Resistant Hypertension- the role of Renal Denervation Therapy Ravi Nair MD, FACC
Hypertension Over 1 billion people worldwide1 Hypertension accounts for over 7 million deaths worldwide annually6 hypertension is a major risk for MI, CVA, CHF For every 20 mmHg rise in SBP , the risk of cardiovascular death doubles3,4 12.8% of drug-treated hypertension patients are resistant hypertension5
.Kearney PM, et al. Global burden of hypertension: Analysis of worldwide data. Lancet. 2005;365(9455):217-23. 1 Roger VL, et al. Heart disease and stroke statistics–2011 update: A report from the American Heart Association. Circulation. 2011;123(4):e18-e209. 2 . Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-13. 3 .Chobanian AV, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA. 2003;289:2560-2572. 4 Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011;57(6):1076-80. 5 Schmieder RE, et al ESH Position Paper: Renal Denervation – an interventional therapy of resistant hypertension; Journal of Hypertension 2012; 30:837-841. 6
Background
• The sympathetic nervous system, in particular renal sympathetic efferent and afferent nerves, is critical in the hypertension disease process • Disruption of renal sympathetic nerves has long been considered an attractive therapeutic target for this condition
Renal Sympathetic Nerves and HTN
Activation of the Efferent renal sympathetic nerves leads to1 – – – –
Increase in renovascular resistance and decrease in renal blood flow Increase in renin release and RAAS activation Increase in sodium and fluid retention Development or worsening of hypertension Afferent Renal Sympathetic Nerves
Activation of the Afferent renal sympathetic nerves leads to1 – Hypertension – Acceleration of cardiovascular diseases
Efferent Renal Sympathetic Nerves
Surgical splanchnicectomy (Smithwick RH, Thompson JE)
“Splanchnicectomy for essential HTN, results in 1,266 cases” JAMA 1953; 1952 • NR trial from 1938 to 1947 • Surgery on 1,266 patients and medical Rx in 467 • 5 year mortality 19% vs 54% • Upto 10 years BP control
XXX CAD
Anatomical Location of Renal Sympathetic Nerves •Arise from T10-L1 •Follow the renal artery to the kidney
Anatomical Location of Renal Sympathetic Nerves • Primarily lie within the adventitia Vessel Lumen Media
Adventitia Renal Nerves
Renal Denervation  Interruption of both efferent and afferent renal fibers  Renal denervation is a catheter-based ablation procedure in which lesions are created along the walls of the renal arteries to disrupt the sympathetic nerve network located within the arterial adventitia 1 Catheter Delivered Lesions
Esler MD, Symplicity HTN-2 Investigators, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet. .2010;376(9756):1903-9
1
RF Ablation Approach to Renal Sympathetic Denervation Electrode
Insulated arch wire
Symplicity速 Catheter System, Ardian, Inc., Palo Alto, CA, USA now from Medtronics
Treatment by Renal RF Catheter
6-Month Histology (Porcine Model) Movat’s pentachrome stain
cutting artifact
Zone of energy delivery
20X magnification
100X magnification
Findings: Minimal intimal thickening and minimal IEL injury overlying areas of mild full thickness medial fibrosis (yellow with green [proteoglycan deposition]), and adventitial fibrosis (yellow). No significant inflammatory cells are present suggesting that the healing process is complete.
Renal Sympathetic Denervation First in Man Study Symplicity Study
Study Sites
• Melbourne, AU (x2) • Newcastle, AU • Krakow, Poland • Frankfurt, Germany
Study Aims • To perform a first-in-man 12-month evaluation of the safety and blood pressure-lowering efficacy of percutaneous renal sympathetic denervation in patients with refractory hypertension
Inclusion/Exclusion Criteria Key Inclusion Criteria • Office SBP ≥160 mmHg despite 3+ antihypertensive medications (including diuretic), or confirmed intolerance to medications • eGFR (MDRD formula) of ≥ 45 mL/min/1.73m2 Key Exclusion Criteria • Known secondary cause of hypertension • Type I diabetes mellitus • Currently taking clonidine, moxonidine, or rilmenidine • Renovascular abnormalities: significant renal artery stenosis, prior renal stenting or angioplasty, dual renal arteries
Study Endpoints Primary Endpoints • Peri-procedural and long-term safety • Office blood pressure levels
Secondary Endpoints • Ambulatory blood pressure monitoring • Renal norepinephrine spillover rate • Renal function (eGFR)
Baseline Patient Characteristics Patients Undergoing Procedure (N=45)
Patients Anatomically Ineligible for Procedure (N=5)
58 ± 9
51 ± 8
Gender (% female)
44
20
Race (% non-Caucasian)
4
0
Diabetes Mellitus II (%)
31
40
CAD (%)
22
20
Heart Rate (bpm)
72 ± 11
79 ± 9
eGFR (mL/min/1.73m2)
81 ± 23
95 ± 15
177/101 ± 20/15
173/98 ± 8/9
Age (years)
BP (mmHg)
Baseline Patient Characteristics Patients Undergoing Procedure (N=45) Number of anti-HTN meds (mean)
Patients Anatomically Ineligible for Procedure (N=5)
4.7 Âą 1.5
4.6 Âą 0.5
ACE/ARB (%)
96
80
Beta-blocker (%)
76
100
Calcium channel blocker (%)
69
100
Vasodilator (%)
18
0
Diuretic (%)
96
60
Results Office BP: All Treated Patients
* *
*
*
*
*
*
*
Repeated measures ANOVA: P=0.026 for SBP, P=0.027 for DBP *P<0.001 vs baseline BP
n=45
*
Copyright Š 2011 American Heart Association. All rights reserved. Print ISSN: 0194911X. Online 72514 Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/HYPERTENSIONAHA.110.163014
;Hypertension 2011;57;911-917; originally published online Mar 14, 2011 Symplicity HTN-1 Investigators Durability of Blood Pressure Reduction Out to 24 Months Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension
Symplicity Study
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: 376:1903-1909
29
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: 376:1903-1909
30
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: 376:1903-1909
31
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: 376:1903-1909
32
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: 376:1903-1909
33
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: 376:1903-1909
34
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: 376:1903-1909
35
Sustained effect of RDS â&#x20AC;˘ Randomized Clinical Trial Data Show Medtronic Symplicityâ&#x201E;˘ Renal Denervation System Continues to Demonstrate Significant Blood Pressure Reduction in All Treatment Groups 18-Month Update from the Symplicity HTN-2 Randomized Clinical Trial Presented at ESC Congress 2012
Symplicity HTN-3 • The Symplicity HTN-3 study is a, multi-center, prospective, single-blind, randomized, controlled study of the safety and effectiveness of renal denervation in subjects with uncontrolled hypertension. • Bilateral renal denervation will be performed using the Symplicity Catheter - a percutaneous system that delivers radiofrequency (RF) energy through the luminal surface of the renal artery • 530 patents to be randomized
Methods of renal denervation(1) • Symplicity catheter (Medtronic)-single electrode RFA • EnligHTN (St. Jude’s)-multi-electrode basket design; 4 RFA sites at once results in less time and pain-ARSENAL trial-Oct 2011 to March 2013 in Greece and Australia, 47 pts • Vessix V2 RDS (Vessix Vascular Inc, CA)OTW low pressure balloon with bipolar RFA electrodes, REDUCE-HTN trial Feb 2012 to Aug 2014 in Eur, Australia- 64 pts
Methods of renal denervation(2) • OneShot catheter(Maya Medical, Campbell,CA)-RAPID trial in Eur, NZ May 2012 with 40 pts • ThermaCool RDS (Biosense Webster,CA)saline irrigated to ablate endoluminal surfaceSWAN-HTN trial Aug 2011 to Aug 2016 with 800 pts • Chilli II –irrigation balloon (BosSci) SAVE trial May 2012 to Dec 2019 with 500 pts
Methods of renal denervation(3) • ULTRASOUND Ablation- PARADISE catheter(ReCor Medical, NY) 6fr catheter with self centering balloon- REALISE study with 20 pts • Therapeutic IVUS catheter system (TIVUS – Cardiosource, Tel Aviv) • Non-invasive US(Kona Medical, Bellevue, WA)-external energy • Pharmacological ablation with neurotoxins (vincristine, guanethedine) via Bullfrog balloon catheter
EnligHTNâ&#x201E;˘ Renal Denervation System
Predictable Lesion Pattern by the EnligHTNâ&#x201E;˘ System
Acute
One Month
Non HTN effects of RED
Small study finds renal denervation reduces AF ď Ž
ď Ž
Renal-artery denervation can help to reduce the recurrence of atrial fibrillation in concert with pulmonary-vein isolation (PVI) in patients with drug-resistant hypertension, results of a small study show [The 13 patients who got both procedures showed significant reductions in average systolic pressure (from 181 to 156 mm Hg, p<0.001) and diastolic blood pressure (from 97 to 87 mm Hg, p<0.001), while there was no significant blood-pressure improvement in the PVI-only group. Nine of the 13 patients (69%) treated with both procedures were completely AF-free at the one-year postablation follow-up examination vs only four of the 14 patients (29%) in the PVI-only group (p=0.033).
Renal denervation improves ventricular systolic function in heart failure patients
Summary • Therapeutic renal sympathetic denervation involves a brief, simple percutaneous procedure • No major complications were observed to either the renal artery or the kidney • Significant and sustained reductions in blood pressure were achieved in patients with resistant hypertension • Large Prospective randomized controlled trials are required to definitively determine the role of this therapy in hypertension