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Renal Nerve Denervation in Resistant Hypertension 강동경희대학교병원 심장혈관센터 김종진 CASE 1 M/41 PMHx DM / HTN / Hep / Tb ( - / + / - / - ) HTN: 1 yrs (not-controlled) + medication for 4 yr Medications amlodipine 10mg / olmesartan 40mg / nebivolol 5mg / indapamide 1.5mg 160/95 mmHg (for 6 months) Lab. Findings AST/ALT: 41/92 IU/L ECG: LVH with strain pattern Chest PA: normal CASE 2 F/53 PMHx DM / HTN / Hep / Tb ( + / + / - / - ) HTN: medication for 10 yrs Medications amlodipine 5mg / losartan 100mg / carvedilol 25mg / indapamide 1.5mg 160/90 mmHg (for 6 months) Lab. Findings HbA1C: 8.0% ECG: NSR Chest PA: mild cardiomegaly CASE 3 M/56 PMHx DM / HTN / Hep / Tb ( - / + / - / - ) HTN: 15 yrs (not-controlled) + medication for 1 yr Medications nifedipine oros 60mg / hydrochlorthiazide 25mg / perindopril 8mg / nebivolol 2.5mg / doxazosin 2mg 165/85 mmHg (for 7 months) Lab. Findings Cr 1.4 mg/dL GFR by MDRD: 52 ml/min/1.73 m2 / Hb 12.7 g/dL ECG: biatrial enlargement / LVH with strain pattern Chest PA: cardiomegaly CASE 4 M/50 PMHx DM / HTN / Hep / Tb ( + / + / - / - ) HTN: medication for 15 yrs Medications tenormin 50mg / amlodipine 10mg / olmesartan 40mg 160/100 mmHg (6 months) Lab. Findings FBS: 104 mg/dL ECG: incomplete RBBB Chest PA: no abnormality CASE 5 F/69 PMHx DM / HTN / Hep / Tb ( - / + / - / - ) HTN: medication for 6 months Medications amlodipine 5mg / omesartan 20mg / indapamide 1.5mg / bisoprolol 5mg 193/126 mmHg (for 1months) Lab. Findings ECG: NSR, LVH Chest PA: no abnormality CASE 6 F/59 PMHx DM / HTN / Hep / Tb ( - / + / - / - ) HTN: medication for 20yrs Medications nisoldipine 20mg bid / indapamide 1.5mg qd / diovan 80mg bid / bisoprolol 5mg bid 169/95 mmHg (for 2yrs) Lab. Findings ECG: sinus bradycardia Chest PA: no abnormality Unmet needs in hypertension therapy Blood pressure lowering -Goals often not reached Combination therapy -Mandatory in most cases Compliance -Poor Organ protection -Incomplete Healing -An illusion? HYPERTENSION A MAJOR PUBLIC HEALTH BURDEN 9 A Major Public Health Burden • Astonishing prevalence – 1 in 3 adults – 1 B people worldwide 1.6 B by 2025 • Single largest contributor to death • Dramatically increases risk of heart attack, stroke, heart failure, kidney failure & insulin resistance 10 Source: American Heart Association, World Health Organization Prevalence, Awareness and Therapy Hypertensives in Hypertensives,kno treated hypertensives controlled * and Germany wing that to be aff treated hyperten ected sives 16 millions 12 millions don´t know problem: 4 Mio. 8 millions don´t do 4 Mio. * = < 140/90 mmHg do little 6 Mio. 2 millions Drugs Work, But Not as Well as You May Think Current approach failing 30% Untreated – Physician inertia 35% Treated but Uncontrolled – Patient compliance – Resistant HTN 35% Treated & Controlled 12 Definition of Resistant Hypertension • Resistant hypertension – RR > 140/90 mmHg, despite treatmant with 3 drug classes including a diuretic AHA Statement Circulation 2008;117:e510ff Predictors of resistant hypertension •Advanced age •High sodium intake •Obesity •Renal condition •Sleep apnea •Diabetes •LVH AHA Statement Circulation 2008;117:e510ff For distribution only in markets where the Symplicity renal denervation system is approved. Not for distribution in the USA or Japan. Trademarks may be registered and are the property of their respective owners. © 2012 Medtronic, Inc. All rights reserved. UC201205566EE Catheter-Based Renal Denervation (RDN) WELL ESTABLISHED SCIENTIFIC FOUNDATION 20 Renal Sympathetic Connection • Role of kidneys & sympathetic nervous system in development & progression of HTN is well established • Pharmaceuticals modify physiology at intermediate steps in pathway • RDN attempts to break the cycle at its source 21 Renal Sympathetic Nerve Activity Kidney as Origin & Recipient of Central Sympathetic Drive • ↑ Contractility • ↑ Heart rate • Vasoconstriction Afferent Nerves Efferent Nerves Blood Pressure Schlaich et al. Hypertension. 2009;54(6):1195-1201. ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 22 Renal Sympathetic Nerve Activity Kidney as Origin & Recipient of Central Sympathetic Drive • Vasoconstriction • Atherosclerosis Afferent Nerves Efferent Nerves Blood Pressure ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function + Increase co-morbidities Schlaich et al. Hypertension. 2009;54(6):1195-1201. • ↑ Contractility • ↑ Heart rate • Hypertrophy • Arrhythmia • Heart Failure 23 Disrupts Renal Nerves, Lowering SNS Activity • ↑ Contractility • ↑ Heart rate • Hypertrophy • Arrhythmia • Heart Failure • Vasoconstrictio n • Atherosclerosis Afferent Efferent -- Renal Denervation (RDN)-Nerves Nerves Blood Pressure ↑ Renin Release RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow ↓ Kidney function - Decrease co-morbidities + Increase comorbidities Schlaich et al. Hypertension. 2009;54(6):1195-1201. 24 Proof of Principle Central Sympathetic Nerve Activity Muscle Sympathetic Nerve Activity (MSNA) Renal Sympathetic Nerve Activity Norepinephrine Spillover Reduction of Renal Contribution to Central Sympathetic Drive: MSNA in Resistant Hypertension Patient * 59 year old male on 7 HTN meds Baseline MSNA (burst/min) BP (mmHg) 56 161/107 1 mo 41 (-27%) 141/90 (-20/-17) 12 mo 19 (-66%) 127/81 (-34/-26) * Improvement in cardiac baroreflex sensitivity after renal denervation (7.8 11.7 msec/mmHg) Schlaich et al. NEJM. 2009; 36(9): 932-934. Proof of Principle: Related Changes in Underlying Physiology ∆ Baseline 1 mo 161/107 141/90 - left kidney 72 37 -48% - right kidney 79 20 -75% Office BP (mmHg) Renal NE spillover (ng/min) Total body NE spillover (ng/min) 600 348 -42% Plasma Renin (μg/l/hr) 0.3 0.15 -50% Renal Plasma flow (ml/min) 719 1126 57% LV Mass (cMRI) dropped 7% (from 78.8 to 73.1 g/m2) from baseline to 12 months Schlaich et al. NEJM. 2009; 36(9): 932-934. Renal Norepinephrine Spillover: 10 cases • Mean total renal norepinephrine spillover ↓ 47%, p=0.023 (95% CI: 28–65%) • Mean total body NE spillover ↓ 28%, p=0.043 (95% CI: 4–52%) Example Case: Left: 75 % reduction Right: 85 % reduction Esler et al. J Htn. 2009;27(suppl 4):s167. Schlaich et al. J Htn. 2009;27(suppl 4):s154. ESRD patient (M; 37 yrs) Submitted for publication Medication at baseline: Tritace 10 mg Avapro 300 mg Zanidip 20 mg Noten 50 mg Minoxidil 5 mg ESRD (FSGS), RRT since 04/2006 Dry Weight: 81 kg no change in HD regimen NTx August 2008 Medication at 33 M FU: Noten 50 mg Change in BP following bilateral denervation 156 95 Blood Pressure (mmHg) 180 160 140 133 120 100 80 81 60 baseline 3 d FU 30 d FU 90 d FU 33 months Sobotka Euro-PCR 2011 Renal Denervation – Summary of Background & Physiology• Trans-catheter Renal Denervation at least modulates central sympathetic over-drive • It might be a physiological treatment modality to treat sympathetic over-drive related disease – Hypertension – Sleep disturbances – Type 2 diabetes mellitus – …. Concept Validated by Surgical History 1952 Effective, but significant morbidity 32 A common question … How will the kidney function without sympathetic control? • Transplanted kidneys lack innervation • Yet effectively maintain fluid and electrolyte balance • Establishes that sympathetic component of control represents “overdrive” system, rather than foundation of basic renal function Blaufox et al. N Engl J Med. 1969;280(2):62-66. 33 A SIMPLER, MORE ELEGANT SOLUTION 34 Renal Anatomy Allows a Catheter-Based Approach Vessel Lumen Media • Arise from T10-L2 • Follow the renal artery to the kidney • Primarily lie within the adventitia • The only location that renal efferent & afferent nerves travel together Adventitia Renal Nerves 35 Symplicity® Catheter System™ • Low profile, electrode tipped catheter • Delivers RF energy to treatment site • Proprietary RF generator - Low power - Automated - Built-in safety control algorithms • Standard interventional technique • 40-minutes from first to last RF delivery In the United States: Caution: Investigational Device. Limited by Uni ted States law to investigational use. Anatomy of Renal Nerve Catheter-Based Approach • Standard interventional technique • 4-6 two-minute treatments per artery • Proprietary RF Generator − Automated − Low-power − Built-in safety algorithms Vascular Safety Predicted by Preclinical Studies • • • • Extensive research in >300 swines Angiography and pathology at 7, 30, 60 & 180 days No stenosis or luminal reduction seen in treated arteries RF Generator algorithm optimized to minimize vascular injury 39 Symplicity Catheter Tip Features Be familiar with the dimensions at the distal end of the catheter 5mm 12mm Flexible Tip Deflectable (self-orienting) Shaft Symplicity Catheter Handle Features Orange section of handle rotates shaft, and trigger flexes the catheter tip Deflect tip by pulling lever towards back of handle Handle rotator has tactile “click” every 45 degrees Dot on rotator gives relative rotational reference Straighten tip by pushing lever towards front of handle Targeting Renal Nerves • Treat distal to proximal • 4-6 focal treatments • 2 min per treatment • ≥ 5 mm between locations • Stable, unique locations • Circumferential coverage • Common strategy (dependent on renal a natomy): • Distal: Inferior and inferolateral locations • Proximal: Superior and superolateral locations • Avoid purely lateral treatments (possible electr ode movement with respiration) • PULL, ROTATE, ASSESS new location and prior treatment site 42 Procedure Overview Areas To Avoid There is no clinical experience treating near areas of visible disease, or in vessels with renal artery aneurysms • Avoid to treat the areas of visible disease – Such as atherosclerosis, calcification, and fibromuscular dysplasia Atherosclerosis (Ostial Stenosis) Avoid treating in segment with stenosis Calcification Avoid energy delivery to area with visible calcification Fibromuscular Dysplasia (FMD) Avoid treating in segment with FMD Angiographic Appearance – Typical Typical appearance to expect at one month post-procedure Pre-Procedure 1 Month Follow-Up Acute Post-Procedure SUMMARY -TECHNIQUE OF RENAL DENERVATION- • The generation 2 Symplicity catheter facilitates the procedure and increases procedure safety •Better catheter navigation •Less traumatic catheter tip •Better vessel wall adaption of the tip • Limitations: •Hostile aorta •Bended course of the renal artery trunk •Short renal artery trunk •Renal artery diameter < 4mm •Atherosclerotic plaques or FMD CLINICAL RESULTS 47 Comprehensive SYMPLICITY Clinical Trial Program follows over 5000 patients across multiple indications This report First-in-Man (AU) SYMPLICITY HTN-3 US Pivotal Trial (US) Series of Pilot Studi es (EU, US & AU) Symplicity HTN-1 Symplicity HTN-2 Initial RCT (EU & AU) Global SYMPLICITY Registry (Approved Regions) Expand HTN Indicat ion (Approved Regions) Post-Market Registry (US) Pilot Studies in New Indications (Approved Regions) SYMPLICITY HF Trials under way Results Recognized for their Importance Lancet. 2010. published electronically on Nov 17, 2010 49 Symplicity HTN-1 Lancet. 2009;373:1275-1281 Initial Cohort – Reported in the Lancet, 2009: -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) - 12-month data \ Expanded Cohort – This Report (Symplicity HTN-1): -Expanded cohort of patients (n=153) -24-month follow-up Sievert et al. European Society of Cardiology. 2010. Symplicity HTN-1: Groundbreaking series of Non-Randomised studies First in Man Cohort: • 45 patients, EU, Australia • Non-Randomised • First patient enrolled: June, 2007 • 12-month initial report in The Lancet, 2009 Expanded Cohort* (this report): • 153 patients, EU, Australia, USA • Non-Randomised • 36-month follow-up Key Inclusion Criteria • • • Office SBP ≥160 mmHg Stable drug regimen of 3+ more anti-HTN medications eGFR ≥45 mL/min/1.73m2 *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) Baseline Patient Characteristics Demographics Co-morbidities Blood Pressure Age (years) 57 ± 11 Gender (% female) 39% Race (% non-Caucasian) 5% Diabetes Mellitus II (%) 31% CAD (%) 22% Hyperlipidemia (%) 68% eGFR (mL/min/1.73m2) 83 ± 20 Baseline BP (mmHg) 176/98 ± 17/15 Number of anti-HTN meds (mean) 5.0 ± 1.4 ACE/ARB (%) 90% Beta-blocker (%) 82% Calcium channel blocker (%) 75% Vasodilator (%) 19% Diuretic (%) 95% Spironolactone (%) 21% Sievert et al. European Society of Cardiology. 2010. Procedure Detail & Safety • 38 minute median time from first to last ablation – Average of 4 ablations per artery • Intravenous narcotics & sedatives used to manage pain during delivery of RF energy • No catheter or generator malfunctions • No major complications • Minor complications 4/153: – 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae – 3 access site complications, treated without further sequelae Sievert et al. European Society of Cardiology. 2010. Chronic Safety (Through 3-Year Follow-up) • 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 unrelated to RF treatment (stented without further sequelae) • Three deaths within the follow-up period; both unrelated to the device or therapy • Two hypotensive events that required hospitalization • Unrelated to device or therapy (sepsis and hypovolemia, each) • No electrolyte disturbances • No change in renal function (∆ eGFR) • 12 Months: -2.9 mL/min/1.73m2 (n.s.) Sievert et al. European Society of Cardiology. 2010. Significant, Sustained BP Reduction 10 0 BP change (mmHg) Systolic Diastolic -20 -10 -24 -11 -25 -11 -23 -11 -26 -14 -32 -14 1M (n=138) 3M (n=135) 6M (n=86) 12 M (n=64) 18 M (n=36) 24 M (n=18) -10 -20 -30 -40 -50 Sievert et al. European Society of Cardiology. 2010. Significant, Sustained Blood Pressure Reductions to at Least 3 Years Change in Blood Pressure (mmHg) 10 Systolic Diastolic 0 -22 -10 -26 -13 -33 -15 -33 -19 6M (n=144) 1Y (n=130) 2Y (n=59) 3Y (n=24) -10 -20 -30 -40 p <0.01 for from baseline for all time points Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) Percentage Responders Increases Over Time Responder was defined as an office SBP reduction ≥10 mmHg (n=143) (n=148) (n=144) (n=130) (n=107) (n=59) (n=24) (n=24) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) Response Rate Among 1-Month Non-responders (n=45) (n=45) (n=44) (n=39) (n=17) *Non-responder defined as a SBP reduction of <10 mmHg (n=8) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) Symplicity HTN-1: SBP Distribution Significantly Improves After Renal Denervation – Lowering Risk of CV Events 100% 8% 90% 30% 80% 7% 11% 6% 6% 21% 70% 42% 60% >=180 mmHG 160-179 mmHg 35% 50% 40% 47% 140-159 mmHg <140 mmHg 65% 30% 20% 36% 40% 41% 10% 0% 5% Baseline (n=150) 1 year (n=132) 2 years (n=105) 3 years (n=34*) Expanded results presented at the Transcatheter Cardiovascular Therapeutics Annual Meeting 2012 (Schlaich, M.) Symplicity HTN-2 Lancet. 2010. published electronically on November 17, 2010 • • • Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomized, controlled, clinical trial Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control Clinical Sites: 24 centers in Europe, Australia, & New Zealand (67% were designated hypertension centers of excellence) Symplicity HTN-2 Investigators. The Lancet. 2010. Symplicity HTN-2 Inclusion Criteria: – Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) – Stable drug regimen of 3+ more anti-HTN medications – Age 18-85 years Exclusion Criteria: – Hemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention – eGFR < 45 mL/min/1.73m2 (MDRD formula) – Type 1 diabetes mellitus – Contraindication to MRI – Stenotic valvular heart disease for which reduction of BP would be hazardous – MI, unstable angina, or CVA in the prior 6 months Symplicity HTN-2 Investigators. The Lancet. 2010. Symplicity HTN-2: Patient disposition Assessed for Eligibility (n=190) Screening Randomised (n=106) 6-month P rimary End -Point Allocated to RDN n=52 Treated n=49 Analysable Excluded During Screening, Prior to Randomisation (n=84) BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) Ineligible anatomy (n=30; 16%) Declined participation (n=10; 5%) Other exclusion criteria discovered after consent (n=8; 4%) Allocated to Control n=54 Control n=51 Analysable Crossover n=46 2 LTFU 12-month Post- 12-month post-RDN n=47 Randomisation 18-month post-RDN n=43 * Crossed-over with ineligible BP (<160 mmHg) Per protocol, 6-mo Post-RDN (Crossover) n=35 18-mo Post-RDN (Crossover) n=31 Not-per-protocol*, 6mo Post-RDN (Crossover) n=9 RDN and Control Populations Well-matched, Severe Treatment Resistant Hypertensives RDN Control p-Value (n = 52) (n = 54) 178 ± 18 178 ± 16 0.97 Baseline systolic BP (mmHg) Baseline diastolic BP (mmHg) 97 ± 16 98 ± 17 0.80 Number anti-HTN medications 0.75 5.2 ± 1.5 5.3 ± 1.8 Age 58 ± 12 58 ± 12 0.97 Gender (female) (%) 35% 50% 0.12 Race (Caucasian) (%) 98% 96% >0.99 BMI (kg/m2) 31 ± 5 31 ± 5 0.77 Type 2 diabetes 40% 28% 0.22 Coronary artery disease 19% 7% 0.09 Hypercholesterolemia 52% 52% >0.99 eGFR (MDRD, ml/min/1.73m2) 77 ± 19 86 ± 20 0.013 Serum creatinine (mg/dL) 1.0 ± 0.3 0.9 ± 0.2 0.003 Urine alb/creat ratio (mg/g)* 128 ± 363 109 ± 254 0.64 Cystatin C (mg/L)† 0.9 ± 0.2 0.8 ± 0.2 0.16 n = 42 forrate RDN and n = 43 for Control. Wilcoxon rank-sum test for independent between-group comparisons of UACR. Heart (bpm) 75two± 15 samples used 71for± 15 0.23 * † n = 39 for RDN and n = 42 for Control. Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.) Primary Endpoint: 6-Month Office BP ∆ from Baseline to 6 Months (mmHg) Systolic Diastolic Diastolic Systolic • • 33/11 mmHg difference between RDN and Control (p<0.0001) 84% of RDN patients had ≥ 10 mmHg reduction in SBP 10% of RDN patients had no reduction in SBP Symplicity HTN-2 Investigators. The Lancet. 2010. Superior to Medical Management, Reductions Sustained to 12M Primary Endpoint (6M post Randomisation) Latest Follow-up (12M post Randomisation) 10 RDN (n= 49) 0 ∆ from Baseline to 6 Months (mmHg) Systolic Diastolic Diastolic p <0.01 for Systolic difference between RDN and Control Primary Endpoint: • 84% of RDN patients: ≥10 mmHg reductio n in SBP • 10% of RDN patients: no reduction in SBP ∆ from -10 Baseline to -20 12 Months (mmHg) -30 -40 -10 Diastolic -28 Systolic p <0.01 for -50 from baseline Latest Follow-up: •Control crossover (n = 35): -24/-8 mmHg (Analysis on patients with SBP ≥ 160 mmHg at 6 M) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.) Superior to Medical Management, Reductions Sustained to 18M Primary Endpoint (6M post Randomisation) RDN (n = 49) Control (n = 51) 10 10 1 0 ∆ from -10 Baseline to 6 Months-20 (mmHg) -30 -50 0 Systolic Diastolic -12 Diastolic -32 -40 Latest Follow-up (18M post Randomisation) Systolic p <0.01 for difference between RDN and Control Primary Endpoint: • 84% of RDN patients: ≥10 mmHg reductio n in SBP • 10% of RDN patients: no reduction in SBP RDN (n=43) 0 ∆ from -10 Baseline to -20 18 Months (mmHg) -30 -12 Diastolic -32 -40 -50 Systolic p <0.01 for from baseline Control Group Also Benefited From RDN After Crossover 220 n = 51 183 180 n = 37 191 178 n = 35 n = 49 Systolic BP (mmHg) 166 147 n = 49 140 n = 33 167 n = 31 162 151 n = 47 145 n = 43 Control Crossover RDN 100 Baseline 6M Baseline 6M Post-RDN 6M Post-RDN 12M Post-RDN 12M Post-RDN 18M Post-RDN 18M Post-RDN Sustained to 18 Months for RDN, Crossover, and Pooled Groups RDN Group 10 0 ∆ in BP from Baseline (mmHg) 10 Crossover Group 0 -10 -12 -8 -12 -20 -20 -30 -30 -32 -10 -11 n= 47 n= 43 -11 -28 -30 -28 -31 -32 -50 -12 -24 -40 n= 49 -12 -32 -40 -50 -10 -20 -24 -28 18-Month BP Reduction 0 -10 -10 10 -40 n= 35 n= 33 n= 31 -50 n= 43 n= 31 p <0.01 for from baseline n= 74 Systolic Diastolic Home & 24 Hour Ambulatory BP Home BP Change BP (mmHg) Change Systolic (mmHg) Diastolic Diastolic Systolic 24-h ABPM: • Analysis on technically sufficient (>70% of readings) paired baseline and 6-month • RDN (n=20): -11/-7 mmHg (SD 15/11; p=0.006 SBP change, p=0.014 for DBP change) • Control (n=25): -3/ -1 mmHg (SD 19/12; p=0.51 for systolic, p=0.75 for diastolic) Symplicity HTN-2 Investigators. The Lancet. 2010. Time Course of Office BP Change 1M 3M 6M 0 RDN ∆ from Baseline (mmHg) -7 †† -10 -20 -30 -20 -8 ††† † -24 † -32 † Systolic Diastolic -40 -50 -12 † p<0.0001 for between-group comparisons p=0.002 for between-group comparisons ††† p=0.005 for between-group comparisons Two-way repeated measures ANOVA, p=0.001 † †† 20 10 Control ∆ from Baseline (mmHg) 0 0 1 0 -4 -10 -20 -30 Systolic Diastolic Symplicity HTN-2 Investigators. The Lancet. 2010. -2 0 Procedural Safety • No serious device or procedure related adverse events (n=52) • Minor adverse events • 1 femoral artery pseudoaneurysm treated with manual compression • 1 post-procedural drop in BP resulting in a reduction in medication • 1 urinary tract infection • 1 prolonged hospitalization for evaluation of paraesthesias • 1 back pain treated with pain medications & resolved after one month • 6-month renal imaging (n=43) • No vascular abnormality at any RF treatment site • 1 MRA indicates possible progression of a pre-existing stenosis unrelat ed to RF treatment (no further therapy warranted) Symplicity HTN-2 Investigators. The Lancet. 2010. Other Safety RDN (n=49) Control (n=51) Hypertensive event unrelated to non-adherence to medication 3 2 Other CV events 0 0 Transient ischemic attack 1 2 Hypertensive event after abruptly stopping clonidine 1 0 Hypotensive episode resulting in reduction of medications 1 0 Coronary stent for angina 1 1 Temporary nausea/edema 1 0 Composite CV Events Other Serious AEs Symplicity HTN-2 Investigators. The Lancet. 2010. Renal Function Δ Renal Function Control Mean ± SD (n) Difference (95% CI) p-value (baseline - 6M) RDN Mean ± SD (n) eGFR (MDRD) 0 ± 11 1 ± 12 -1 (mL/min/1.73m2) (49) (51) (-5, 4) 0.76 Serum Creatinine 0.0 ± 0.2 0.0 ± 0.1 0.0 (mg/dL) (49) (51) (-0.1, 0.1) Cystatin-C 0.1 ± 0.2 0.0 ± 0.1 0.0 (mg/L) (37) (40) (-0.0, 0.1) Symplicity HTN-2 Investigators. The Lancet. 2010. 0.66 0.31 Renal Function 100 88.8 eGFR (mL/min/1.73m2) 80 78.2 77.1 76.9 Stage I 85.2 81.2 Stage II 60 Stage III 40 Stage IV 20 ESRD Stage V 0 n = 49 n = 35 Baseline n = 49 n = 35 6M post-RDN n = 45 n = 31 12M post-RDN RDN Crossover Symplicity RDN Safety Record Continues to be Strong in Expanded Results RDN N=47 Treated at Randomisation Baseline 6 month 12 months eGFR (ml/min/1.73m2) 76.9 ±19.3 (n= 49) 77.1±18.8 (n=49) 78.2±17.4 (n=45) Cystatin C (mg/L) 0.91±0.25 (n=38) 0.98±0.36 (n=40) 0.98±0.30 (n=38) Treated after 6-mo follow-up Crossover N=35 Baseline 6 month 12 months eGFR (ml/min/1.73m2) 88.8 ± 20.7 (n = 35) 89.3±19.5 (n = 35) 85.2±18.3 (n = 35) Cystatin C (mg/L) 0.78 ± 0.17 (n=27) 0.82±0.16 (n=26) 0.89±0.20 (n=26) Symplicity HTN-2 Investigators. The Lancet. 2010. Medication Changes at 6 and 12 Months Post-Renal Denervation RDN (n=47) 6 month 12 months Decrease (# Meds or Dose) 20.9% (9/43) 27.9% (12/43) Increase (# Meds or Dose) 11.6% (5/43) 18.6% (8/43) Crossover (n=35) 6 months post-RDN Decrease (# Meds or Dose) 18.2% (6/33) Increase (# Meds or Dose) 15.2% (5/33) Physicians were allowed to make changes to medications Once the 6 month primary endpoint was reached* *Further analysis of Medications is ongoing Impressive Safety Record • No device-related SAEs and vascular complications • No clinically significant changes to eGFR • Two hypotensive events that required hospitalisation • One in crossover cohort and 1 in RDN cohort • Ten hypertensive events requiring hospitalisation through 18 months post RDN in combined cohort • One mild transient acute renal failure • Two deaths within the follow-up period • All unrelated to the device or therapy Symplicity HTN-1 Three Year and Symplicity HTN-2 One Year Summary • Sustained BP Reductions to Three Years • First Symplicity HTN-1 patient treated June 2007 • Three year reporting shows no diminishment of effect and impressive long term safety • For patients that have completed 3 year follow up, 100% have been classified as responders (>10 mmHg reduction), while at 6 months 71% of patients were classified as responders. • Superior Results Confirmed in Randomised Study • Symplicity HTN-2 treatment population shows sustained treatment effect at 12 month follow-up • Control cross-over patients also show significant BP reduction Only the Symplicity™ renal denervation system has proven safe, superior and sustained BP reductions RENAL DENERVATION & INSULIN RESISTANCE Effects of Renal Denervation on Glucose Handling in Patients with Resistant HTN • • • • • • • Mahfoud et al. European Society of Cardiology. 2010. 25 Treatment, 11 Control Age 56.9 ± 10 years BMI 31.4 ± 5.5 kg/m² Type 2 DM on oral medication, n=15 No patients on insulin treatment Baseline BP: 178/94 ± 16/13 mmHg 5.6 ± 1.4 antihypertensive meds Reduction in HOMA Index at 1 & 3 Months following Renal Denervation Fasting Glucose (mg/dl) Fasting Insulin (mU/l) C-peptide (µg/l) HOMA-IR Baseline (25) 118 ± 20 20.7 ± 11.8 6.1 ± 3.6 6.1 ± 4.3 1 month (25) 110 ± 14* 12.9 ± 7.3* 3.3 ± 1.5* 3.5 ± 1.8* 3 months (25) 106 ± 12* 11.1 ± 4.8* 3.1 ± 1.1* 2.9 ± 1.3* Treatment Group *significant reduction (p<0.05) compared to baseline HOmeostasisModelAssessment-InsulinResistance (HOMA-IR) = (FPI x FPG)/405 Mahfoud et al. European Society of Cardiology. 2010. Change in Status: Diabetes (DM) Glucose Intolerance (GIT) Normal • Worsening of diabetic status: (normal glucose intolerance diabetes) - Renal Denervation: 0/25 - Control: 2/11 (18%) • Improvement in diabetic status: (diabetes glucose intolerance normal) - Renal Denervation: 4/25 (16%) - Control: 0/11 Mahfoud et al. European Society of Cardiology. 2010. Can Excessive NeuroStimulation Cause Heart Disease? • Can excessive sympathetic drive contribute to – Atrial fibrillation • High ventricular response to atrial fibrillation • Low conversion success – Ventricular tachyarrhythmias • Electrical Storm • Long QT pathology • Can sympathetic drive cause functional ventriular abn ormalities or systolic or diastolic function? • Is sympathetic stimulation related to overall cardiovascular death? CASE 1 Medications amlodipine 10mg / olmesartan 40mg / nebivolol 5mg / indapamide 1.5mg 160/95 mmHg (for 6 months) F/U; 2 weeks after RDN 147/87mmHg at office D/C amlodipine 180 160 140 120 100 80 60 40 20 0 SBP DBP 3/30 4/25 much improved subjective symptoms 7/27 10/26 CASE 2 Medications amlodipine 5mg / losartan 100mg / carvedilol 25mg / indapamide 1.5mg 160/90 mmHg (for 6 months) F/U; 1 month after RDN 116/73mmHg at home 154/87mmHg at office D/C amlodipine 200 180 160 140 120 100 80 60 40 20 0 SBP DBP 3/14 5/14 8/13 10/15 12/03 CASE 3 Medications nifedipine 60mg / hydrochlorthiazide 25mg / perindopril 8mg / nebivolol 2.5mg / doxazosin 2mg 165/85 mmHg (for 7 months) F/U; 2 weeks after RDN admission due to suicide (drug intoxication) same medication normal BP 180 160 140 120 100 80 60 40 20 0 SBP DBP 3/15 5/30 7/22 9/25 CASE 4 Medications tenormin 50mg / amlodipine 10mg / olmesartan 40mg 160/100 mmHg (6 months) F/U; 1 month after RDN normal BP at home 160/90mmHg at office same medications 200 150 100 SBP 50 DBP 0 10/24 5/2 7/5 1/23 CASE 5 Medications amlodipine 5mg qd / omesartan 20mg qd / indapamide 1.5mg qd / concor 5mg qd 193/126 mmHg (for 1months) F/U; 2wks after RDN 141/77mmHg at office same medications 250 SBP 200 DBP 150 100 50 0 6/4 6/25 9/24 CASE 6 Medications nisoldipine 20mg bid / indapamide 1.5mg qd / diovan 80mg bid / bisoprolol 5mg bid 169/95 mmHg (for 2yrs) F/U; 1 month after RDN occasionally high BP at home 138/84mmHg at office D/C nisodipine 180 160 140 120 100 80 60 40 20 0 SBP DBP 3/26 6/13 7/5 11/14 2/20 Conclusion Renal Sympathetic Nerve Denervation 1. Safe and effective in resistant hypertension treatment. 2. In the future, will be a promising interventional procedure for other territories with hypertension or for diseases with overdrive sympathetic activity.