1. 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.

2. 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.

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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)

9. 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

10. 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?

11. 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

12. 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

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

14. 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

15. 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

16. 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

17. 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

18. 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!