Treating Hypertension With a Catheter..Wait What? David P. Lee, M.D. 22 June 2013 Stanford University

Treating Hypertension With a Catheter..Wait What? David P. Lee, M.D. 22 June 2013 Stanford University

COI Medtronic: Research Grant, Consultant Boston Scientific: Research Grant, MAB

Worldwide Prevalence of Hypertension Is Increasing In 2000, 972 million (26%), of the adult population had hypertension Prevalence of Hypertension by World Region By year 2025, 1.56 billion (29%) are projected to have hypertension Most of the expected increase will be in economically developing regions Number of People With Hypertension (millions) Kearney PM, et al. Lancet. 2005;365:217-223.

Blood Pressure Classification BP Classification SBP mmhg DBP mmhg Normal <120 and <80 Prehypertension 120 139 or 80 89 Stage 1 Hypertension 140 159 or 90 99 Stage 2 Hypertension >160 or >100

Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmhg) (<130/80 mmhg for those with diabetes or chronic kidney disease) Initial Drug Choices Without Compelling Indications With Compelling Indications Stage 1 Hypertension (SBP 140 159 or DBP 90 99 mmhg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension (SBP >160 or DBP >100 mmhg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

Definition of Resistant Hypertension Uncontrolled Hypertension Includes all patients who lack BP control on treatment, including those on inadequate treatment regimens, those with poor adherence, those with undetected secondary hypertension, as well as those with true treatment resistance 1 Uncontrolled Hypertension Resistant Hypertension Resistant Hypertension BP that remains above goal in spite of compliance with full doses of 3 antihypertensive medications of different classes; ideally, 1 of the 3 agents should be a diuretic 1 The treatment plan must include attention to lifestyle measures 2 Includes those patients who achieve BP control but require 4 antihypertensive agents to do so 1 1. Calhoun DA, et al. Circulation. 2008;117:e510-e526. 2. Mancia G, et al. Eur Heart J. 2007;28:1462-1536.

Resistant Hypertension Causes of Pseudoresistant Hypertension 1,2 Suboptimal dosing of antihypertensive agents White coat effect Suboptimal BP measurement technique Physician inertia Lifestyle factors Medications that interfere with BP control Pseudoresistance caused by poor adherence to prescribed medication 1. Calhoun DA, et al. Circulation. 2008;117;e510-e526. 2. Makris A, et al. Int J Hypertens. 2011;doi: 10.4061/2011/598694. 3. Papademetriou V, et al. Int J Hypertens. 2011;doi:10.4061/2011/196518. Secondary Causes of Hypertension 1,2 Obstructive sleep apnea Primary aldosteronism Renal artery stenosis However, a majority of patients with resistant hypertension and no identifiable secondary causes have an activated sympathetic nervous system and increased sympathetic outflow 3 Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use.

Consequences of Resistant Hypertension Patients with resistant hypertension have approximately 3-fold increased risk for CV events compared with that of patients with controlled hypertension 1 No longitudinal study has specially evaluated the prognosis of resistant hypertension 1 The degree to which CV risk is reduced with treatment is unknown, however the benefits of successful treatment are likely substantial 2 DBP = diastolic blood pressure. 1. Doumas M, et al. Int J Hypertens. 2011;doi: 4061/2011/318549. 2. Calhoun DA, et al. Circulation. 2008;117:e510-e526.

Causes of Resistant Hypertension Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication Inadequate doses Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives) Over-the-counter (OTC) drugs and herbal supplements Excess alcohol intake Identifiable causes of HTN

Renal Nerves and the SNS Efferent Sympathetics Afferent Renal Sympathetics Sympathetic signals from the CNS modulate the physiology of the kidneys The kidney is a source of central sympathetic activity, sending signals to the CNS Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

Renal Nerve Anatomy Allows a Catheter-Based Approach Standard interventional technique 4-6 two-minute treatments per artery Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use. 12

Symplicity Investigational Catheter Device Generator will automatically control RF energy delivery: Power automatically ramped and maintained (5-8W) Continuously monitors temperature and impedance Automatically shuts off after 2 min or when either impedance or temperature exceed program limits 5mm Flexible Tip (self-orienting) 12mm Deflectable Shaft Caution: The Symplicity Renal Denervation System is an Investigational Device. Limited by U.S. law to investigational use.

St. Jude EnligHTN Boston Scientific/Vessix V2 Covidien OneShot ReCor Paradise

Six Month Post-Procedure Histology (Porcine Model) Movat s Pentachrome Stain An area of medial injury (yellow) is located between the arrows on the left. An enlargement of the boxed region is shown on the right Findings: minimal intimal thickening and minimal internal elastic lamina injury overlying areas of mild full thickness medial fibrosis (yellow [fibrosis] with green [proteoglycan deposition]) and adventitial fibrosis (yellow) Reproduced with permission from Rippy MK, et. al. Clin Res Cardiol. 2011;doi:101007s00392-011-0346-8.

Six Month Post-Procedure Nerve Histology (Porcine Model) H&E Nerve from untreated vessel: Periarterial nerve bundle surrounded by a thin fibrous connective tissue sheath (perineurium) Nerve from treated vessel: Periarterial nerve bundle has a hypercellular appearance and the perineurium has a thickened and fibrotic appearance. Nerve from Untreated Vessel Nerve from Treated Vessel Reproduced with permission from Rippy MK, et. al. Clin Res Cardiol. 2011;doi:101007s00392-011-0346-8.

Symplicity Staged Evaluation in Hypertension and Beyond First-in-Man 1 Symplicity HTN-1 2 Series of Pilot Studies Symplicity HTN-2 3 EU/AU Randomized Clinical Trial USA Symplicity HTN-3 4 US Randomized Clinical Trial Sources: 1. Krum H, et al. Lancet. 2009;373:1275-1281. 2. Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917. GLOBAL Registry EU/AU Other Areas of Research: 4 Insulin Resistance, HF/Cardiorenal, Sleep Apnea, More 3. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. 4. Data on file, Medtronic.

The Symplicity HTN-1 Trial: Overview Design Multicenter (19 sites in Europe, Australia, and the United States), nonrandomized, open-label, proof-of-concept study Population 153 patients with treatment-resistant hypertension Treatment Endovascular catheter-based RDN using the Symplicity Renal Denervation System plus baseline antihypertensive medications Duration 36 months (assessments at 1, 3, 6, 12, 18, 24, and 36 months) Outcome Measures Primary efficacy measure: change in office BP Primary safety measures: based on physical examination, basic blood chemistries, and anatomic assessment of renal vasculature Source: Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

Symplicity HTN-1 Trial: Key Inclusion/Exclusion Criteria * Inclusion Criteria >18 years of age Elevated office systolic blood pressure (SBP) 160 mm Hg 3 antihypertensive medications (including 1 diuretic) Exclusion Criteria Estimated glomerular filtration rate (egfr) <45 ml/min/1.73m 2 Type 1 diabetes mellitus Known secondary cause of hypertension other than sleep apnea or chronic kidney disease Significant renovascular abnormalities * Inclusion/exclusion criteria in the trial settings were stringent and conservative in order to ensure a homogenous population in clinical practice, individual patient characteristics and physician judgment should guide patient selection Source: Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917.

BP change (mmhg) 0-5 -10-15 -20-25 -30-35 -40-45 Symplicity HTN-1 Trial Change in Office BP Through 36 Months -19-9 -10-10 -21-22 -27-14 -14-29 -34-17 -31-16 SBP mmhg Schlaich M, TCT 2012 P<0.01 for from BL for all time points 1 mo (n=143) 3 mo (n=148) 6 mo (n=144) 12 mo (n=132) 24 mo (n=105) Reported as mean with 95% confidence intervals *Number of patients represents data available at time of data-lock 30 mo (n=44) 36 mo (n=34)*

% Patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Schlaich M, TCT 2012 SYMPLICITY HTN-1 Distribution of SBP Change at Baseline, 1, 12, 24, and 36 Months Baseline 1 mo 12 mo 24 mo 36 mo (n=150) (n=143) (n=132) (n=105) (n=34)* *Number of patients represents data available at time of data-lock 180 mmhg 160-179 mmhg 140-159 mmhg < 140 mmhg

Conclusions The magnitude of clinical response is significant compared to baseline and sustained through 36 months Average number of medications were similar at each time point Increasing responder rates indicate: Some subjects respond late to RDN No loss of treatment effect out to 36 months The treatment effect was consistent across subgroups (age, diabetes status, and baseline renal function) Observed significant decrease in pulse pressure through 36 months No late adverse events related to RDN were reported through 36 months Schlaich M, TCT 2012 Analysis includes data on patients available through 36 months

Symplicity HTN-2 Trial Overview Design Multicenter (24 sites in Europe, Australia, and New Zealand), prospective, randomized, controlled study Population 106 patients with treatment-resistant hypertension Treatment Intervention group (endovascular catheter-based RDN with the Symplicity Renal Denervation System plus baseline antihypertensive medications) Control group (baseline antihypertensive medications alone) Duration 6 months (for the primary endpoint) with follow-up to 3 years Outcome Measures Primary endpoint: between-group changes in average office SBP from baseline to 6 months Secondary endpoints: acute and chronic procedural safety, a composite cardiovascular endpoint, occurrence of 10 mm Hg SBP reductions, achievement of target SBP, change in 24-hour ambulatory BP, and change in home BP Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2 Trial Key Inclusion/Exclusion Criteria * Inclusion Criteria 18-85 years of age Elevated office SBP 160 mm Hg (or 150 mm Hg for type 1 diabetics) Documented compliance with 3 antihypertensive medications Exclusion Criteria egfr <45 ml/min/1.73m 2 Type 1 diabetes mellitus Contraindications to MRI Substantial stenotic valvular heart disease Pregnancy or planned pregnancy during the study Myocardial infarction, unstable angina, or cerebrovascular accident in previous 6 mo Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention * Inclusion/exclusion criteria in the trial settings were stringent and conservative in order to ensure a homogenous population in clinical practice, individual patient characteristics and physician judgment should guide patient selection. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2 Trial: 1-, 3-, and 6-Month Office BP Reduction * Mean Office BP Change (mm Hg) 10 0-10 -20-30 -40-20 -7 0 0-24 -8-4 -2-32 -12 1 0 SBP DBP -50 Symplicity RDN Group Control Group Symplicity RDN Group Control Group Symplicity RDN Group Control Group 1M 3M 6M (Primary Endpoint) * P 0.005 for changes in SBP and DBP at all time points between Symplicity RDN and control groups; error bars represent 95% CIs. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2 Trial: Distribution of Office SBP at 6 Months 1,2 1. Data on file, Medtronic. 2. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Change in Office Blood Pressure through 30-Months Post-Procedure* Initial RDN Group Crossover Group 0 0-10 -20-12 -10-10 -13-10 -8-10 -10-30 SBP DBP -20-13 SBP DBP -40-50 -32 Esler M, ASH 2013-28 -29-35 6m 12m 24m 30m -30 P<0.01 at all time points for both groups -40-24 -24-28 -35 6m 12m 18m 24m n=49 n=47 n=43 n=37 n=35 n=33 n=31 n=26 *Only 7 patients in the Crossover group had available BP data at time of 30m data lock

SBP Response Rate Through 30 Months Represents Pooled Data 100% 80% 75% 63% 60% 10 mm Hg 20 mm Hg 84% 77% 80% 68% 70% 71% 64% 53% 40% 20% 0% 6 Months Post 12 Months 18 Months 24 Months 30 Months Procedure Post Procedure Post Procedure Post Procedure Post Procedure n=84 n=80 n=74 n=66 n=44 Esler M, ASH 2013

BP Medication Changes Post-Procedure 6 M (n=76) 12 M (n=76) 18 M (n=74) 24 M (n=64) 30 M (n=42) 0% 20% 40% 60% 80% 100% # Med or Dose No Change # Med or Dose Physicians were encouraged to maintain medications and dosages up to the 6-month primary endpoint. Increase: if any or both meds and/or dose increase, Decrease: if any or both meds and/or dose decrease. Values may not total to 100% due to indeterminate modifications, e.g., combination of med/dose increase and decrease. Esler M, ASH 2013

Symplicity HTN-2 Trial: Short-Term Procedure Safety No serious device- or procedure-related adverse events Minor complications in 5 of 52 patients: 1 access-site complication (femoral artery pseudoaneurysm); treated with manual compression 1 post-procedural drop in BP 1 urinary tract infection 1 extended hospital admission for assessment of parasthesias 1 case of back pain; treated with pain medication and resolved after 1 month Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Symplicity HTN-2 Trial: Chronic Safety 43 RDN patients underwent CTA, MRA, or duplex evaluation at 6 months No new vascular abnormalities or stenoses at any site of RF delivery 1 possible progression of a pre-existing stenosis unrelated to RF treatment; no further therapy warranted Serious adverse events at 6 months requiring hospital admission: Composite Cardiovascular Events Hypertensive event unrelated to non-adherence to medication Symplicity RDN Group (n=49) Control Group (n=51) 3 2 Other cardiovascular events 0 0 Other Serious Adverse Events Transient ischemic attack 1 2 Hypertensive crisis after abruptly stopping clonidine 1 0 Hypotensive episode resulting in reduction of medications 1 0 Coronery stent for angina 1 1 Temporary nausea/edema 1 0 Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

Global SYMPLICITY Registry: Real-World Clinical Outcomes Worldwide evaluation of the safety and efficacy of treatment with the Symplicity renal denervation system in real world uncontrolled hypertensive patients Consecutive patients treated in real world population ~ 5000 patients GREAT Registry N=1000 Korea Registry* N=102 South Africa Registry* N=400 Canada and Mexico* Rest of GSR N~3500 ~ 200 Global Sites Minimum 10% randomly assigned to 100% monitoring 30% monitoring to date Follow-up schedule 3mo 6mo 1yr 2yr 3yr 4yr 5yr Mahfoud F, EuroPCR 2013

Baseline Patient Characteristics (n=617) Mahfoud F, EuroPCR 2013 * 617 patients treated as of January 11, 2013 Demographics Age (years) 60 ± 13 Gender (% male) 63% Race (% caucasian) 87.5% BMI 30 ± 5.6 Co-Morbidities Diabetes Mellitus II (%) 38% Cardiac Disease (%) 49% egfr (ml/min/1.73 m 2 ) n=578 80 ± 53.1 Serum Creatinine (mg/dl) n=227 1.2 ± 1.7 egfr > 45 ml/min/1.73 m 2 97% Blood Pressure Baseline BP (mm Hg) 164/89 ± 23/16 Number of anti-htn medication classes (mean) 4.35 ± 1.34 Diuretic (%) 77% Aldosterone blocker (%) 19% ACE (%) 33% ARB (%) 67% Beta-Blocker (%) 79% Calcium Channel Blocker (%) 74% Alpha-adrenergic blocker (%) 34% Vasodilator (%) 14%

Population Characteristics 617 patients treated as of January 11, 2013 85% with SBP 140 mm Hg Approx 60% of patients treated according to ESC Consensus paper on Renal Denervation 1 SBP 160 mm Hg ( 150 mm Hg Diabetes II), 3+ meds, including diuretic 22% with SBP 180 mm Hg Co-morbidities include Diabetes II 38.2% Renal Disease 30.1% Sleep Apnea 16.3% Hx of Cardiac Disease 49% Heart Failure 9.3% Atrial Fibrillation 11.9% 1 Mahfoud F et al. Expert consensus document from the European Society of Cardiology on catheter-based renal denervation, Eur Heart J April 2013 Mahfoud F, EuroPCR 2013

Procedure Detail and Safety Varied Patient Anatomies 98% anatomically eligible Average number renal arteries: 2.16 Mean length of renal artery: 43 +/- 14 mm Mean diameter of artery: 5.7 +/- 1.2 mm Procedure (n=617) 9% incidence of spasm 2 patients with vascular complications Pseudoaneurysm/hematoma No serious adverse events related to delivering RF to the renal artery with the Symplicity Flex catheter Post-Procedure through 6M* No new vascular abnormalities 2 hypertensive crises 1 death deemed unrelated to device or procedure 1 new onset of end-stage renal disease due to nephrotoxic overdose 2 MI *Data collected on all patients who reached either 3 or 6 month follow up Mahfoud F, EuroPCR 2013

5 Change in Office BP According to Baseline Measurement 3 Months 6 Months -5 BP change (mmhg) -15-25 -13-6 -17-8 -18-15 -8-9 -18-16 SBP DBP -35-28 -45-30 140 160/150* 180 140 160/150* 180 n=274 n=220 n=36 n=135 n=114 n=17 * 150 mm Hg in Type II Diabetes P<.0001 for all values compared to baseline except: Mahfoud F, EuroPCR 2013 p=0.0002 (SBP 180 mm Hg, 6 mo) p=0.0008 (DBP 180 mm Hg, 6 mo)

Change in ABPM According to Baseline Measurement 0 3 Months 6 Months P <.0001 P=.0020 P <.0001 P=.0021 P=.0195 P=.0619 P <.0001 P=.0183 P <.0001 P=.0256 P=.0156 P=.0421-10 -3-4 -4-4 BP change (mmhg) -20-8 -10-11 -11-11 SBP DBP -30-13 -19-40 140 160/150* n=104 n=76 * 150 mm Hg in Type II Diabetes -22 180 n=10 140 n=34 160/150* n=30 180 n=5 Mahfoud F, EuroPCR 2013

Conclusions Preliminary data demonstrated excellent procedural and clinical safety profile of renal denervation in a real world population Majority of patients treated resembled current consensus statements Early look at clinical data showed RDN had a significant reduction in both Office and Ambulatory BP compared to baseline Enrolment and analyses continue to meet goal of establishing procedure safety and efficacy of the Symplicity Flex catheter Mahfoud F, EuroPCR 2013

Design Symplicity HTN-3: Overview Multicenter (90 sites in the United States), prospective, randomized, blinded, controlled study Population 530 patients with treatment-resistant hypertension Treatment Treatment group (endovascular catheter-based RDN with the Symplicity Renal Denervation System plus baseline antihypertensive medications) Control group (sham procedure * plus baseline antihypertensive medications) Primary Outcome Measures Change in office SBP from baseline to 6 months Safety * The renal angiogram also acts as the sham procedure for patients in the control group. Data on file, Medtronic.

Symplicity HTN-3 Trial: Study Design Office SBP? 160 mmhg Full doses of? 3 meds Initial past 2 wks Screening No plan to change meds for 6 M Initial Screening 2 weeks Home BP & Med Diary Confirmatory Screening ABPM Treatment Renal Angiogram Control 1M 3M 1M 3M 2 weeks Home BP & Med Confirmation 2 weeks 6M Primary Endpoint Home BP & Med Confirmation 6M 12-36M Patient and Research staff assessing BP are blinded to treatment status No changes in medications for 6M 41

Symplicity HTN-3 Trial: Exclusion Criteria Hemodynamically or anatomically significant renal artery abnormalities or stenosis (>50%) or prior renal artery intervention egfr < 45 ml/min/1.73m 2 (MDRD formula) In-patient hospitalization for HTN Crisis in past year 24 hour average ABPM SBP <135mm/Hg Type 1 diabetes mellitus Symptomatic orthostatic hypotension in past year Stenotic valvular heart disease for which BP would be hazardous MI, unstable angina, or CVA in the prior 6 months Planned surgery or CV intervention within the next 6 months Known primary pulmonary HTN Known pheochromocytoma, Cushing's disease, coarctation of the aorta, hyperthyroidism or hyperparathyroidism Known alcohol or drug abuse

Symplicity HTN-3: Summary Office SBP >160mmHg 3 antihypertensive medications (one must be a diuretic) On stable, 3 full tolerated dose antihypertensive medication regimen for at least 2 weeks No significant renal insufficiency (egfr < 45 ml/min) Meets inclusion/exclusion criteria by general medical review No known renal artery anatomy exclusion (i.e. dual renal arteries, known RA stenosis >50%) Until 6 month primary endpoint: Patients must remain blinded No changes in medication unless medically necessary After 6 mo endpoint, control patients can crossover if still meet all initial criteria

Summary We can do a better job with HTN recognition and management Data for renal denervation thus far is very positive Renal denervation is coming (already approved in Europe) for refractory/resistant HTN

Questions?