Renal Denervation: The Case for Cardiology

Transcription

1 Renal Denervation: The Case for Cardiology John C. Gurley, MD University of Kentucky Presenter Disclosure Information John C Gurley, MD Renal Denervation: The Case for Cardiology FINANCIAL DISCLOSURE: Investigator: Medtronic (SYMPLICITY HTN), St. Jude Medical (EnligHTN) Grants: None related to this topic Speakers Bureau: None related to this topic Development Interests: None related to this topic UNLABELED/UNAPPROVED USES DISCLOSURE: This presentationmay describe hardware that has been modified and/or utilized in a manner that is not consistentwith labeled instructionsfor use. Access Surgery Interventional Nephrology Vascular Surgery Financial Interests Investors Entrepreneurs Device Companies Benefits Managers Many Others Interventional Cardiology EP (Electrophysiology) Interventional Radiology Patient Care Interests Heart Failure Specialists Primary Care Physicians Nephrologists Patients Many Others Hypertension is a global epidemic More than 1/4 th of the population now has hypertension 1 By year 2025, 1.56 billion (29%) are projected to have hypertension 1 HTN 1. Kearney PM, et al. Lancet. 2005;365: Medtronic paid $800 million to acquire RDN assets from Ardien Inc. Final 3-year results of SYMPLICITY HTN-1 Open-label study enrolled 153 patients, 111 consented to follow-up Estimated that it would gain U.S. approval for their SYMPLICITY device by 2015 Banked on RDN as one of two major products that would drive future sales growth 1. Krum H, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:

2 Results of the SYMPLICITY HTN-2 Trial 1 Randomized, non-blinded trial with 190 patients qualified by office BP European Society of Cardiology Position Statement on Renal Denervation Current evidence from the available clinical trials strongly support the notion that catheter-based radiofrequency ablation of renal nerves reduces blood pressure and improves blood pressure control in patients with drug-treated resistant hypertension, with data now extending out to 36 months. P < Accordingly, renal denervation can be considered as a therapeutic option in patients with resistant hypertension, whose blood pressure cannot be controlled by a combination of lifestyle modification and pharmacological therapy according to current guidelines Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376: Mahfoud F, Eur Heart J.2013 Apr 25. [Epub ahead of print] SYMPLICITY HTN-3 Pivotal Trial Adequate sample of 535 patients Randomized, blinded, placebo controlled Sham control group with angiography only Rigorous entry criteria for drug-resistant HTN >160 mmhg Ambulatory BP monitoring Status of Renal Denervation January 9,

3 CARDIOLOGISTS: THE ORIGINAL EARLY ADOPTERS Those cardiologists are smart thinkers Lesson #1 If it sounds too good to be true, it probably is. I hear they re still working on renal denervation!! The Autonomic Nervous System Still present after Medtronic s press release! A Positive Feedback Loop in Heart Failure Illustration: Sobotka PA. The Role of Renal Denervation in the Treatment of Heart Failure. Curr Cardiol Rep (2012)14: Drugs for Heart Failure (Not Great) Cornerstone of HF treatment ACEIs & ARBs block renin-angiotensin-aldosterone Beta blockers for the sympathetic nervous system Improved mortality, hospitalization and QOL Drugs provide incomplete sympathetic blockade and are poorly tolerated in HF α1-adrenergic agents are contraindicated in CHF patients because they expand extracellular and plasma volumes Drugs represent a shotgun approach that targets all compensatory mechanisms whether harmful or beneficial The hope for non-drug options in HF Target the renal contribution to central sympathetic drive without blunting other (beneficial) compensatory mechanisms Reverse the effects of increased α-adrenergic tone on renal blood flow, tubular excretion of sodium, and systemic vasoconstriction Eliminate the release of other transmitters (neuropeptide Y) that contribute to sympathetically-mediated renal vasoconstriction SYMPLICITY-HF and REACH will provide insight 3

4 Renal Denervation in Heart Failure Sympathetic Nerves and Cardiac Arrhythmias Renal nerves are activated in heart failure (HF) Key role in pathogenesis and progression of HF Renal efferent (sympathetic) activation causes renin release, sodium and water retention, and reduced renal blood flow Renal norepinephrine spillover predicts reduced survival Renal afferent (sensory) nerves trigger a reflex increase in sympathetic tone Contributes to the progression of CHF Surgical renal denervation in experimental HF improves both cardiac and renal function Illustration: Atrial Autonomic Innervation: A Target for Interventional Antiarrhythmic Therapy? Linz D, et.al. J Am Coll Cardiol 2014;63: Autonomic Targets for Arrhythmia Ablation RDN for suppression of cardiac arrhythmias Antiarrhythmic effects of RDN superior to drugs (amiodarone, sotalol, BBs) in animal models 1 Improved AF rate control in humans 2 Structural and electrophysiological remodeling (HR, BP, blood volume, hypertrophy, fibrosis, stiffness, loading, sympathetic tone, etc. 3,4 Illustration: Atrial Autonomic Innervation: A Target for Interventional Antiarrhythmic Therapy? Linz D, et.al. J Am Coll Cardiol 2014;63: Linz D, et al. Combined blockade of early and late activated atrial potassium currents suppresses atrial fibrillation in a pig model of obstructive apnea. Heart Rhythm. 2011;8: Ukena C, et al. Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension. Int J Cardiol 2013;167: Pokushalov E, et al. A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation. J Am Coll Cardiol 2012;60: Schoonderwoerd BA, et al. New risk factors for atrial fibrillation: causes of not-so-lone atrial fibrillation. Europace 2008;10: RDN and Recurrence of Atrial Fibrillation 1 Drug-resistant HTN is still a major cardiovascular problem 1. Pokushalov E, et al. A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60:

5 Each 20/10 mmhg doubles IHD mortality 1 Ischemic heart disease mortality risk doubles with each 20/10 mmhg increase in BP Lowering BP by 10/5 mmhg = 40% lower risk of stroke death 30% lower risk of ischemic heart disease death Interpreting the SYMPLICITY HTN-3 Press Release CAUTION: the actual data have not been presented It is unfair to abandon neural modulation as a treatment for HTN after one press release Patient selection, device and technique of RDN may be important SYMPLICITY system is a first generation device with issues of energy delivery, wall contact, lesion depth, distribution of lesions, completeness of denervation 1.Ischemic heart disease mortalityand BP. LewingtonS, et al. Lancet. 2002;360: An Equal Opportunity University Magnitude of BP Reduction Expected from Renal Denervation 1 Insights from meta-analysis of drug and RND trials In un-blinded trials, office BP drops were 27.6 mm Hg versus pretreatment, and 26.6 mm Hg versus controls. Discrepancies in drug trials between office and ambulatory blood pressure reductions disappear once double-blinded placebo control is implemented Office BP drops should match the ambulatory drops (10 to 15 mmhg range) Lesson #2 It s never as good as it seems or as bad as it seems. 1. Howard JP1, NowbarAN, Francis DP. Size of blood pressure reduction from renal denervation:insights from meta-analysisof antihypertensive drug trials of 4,121 patients with focus on trial design: the CONVERGE report. Heart. 2013;99(21): This is the beginning, not the end of renal denervation for treatment of hypertension. 5

6 Thank you! White Coat Effect in Early Renal Denervation Trials Relationship Between Trial Design and Office BP Reduction in Renal Denervation 1 There was an average mm Hg reduction in white coat effect. 1. Howard JP1, NowbarAN, Francis DP. Size of blood pressure reduction from renal denervation:insights from meta-analysisof antihypertensive drug trials of 4,121 patients with focus on trial design: the CONVERGE report. Heart. 2013;99(21): Howard JP1, NowbarAN, Francis DP. Size of blood pressure reduction from renal denervation:insights from meta-analysisof antihypertensive drug trials of 4,121 patients with focus on trial design: the CONVERGE report. Heart. 2013;99(21): Magnitude of effect Target population Optimum technique Key questions Treatment-Resistant Hypertension Prevalent o 5% in general practice 1 o 50% in nephrology clinics 2 o 12.8% of drug-treated adults in the US 3 Dangerous o 3X risk CV events versus controlled HTN 4 1. Calhoun DA, et al. Circulation. 2008;117:e510-e Kaplan NM. J Hypertens. 2005; 23: Persell SD. Hypertension. 2011;57: Doumas M, et al. Int J Hypertens. 2011;doi: 4061/2011/

7 Dozens of Competing RDN Technologies Endovascular Renal Denervation Objectives: Assess procedural and long term safety of renal denervation Evaluate effectiveness of renal denervation on clinical outcomes Evaluate the effect of geographical variations in patients and procedural characteristics on clinical outcomes Perform Quality of Life analysis Scope: Over 200 sites world wide; at least 5000 patients Prospective, single-arm, open-label, non-interventional registry Geographies with commercial availability of Medtronic Symplicity Renal Denervation System SJM EnligHTN System 4-channel RF generator 4-electrode basket Even lesion pattern Likely advantages Improved pattern consistency Reduced contrast and x-ray doses Reduced procedure time (~7 minutes per kidney) 1 1. Börgel J, Vessix V2 RFA Catheter 3 Analysis of Simplicity 3 Crash 7

8 OneShot RFA catheter Ultrasonic Renal Denervation Single balloon based-treatment, designed to provide desired helical treatment pattern during RFA eliminating user variance Irrigated catheter tip reduces the risk of overheating and clot formation during RFA delivery. TIVUS Ultrasonic Catheter EP Catheters (RF and cryo) 3 Pharmacologic Renal Ablation: Bullfrog Microinfusion Catheter Schlaich MP, et al. New Engl J Med. 2009;361: Renin release Vo ume expa sio Increased Angiotensin II RBF GFR Renal vasoconstriction 8

9 Hard Lesson #1 If it sounds too good to be true, it probably is. Hard Lesson #2 Hard Lesson #3 It s never as good as it seems or as bad as it seems. Procedures don t work for lifestyle diseases. Hard Lesson #4 Hard Lesson #5 Complex diseases seldom have simple cures. Medicine is biased toward DOING PROCEDURES, not thinking 9

10 Status of Renal Denervation: 2014 Heart Failure Normal compensatory mechanisms become counterproductive in CHF CHF patients often develop renal dysfunction Activation of renal sympathetic efferent nerves renin release sodium and water retention reduced renal blood flow Functional Anatomy of the Renal Nerves Renal nerve terminals contain neurotransmitters neuropeptide Y and norepinephrine Sympathetic activation causes constriction of (afferent > efferent) arterioles to the glomerulus (GFR). Renal sympathetic tone influences RBF and GFR, which influences sodium and water retention Despite Hypertension Treatment, Many Patients Are Not Controlled 1 Country Men in Developing Countries Men in Developed Countries Women in Developing Countries Prevalence (%) 2 Aware (%) Treated (%) Controlled (%) xxx Women in Developed Countries Periera, M, et al. J Hypertens May;27(5): Proportion of control among treated hypertensive patients 3. Age-adjusted predictions Renal Denervation Theory Neurohormones Blood Pressure What drives treatment-resistant hypertension? Disrupt the renal nerves, break the cycle Simultaneously reduce both efferent & afferent effects Adapted from Schlaich MP, et al. Hypertension. 2009;54:

11 Chronic Effect of Increased Sympathetic Nerve Activity Simplicity HTN-2 Blood Pressure Hypertension Wall Thickness Compliance Atherosclerosis Hypertrophy Ischemia Arrhythmia Heart Failure Worsening HF GFR Ischemia Kidney Failure Adapted from Schlaich MP, etal.. Hypertension. 2009;54: Simplicity HTN patients over 18 months ( ) 24 centers in Poland, Germany, New Zealand, Australia Inclusion: Office SBP 160 on 3+ meds ( 150 if diabetic ) with suitable renal artery anatomy BP qualified with 2 weeks of med dosing diary Exclusion: Unsuitable renal artery anatomy, egfr <45 ml/min, type I diabetes, major comorbidities SYMPLICITY-HTN-1 Trial Nonrandomized, proof-of-concept study 153 patients with resistant HTN SBP 160 on 3 medications (including 1 diuretic Key exclusions GFR <45 ml/min/1.73m 2 Type 1 diabetes Known secondary hypertension Significant renovascular disease BP Change (mm Hg) SYMPLICITY-HTN-1 Trial: 36-Month Results P < 0.01 for from BL for all time points 1 Mo (n = 143) 3 Mo (n = 148) Mo (n = 144) Mo (n = 132) Mo (n = 105) Mo (n = 34) -16 Systolic BP Diastolic BP 1. Sobotka P. Symplicity HTN-1: Long-term follow-up of catheter-based renal sympathetic denervation for resistant hypertension confirms durable blood pressure reduction. Presented at: ACC, March 2012,Chicago 11

12 SYMPLICITY-HTN-1 Trial: Distribution of Office SBP 1 Symplicity Staged Evaluation First-in-Man 1 13% 9% 1% 1% 11% 1% Additional Pilot Studies = Symplicity HTN % 21% 26% 35% 42% 57% 180 mm Hg Symplicity HTN-2 3 EU/AU Randomized Clinical Trial 65% 39% mm Hg mm Hg 40% <140 mm Hg 35% 41% 22% 5% Baseline 1 Mo 12 Mo 24 Mo 36 Mo (n = 150) (n = 143) (n = 132) (n = 105) (n = 34) 1. Sobotka P. Symplicity HTN-1: Long-term follow-up of catheter-based renal sympathetic denervation for resistant hypertension confirms durable blood pressure reduction. Presented at: ACC.12 61st Annual Scientific Sessions, March 2012, Chicago USA SYMPLICITY HTN-3 4 Continued use restricted to FDAapproved clinical trial sites SIMPLICITY-4 (Medtronic) EnligHTN (St. Jude Medical) Approved Countries Global SYMPLICITY Registry Heart Failure Insulin Resistance Sleep Apnea Other Areas of Research 4 1. Krum H, et al. Lancet. 2009;373: ; 2. Symplicity HTN-1 Investigators. Hypertension. 2011;57: ; 3. Symplicity HTN-2 Investigators. Lancet. 2010;376: Data on file, Medtronic. The problem with surgery Targeting Renal Sympathetic Nerves Arborize around artery Vessel Lumen Media Adventitia Significant morbidity, unpredictable results and the development of antihypertensive medications led to the abandonment of surgical sympathectomy by Gewirtz JR, et al. Cardiol J. 2011;18: Nerves Data on file. Medtronic, Inc.Renal nerves arise T10-L2 1 Located mainly in adventitia 1. Doumas M, et al. Renal sympathetic denervation and systemic hypertension. Am J Cardiol. 2010;105: Catheter-based & Interventional Renal Nephrology Denervation 5mm flex tip 12mm deflectable shaft Spiral Pattern 12

13 Safety profile: six month post- procedure histology (porcine model) Medial injury Heart Failure Intact endothelium by 7 days Vascular healing observed at 30, 60 and 180 days No inflammatory cells indicating complete healing process No stenosis or luminal reduction seen in any treated artery through 180 days Rippy MK, et. al. Clin Res Cardiol. 2011;doi:101007s Arrhythmias Hypertension Status of Renal Denervation December, 2013 Antiarrhythmic drugs are not very good 13

14 The Heart-Brain-Kidney Connection 1 Central Sympathetic Drive in Hypertension 80 Sympathetic Activity per Minute s-msna # * Baseline activity (normo-tensives) 0 Normotensives High Normals White Coat Borderline Hypertension Essential Hypertension (Stage 1) Essential Hypertension (Stage 2/3) Essential Hypertension With LVH 1. Bunte C, et al, JACC Cardiovasc Interv Jan;6(1): Smith P, et al. Am J Hypertens. 2004; 17: Renal Sympathetic Activity 1 Spillover Norepinephrine Levels Renal Denervation to Treat HTN Central Sympathetic Activity 2 Muscle Sympathetic Nerve Activity (MSNA) Dr. Reginald H. Smithwick Photo of Dr. Smithwick reproduced with permission from JAMA. Results from Surgical Sympathectomy 1 Overall mortality rate at 5 years: 19% surgical, 54% medical Survival rate of normal population Age 43 Group 1 Group Group 1 2 % Survival Group 2 Group 3 30 Group 4 20 Group 3 Surgicaln = Group 4 Medicaln = Time in Years 1. Adapted and reproduced with permission from Smithwick RH, Thompson JE. JAMA. 1953;152: Gewirtz JR, et al. Cardiol J. 2011;18: