmHg) versus those with Moderate (140-160mmHg) is indefensible A 20 mmHg reduction of bp generates same benefit for a patient with ultra and with moderate hypertension A 20 mmHg reduction of bp attains infinite individual and social benefit for the non compliant patient

Risk:Benefit Device Therapy HTN Symptom reduction Prevention Mortality reduction Risk of native disease

Risk:Benefit Device Therapy HTN Symptom reduction Prevention Mortality reduction MHTN SHTN rHTN Afib CKD CHF Risk of native disease

Risk:Benefit Device Therapy HTN Symptom reduction Prevention Mortality reduction CHF CKD Afib Magnitude of benefit SHTN rHTN MHTN Risk of native disease Resistant could be either moderate or severe

Risk:Benefit Device Therapy HTN Symptom reduction Prevention Mortality reduction CHF Afib Magnitude of benefit SHTN rHTN CKD MHTN Risk of native disease Inherent Procedure Risk ADD SPHERES instead of circles The benefit is related to the biologic limits of improvements: A patient with 180mmHg baseline can experience a 40 mmHg reduction A patient with a 160mmHg baseline can experience only a 20 mmHg improvement

Vascular and Renal Safety Vascular Safety Acute Renal Artery structure and function Preclinical: structural integrity of artery Human: post procedure arterial imaging Chronic Renal Artery structure and function Preclinical: 3 month pig anatomy and histology Human: 6 month follow up demonstration of patency and lack of therapy related aneurysms, or clinically important stenosis Renal Safety Human: serial tracking of changes in kidney function relative to adequate control population (eGFR can hide mischief )

Clinical Endpoints Hypertension Non Hypertension Refractory, resistant, difficult to treat, moderate, patient preference (non compliance) Non Hypertension HFrEF, HFpEF, prevention or treatment of tachy atrial or ventricular arrhythmias, ADHF, prevention of CKD progression, SDB (central, obstructive), insulin resistance…..

Terminal Thoughts A final cautionary thought. I’ve been traveling through a lot of airline terminals lately. Here’s a diagram of several of them. Most people looking at this diagram will conclude there are many ways to build an airport. But I’m more cynical. I think it means we haven’t yet learned how to build one!