Measuring success of device therapy for hypertension Endpoints or Surrogates 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.

Goals of Renal Denervation Trials High Blood Pressure (hemodynamics) vs. Hypertension (syndrome) Devices that restore sympathetic balance BP changes may be one marker of success

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

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.

Is BP an endpoint or surrogate? Elevated BP is the disease Hemodynamic hypothesis OR Elevated BP is a marker of underlying disorders- e.g. autonomic nervous or hormonal imbalance Reduction of BP is the goal vs. treatment of underlying disorders which will result in blood pressure amelioration

BP Metrics Systolic/Diastolic/Pulse pressure Office measurement Home measurement BP during exercise, in recovery from exercise Continuous Measurement (ABPM) daytime, nighttime, average 24 hour, dipping BP variability % of beats with high or low bp Central Aortic pressure metrics

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)

ABPM 24 or 48 hours continuous monitoring APBM Hypertension diagnosis: 24 hour average, awake average, variability APBM Hypertension diagnosis: 24 hour average >130 systolic, or >80 diastolic Average awake: >135 systolic, or >85 diastolic Average asleep: >120 systolic, or >75 diastolic ABPM is helpful when office pressures are suspected not to be representative measures WCHTN- office measure gives higher than representative BP

ABPM vs Office BP ABPM may be more useful than single office pressure in predicting LVH CV morbidity and mortality Risk of ESRD, CV events or mortality in patients with CKD ABPM identifies ~20% of office hypertensives not to have elevated home BP (WCHTN) which has a better prognosis than persistent htn. Why is this important?

ABPM vs Office BP ABPM may or may not be better than repeated electronic office BP in predicting health outcomes ABPM, home electronic bp monitoring and repeated office electronic measurements may all have the same predictive accuracy The value is the repeated measures

Interpretation of ABPM vs Office BP Changes in office and daytime ABPM should be proportionate Changes in office and 24 hour average ABPM should be directionally similar Changes in office and nighttime ABPM should be interesting

The Role of ABPM in Symplicity III HTN Trial Exclude patients with WCHTN Define a population with both ULTRA SEVERE & Drug Resistant hypertension

Blood Pressure is the endpoint Any measure that is reproducibly performed is an adequate endpoint Office electronic, home electronic, ABPM While different treatment strategies for HTN treatment have resulted in varying impact on clinical endpoints, the differences may not reflect failure of the hemodynamic hypothesis

Have we missed the point? Is the purpose of devices is to address sympathetic imbalance, and a desirable result is reduction of bp BP is a surrogate for hypertension BP is a surrogate for cardiovascular and renal diseases BP reduction may not be a sensitive measure of correction of sympathetic imbalance

Restoring Sympathetic Balance RDN, Carotid Sinus Stimulation, and Carotid body denervation selectively remove a source of excessive signaling to the hypothalamus Therapeutic success restores sympathetic balance Sympathetic balance is notoriously complicated to document and measure BP changes often but not always happen following RDN Successful treatment may not reduce BP

In a Perfect World We could measure sympathetic We would fully understand the relationship sympathetic imbalance and chronic diseases Devices are tools to restore sympathetic balance BP change would be one valued consequence of successful RDN

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!