1. Radial Frequency Ablation for Hypertension Treatment: Help or Hype? J. Dawn Abbott, M.D., F.A.C.C., F.S.C.A.I. Director, Interventional Cardiology Fellowship Assistant Professor of Medicine Brown Medical School Division of Cardiology, Rhode Island Hospital

2. Disclosure Information The following relationships exist related to this presentation: None Off label use of products will be discussed in this presentation. -Investigational Devices

3. Arterial Hypertension  Most frequent cause of death worldwide  20mmHg increase in BP doubles cardiovascular mortality  > 80% of patients with arterial hypertension are not treated adequately or can not be treated adequately  20-30% of patients with HTN have or will develop resistant HTN Resistant HTN-failure to achieve goal BP (140/90, 130/80 DM/CKD) when adhering to maximally tolerated doses of 3 drugs including a diuretic.  Reduction of systolic blood pressure by 10 mmHg reduces the risk of stroke by 30%

4. Role of Kidney in Blood Pressure Regulation  The kidney plays a pivotal role in BP regulation through sodium, volume, renin modulation, and renal-sympathetic neuronal interactions.  Renal sympathetic efferent and afferent nerves contribute to the pathogenesis of hypertension.

5. Regulators of Renal Efferent Nerves  Central sympathetic nervous system  Aortic and carotid baroreflexes  Cardiac stretch receptors with vagal afferents  Renorenal reflexes that alter the level of efferent nerve activity in the contralateral kidney  Kidney is the recipient of sympathetic signals via the renal efferent nerves Increases renin release –Activation of RAAS system Increases sodium retention Decreases Renal blood flow

6. Essential HTN and CKD Hypertrophy Arrhythmia O2 consumption Heart failure Vasoconstriction Arteriosclerosis Renin- release NaCL-retention Renal blood flow Renal Afferent Nerves Insulin resistance

7. Early Proof of Concept Studies Sympathectomy in Hypertension Smithwick RH, J Am Med Assoc. 1953;152:1501-1504 Mortality benefit at the expense of side effects

8. Selective Renal Sympathetic Denervation: Therapeutic Target.  Preclinical studies catheter based RFA main renal artery reduces noradrenaline content in the kidney by more than 85% comparable to direct surgical renal denervation via artery transection and re-anastomosis. No severe vascular or renal injury at 6 months

9. The Catheter System Symplicity by Ardian Inc, Palo Alto, CA, USA*  6F compatible, articulating tip RF electrode  Energy maximum 8 Watt  Energy application up to 5x for each renal artery, depending on length  2 minutes per energy application *Investigational Device. Limited by U.S. law to investigational use.

10. Case Example of RFA Application

11. Clinical Data

12. Initial Cohort  First-in-man, non-randomized  Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min)  Mean age 58, 44% female, 32% DM, 22% CAD  Mean antihypertensive drugs 4.7  12-month data  Subgroup - NE spillover reduced 47%  5 pts unsuitable anatomy Lancet. 2009;373:1275-1281

13. Change in Office BP Lancet. 2009;373:1275-1281

14. Symplicity HTN-1: Expanded Cohort and Follow-up Sievert et al. European Society of Cardiology 2010. (n=153)

15. Procedural Specifics and Safety  38 minute median procedure time  Average of 4 ablations per artery  IV narcotics & sedatives for pain  No catheter or generator malfunctions Complications 1 renal artery dissection from catheter 3 access site  81 patients with 6-month renal CTA, MRA, or Duplex No vascular abnormalities at any site of RF delivery One progression of a pre-existing stenosis  Two deaths within the follow-up period unrelated to the device or therapy  No orthostatic or electrolyte disturbances  No change in renal function (Δ eGFR)

16. Transient vasospasm

17.  Randomized, controlled, clinical trial  106 patients randomized 1:1 to treatment with renal denervation vs. control  24 centers in Europe, Australia, & New Zealand  Inclusion Criteria: Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) ≥3 anti-HTN medications  Exclusion Criteria: Significant renal artery abnormalities/prior renal artery intervention eGFR < 45 mL/min/1.73m2 (MDRD formula) Type 1 diabetes mellitus Contraindication to MRI Stenotic valvular heart disease MI, unstable angina, or CVA in the prior 6 months Lancet. 2010;376:1903-1909

18. Trial Profile Lancet. 2010;376:1903-1909

19. Primary Endpoint: 6-Month Office BP 84% of RDN patients had ≥ 10 mmHg reduction in SBP (vs 35% controls) 10% of RDN patients had no reduction in SBP

20. BP Distribution in RDN and Controls at 6 Months >180 160-179 140-159 <140

21. Additional BP Outcome Measures

22. Conditions Likely to Respond to Renal Denervation  Resistant essential hypertension  Essential hypertension intolerant to medications  Nondipping essential hypertension  Resistant renovascular hypertension  Hypertension with chronic renal disease (unilateral or bilateral)  Hypertension with obstructive sleep apnea intolerant to continuous positive airway pressure  Congestive heart failure (with reduced or preserved left ventricular systolic function) with cardiorenal syndrome  Hypertension in end-stage kidney disease on dialysis with native kidneys  Hypertension in renal transplant patients with remaining native kidneys

23. Potential Long-term Benefits of Renal Denervation  Attenuation of arterial pressure*  Attenuation of arterial pressure during exercise*  Stabilization of renal function with attenuation of the rate of decline of estimated glomerular filtration rate and reduction of proteinuria in hypertensive patients  Restoration of nocturnal dipping*  Regression of left ventricular hypertrophy  Decreased insulin resistance*  Slower progression of vascular disease  Decreased incidence of congestive heart failure with reduced ventricular hypertrophy, reduced salt and water retention, and improved exercise tolerance  Decreased risk of stroke  Decreased risk of atrial and ventricular arrhythmias  Decreased risk of sudden cardiac death * Demonstrated in clinical trials

24. Cardiorespiratory Response to Exercise After RSD  46 patients with therapy-resistant hypertension in Symplicity HTN-2  Cardiopulmonary exercise tests were performed at baseline and 3-month follow-up  RSD reduces blood pressure during exercise without compromising chronotropic competence  Heart rate at rest decreased and heart rate recovery improved after the procedure

25. Ukena, C. et al. J Am Coll Cardiol 2011;58:1176-1182 Changes in BP with Exercise

26.  Bidirectional relationship between sympathetic overactivity and insulin resistance and hyperinsulinemia producing sympathetic activation  Renal denervation improves glucose metabolism and insulin sensitivity Renal Denervation and Insulin Resistance fasting glucose (A), fasting insulin (B), C-peptide (C), and homeostasis model assessment–insulin resistance (HOMA-IR; D)

27. Additional Novel Therapies for Resistant HTN  Baroreflex activation therapy (BAT)  Surgically implantable device that works by electrical stimulation of the carotid baroreceptors.  BAT acutely reduced muscle sympathetic nerve activity and increased parasympathetic activity

28. Rheos System (CVRx, Inc., Minneapolis, MN The device consists of bilateral electrodes and a pulse generator. Programming is accomplished via an external programming system.

29. Rheos Pivotal Trial  Randomized, double-blind, placebo-controlled study  265 subjects with resistant hypertension implanted and subsequently randomized (2:1) 1 month after implantation. Subjects received either BAT (Group A) for the first 6 months or delayed BAT initiation following the 6-month visit (Group B).  The 5 coprimary endpoints were: 1) acute SBP responder rate at 6 months 2) sustained responder rate at 12 months 3) procedure safety 4) BAT safety 5) device safety Bisognano JD et al. J. Am. Coll. Cardiol. 2011;58;765

30. Reduction in BP but High Adverse Event Rate  Procedural 68 (25.5) Surgical complication 13 (4.8) Nerve injury with residual deficit 13 (4.8) Transient nerve injury 12 (4.4) Respiratory complication 7 (2.6) Wound complication 7 (2.6)  BAT Hypertensive crisis (Group A) 9 (5.0) Hypertensive crisis (Group B) 7 (8.3)  Device 34 (12.8) Hypertension-related stroke 6 (2.3)

31. Conclusions  Catheter based renal renervation results in significant reductions in BP  The therapy appears safe out to 2 years  The magnitude of BP reduction should reduce the risk of HTN related morbidity and mortality  Secondary benefits deserve further study