Autumn Meeting Birmingham. Renal Denervation

Transcription

1 Autumn Meeting Birmingham Renal Denervation Andreas Baumbach, MD, FRCP, FESC Consultant Cardiologist, hon. Reader in Cardiology Bristol Heart Institute University Hospitals Bristol

2 Renal Denervation BACKGROUND

3 Background: Hypertension 230 million in Europe, Japan and US 1 billion worldwide every 20/10 mmhg above target BP cardiovascular mortality increases twice Stroke MI Renal Failure Death ~10% resistant HTN 30% treated & controlled 30% untreated 30% treated & uncontrolled WHO 2009 Vasan RS, et al. JAMA. 2002;287:

4 Renal Sympathetic Connection Role of kidneys and sympathetic nervous system in development and progression of HTN is established Main HTN Models: Sympathetic Overdrive Cerebral Blood Flow

5 Renal Sympathetic Nerve Activity: Kidney as Origin & Recipient of Central Sympathetic Drive Vasoconstriction Contractility Heart rate Efferent Nerves Afferent Nerves Blood Pressure Renin Release RAAS activation Sodium Retention Renal Blood Flow Schlaich et al. Hypertension. 2009;54(6):

6 Renal Sympathetic Nerve Activity: Kidney as Origin & Recipient of Central Sympathetic Drive Vasoconstriction Atherosclerosis Efferent Nerves Afferent Nerves Contractility Heart rate Hypertrophy Arrhythmia Heart Failure Blood Pressure + Increase co-morbidities Renin Release RAAS activation Sodium Retention Renal Blood Flow Kidney function Schlaich et al. Hypertension. 2009;54(6):

7 Renal Sympathetic Nerve Activity: RDN Disrupts Renal Nerves, Lowering SNS Activity Vasoconstriction Atherosclerosis Efferent Nerves Afferent Nerves -- Renal Denervation (RDN)-- Contractility Heart rate Hypertrophy Arrhythmia Heart Failure Blood Pressure - Decrease co-morbidities + Increase co-morbidities Renin Release RAAS activation Sodium Retention Renal Blood Flow Kidney function Schlaich et al. Hypertension. 2009;54(6):

8 Surgical History: Sympathectomy 1952 Effective, but significant morbidity

9 Effects of Denervation on Kidney Function 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.

10 Targeting Renal Nerves Nerves arise from T10-L2 The nerves arborize around the artery and primarily lie within the adventitia Vessel Lumen Media Adventitia Data on file. Medtronic, Inc. Renal Nerves

11 Treatment with the Symplicity Catheter Renal nerves lie in adventitia of the renal arteries Catheter delivers 4-6 two minute RF energy treatments to each renal artery Goal is to maximize renal nerve coverage without circumferential arterial energy delivery in a segment Symplicity Catheter System Ardian, Medtronic Inc., Palo Alto, CA, USA 6F compatible Articulating tip with RF electrode Designed for renal artery use In the United States: Caution: Investigational Device. Limited by U.S. law to investigational use.

12 Targeting Renal Nerves

13 Renal Denrvation THE SCIENCE

14 Vascular Safety Predicted by Preclinical Studies Extensive research in >300 swine Angiography and pathology at 7, 30, 60 and 180 days No stenosis or luminal reduction seen in treated arteries RF generator algorithm optimised to minimise vascular injury

15 Quantifying Human SNS Activity Central sympathetic nerve activity Muscle sympathetic nerve activity (MSNA) recording postganglionic nerve traffic Renal sympathetic nerve activity Norepinephrine spillover measuring transmitter release from sympathetic nerves to plasma

16 Proof of Principle Direct measurement of reduced central sympathetic nerve activity Denervation of Patient with Essential HTN Baseline 59-Year-Old Male on 7 HTN Meds MSNA (burst/min) BP (mmhg) /107 1 month 41 (-27%) 141/90 (-20/-17) 12 months 19 (-66%) 127/81 (-34/-26) Improvement in cardiac baroreflex sensitivity after RDN ( msec/mmhg) Schlaich et al. NEJM. 2009;36(9):

17 Renal NA Spillover (ng/min) Renal Norepinephrine Spillover: 10 Cases Mean total renal norepinephrine spillover 47%, p = (95% CI: 28 65%) Mean total body NE spillover 28%, p = (95% CI: 4 52%) Example Case Left: 75% reduction Right: 85% reduction Left Kidney Right Kidney % 75% 50 0 Baseline 30-Day Post Right Denervation 30-Day Post Left Denervation Esler et al. J Htn. 2009;27(Suppl. 4):s167. Schlaich et al. J Htn. 2009;27(Suppl. 4):s154.

18 Renal Denervation THE DATA

19 Staged Clinical Evaluation Symplicity HTN-1 First-in-man Series of pilot studies Symplicity HTN-2 EU/AU randomised clinical trial USA Symplicity HTN-3 US randomised clinical trial (upcoming) EU/AU Other areas of research Insulin resistance, HF/cardiorenal, sleep apnea, more

20 The Papers So Far The Lancet. Published electronically on Nov 17, 2010.

21 Symplicity HTN-1 The Lancet. 2009;373: Initial cohort reported in The Lancet, 2009: First-in-man, nonrandomised 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* Symplicity HTN-1: Expanded cohort of patients (n = 153) 24-month follow-up * Symplicity HTN-1 Investigators. Hypertension

22 Baseline Patient Characteristics Demographics Age (yr) 57 ± 11 Gender (female) (%) 39 Race (noncaucasian) (%) 5 Comorbidities Diabetes mellitus type 2 (%) 31 CAD (%) 22 Hyperlipidemia (%) 68 egfr (ml/min/1.73m 2 ) 83 ± 20 Blood pressure 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 Symplicity HTN-1 Investigators. Hypertension

23 Procedure Detail and Safety 38-minute median time from first to last ablation Average of 4 ablations per artery Intravenous narcotics and 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 sequellae 3 access site complications, treated without further sequellae Symplicity HTN-1 Investigators. Hypertension

24 Chronic Safety 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 sequellae) Two deaths within the follow-up period; both unrelated to the device or therapy No orthostatic or electrolyte disturbances No change in renal function ( egfr) 12 months: -2.9 ml/min/1.73m2 (n.s.) Symplicity HTN-1 Investigators. Hypertension

25 Significant, Sustained BP 10 Reduction Systolic Diastolic BP change (mmhg) M (n=138) 3 M (n=135) 6 M (n=86) 12 M (n=64) 18 M (n=36) 24 M (n=18) Symplicity HTN-1 Investigators. Hypertension

26 RF Ablation of hypertension Krum et al. Lancet 2009;127

27 Symplicity HTN-2 Purpose: to demonstrate the effectiveness of catheter-based RDN for reducing blood pressure in patients with uncontrolled hypertension in a prospective, randomised, controlled clinical trial Patients: 106 patients randomised 1:1 to treatment with RDN vs. control Clinical sites: 24 centres in Europe, Australia and New Zealand (67% were designated hypertension centres of excellence) Symplicity HTN-2 Investigators. The Lancet

28 Symplicity HTN-2 Trial Inclusion criteria: Office SBP 160 mmhg ( 150 mmhg with type II diabetes mellitus) Stable drug regimen of 3+ more anti-htn medications Age 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 past 6 months Symplicity HTN-2 Investigators. The Lancet

29 Symplicity HTN-2 Study Centers Europe and Australia/New Zealand Universitätsklinikum des Saarlandes, Homburg, Germany CardioVascular Center Frankfurt, Frankfurt, Germany Universitätsklinikum Düsseldorf, Düsseldorf, Germany Universität Erlangen-Nürnberg, Erlangen, Germany William Harvey Research Institute, Queen Mary University of London and Barts, London, UK Pauls Stradins Clinical University Hospital, Riga, Latvia PI: Prof. Murray Esler Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France John Hunter Hospital, Newcastle, Australia Cliniques Universitaires Saint-Luc, Brussels, Belgium Universitaetsklinikum Schleswig-Holstein, Lübeck, Germany Universität zu Köln, Köln, Germany The Alfred Hospital, Melbourne, Australia Universität Leipzig Herzzentrum, Leipzig, Germany Allgemeines Krankenhaus der Stadt Wien, Vienna, Austria Samodzielna Pracownia Hemodynamiczna, Warsaw, Poland Hospital 12 de Octubre, Madrid, Spain St. Vincent s Hospital, Melbourne, Australia Universitätsklinikum Essen, Essen, Germany Kent and Canterbury Hospital, Canterbury, UK University Hospital Zurich, Zurich, Switzerland University of Glasgow, Glasgow, UK Auckland City Hospital, Auckland, New Zealand Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany The John Paul II Hospital, Krakow, Poland Symplicity HTN-2 Investigators. The Lancet

30 Patient Disposition Assessed for Eligibility (n = 190) Screening Excluded Prior to Randomisation (n = 84) BP <160 after 2 weeks of compliance confirmation (n = 36; 19%) Ineligible anatomy (n = 30;16%) Declined participation (n = 10; 5%) Other exclusion criteria discovered after consent (n = 8; 4%) Randomised (n = 106) Allocation Allocated to RDN (n = 52) Allocated to Control (n = 54) Follow-Up No 6-Month Primary Endpoint Visit (n = 3) Reasons: Withdrew consent (n = 1) Missed visit (n = 2) No 6-Month Primary Endpoint Visit (n = 3) Reasons: Withdrew consent (n = 2) Lost to follow-up (n = 1) Analysis Analysed (n = 49) Analysed (n = 51) Symplicity HTN-2 Investigators. The Lancet

31 Primary Endpoint: 6-Month Office BP from Baseline to 6 Months (mmhg) Diastolic Systolic 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

32 Time Course of Office BP Change RDN from Baseline (mmhg) * * * * Control from Baseline (mmhg) * p < for between-group comparisons p = for between-group comparisons p = for between-group comparisons Two-way repeated measures ANOVA, p = Symplicity HTN-2 Investigators. The Lancet

33 Procedural Safety No serious device or procedure related adverse events (n = 52) Minor adverse events 1 femoral artery pseudoaneurysm treated with manual compression 1 postprocedural drop in BP resulting in a reduction in medication 1 urinary tract infection 1 prolonged hospitalisation for evaluation of paraesthesias 1 back pain treated with pain medications and resolved after 1 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 unrelated to RF treatment (no further therapy warranted) Symplicity HTN-2 Investigators. The Lancet

34 Potential! Reduced Sympathetic Drive in Heart Failure HTN in end stage renal failure Improved glucose tolerance Reduction of obstructive sleep apnea..

35 Renal Denervation Procedure THE DETAILS

36 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 United States law to investigational use.

37 Technique and Patient Management 6 Fr femoral access Selective intubation of renal a. Renal angiography Anticoagulation Pain management Monitoring Ablation procedure Sheath removal/ closure

38 CT Angio / MRI: Size Length Single artery No lesion First Things First: Preassessment Femoral/Iliac

39 Cathlab Setup Standard setting for right femoral access Single plane Vascular System* Digital Subtraction Angiography* Overlay*

40 Femoral Access 6mm 6 French sheath

41 Eligible Anatomy Absence of flow-limiting obstructions and significant disease Diameter 4 mm in targeted area Absence of prior renal angioplasty, indwelling renal stents, or aortic graphs Renal Angiogram

42 For distribution only in markets where the Symplicity Catheter System is approved. Not for distribution in the USA or Japan Medtronic, Inc. All rights reserved. MKG027 RevA Symplicity Catheter Handle Features Deflect tip by pulling lever towards back of handle Straighten tip by pushing lever towards front of handle Handle rotator has tactile click every 45 degrees Dot on rotator gives relative rotational reference Data on file. Medtronic, Inc.

43 Areas to Avoid There is no clinical experience treating areas near visible disease or in vessels with renal artery aneurysms Avoid treating areas of visible disease For example: atherosclerosis, calcification, or fibromuscular dysplasia Atherosclerosis (Ostial Stenosis) Calcification Fibromuscular Dysplasia (FMD) Avoid treating in segment with stenosis Avoid energy delivery to area with visible calcification Avoid treating in segment with FMD Data on file. Medtronic, Inc.

44 Pain Management: Bristol Midazolam 2mg i.v pre procedure (Repeat) Fentanyl i.v. 50 mg before each ablation Repeat until pain is controlled Be proactive!

45 Post Procedural Care Access site monitoring according to protocol Hydration Continue Medication FU investigations scheduled

46 Known Complications 1/ 50: Renal artery dissection: stented 1/50: Femoral aneurysm! Antibiotics 1/ 52: Femoral aneurysm! Compressed 7 Transient bradycardia 1 Transient BP drop 1 Paresthesia 1 Back pain Krum et al, Lancet 2009 HTN2 Trial, Lancet 2010

47 Future Improvements (the pigs might fly) Radial access One burn/freeze technique Painless? Probably not Detection of successful ablation

48 Conclusion Renal Denervation is the first interventional procedure to treat resistant hypertension Successful reduction in BP can be achieved in the majority of patients The current procedure appears safe More research is required to understand and improve this approach