Renal denervation: Current evidence and remaining uncertainties

Transcription

1 Renal denervation: Current evidence and remaining uncertainties Michel Azizi Georges Pompidou European Hospital Hypertension Unit ESH excellence Center Paris Descartes University Clinical Investigation Center INSERM CIC9201 Disclosures: Ardian/Medtronic, Cordis, Vessix

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3 BP Control (<140/90 mmhg) among treated, % France, ENNS Survey Men Women to 54 y 55 to 64 y 65 to 74 y Total to 54 y 55 to 64 y 65 to 74 y Total Godet-Thobie H et al. BEH 2008;49-50: 478

4 Resistant hypertension 1. Estimated Prevalence : 5 to 25% in tertiary Hypertension Clinics 8-12 % in general population 2. Incidence: 0.7 cases per 100 person-years follow-up 3. Associated with TOD and high cardiovascular risk 4. Associated with increased cardiovascular morbidity and mortality Prognosis over 3.8 years of median follow-up: unadjusted CVE rates: RH : 18.0% vs. non-rh: 13.5%, P<0.001 HR: 1.47 (95%CI: ) Calhoun et al Circulation 2008;117:e510 de la Sierra A et al. Hypertension. 2011;57:898 Persell SD. Hypertension. 2011;57 Daugherty SL et al. Circulation 2012, 125:1635

5 Novel strategies Clinical development stage 1. Vasopeptidase inhibition, safety issues. 2. Dual angiotensin receptor-neprilysin inhibition (ARNI) 3. Aldosterone synthase inhibition 4. DHP-like new MRA 5. Endothelin antagonism Preclinical development stage 1. Aminopeptidase A inhibition 2. Pro(renin) receptor blockade (handle region peptide) 3. ACE2 inhibition 4. ECE inhibition 5. Dual inhibitors 6. NHE3 inhibitors 7. Rho kinase inhibitors 8. Antisens therapy, sirna

6 Treatment of resistant hypertension by renal denervation

7 Renal Sympathetic efferent and afferent Nerves: Kidney as Recipient of Sympathetic Signals Kidney as Origin of Central Sympathetic Drive Vasoconstriction Atherosclerosis Insulin Resistance Renal Afferent Nerves Renal Ischemia Hypoxia Acidosis Oxidative stress Inflammation Endothelial factors Adenosine Hypertrophy Arrhythmia Oxygen Consumption Heart Failure Renal Efferent Nerves Renin Release RAAS activation Sodium Retention Rightward Shift of Pressure- Natriuresis Curve Renal Blood Flow

8 The central sympathetic overdrive in essential Hypertension Normotensives High Normals White Coat Borderline Htn Essential Htn Stage 1 Essential Htn Stage 2/3 Essential Htn with LVH Central Sympathetic Drive Assessed by MSNA Smith et al. AJH 2004; 17:

9 Increased renal sympathetic activity in young and middle-aged untreated hypertensive patients Di Bona et al. Am J Physiol Regul Integr Comp Physiol 2010; 298: R245.

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11 Renal Nerves as a Therapeutic Target Arise from ~ T10-L2 Follow the renal artery to the kidney Primarily lie within the adventitia Vessel Lumen Media Adventitia Renal Nerves

12 Percutaneous catheter-based transluminal renal ablation by delivery of RF energy 40-minute catheter-based procedure Selective denervation by delivery of 4 to 6 focal low power RF energy ablations (5-8W) starting close to the hilum before renal artery bifurcation and then every 5 mm after pulling back and rotating the catheter along the length of both renal arteries. Blood flow minimizes surface/endothelial injury

13 Focal medial and adventitial fibrosis with minimal intimal thicknening and disruption of the internal elastic lamina 6 months after renal denervation All treated vessels were completely endothelialized after 6 months. There was no inflammatory cells, renal arterial stenosis or thrombosis Kippy, R et al. Clin Res Cardiol DOI /s

14 Preclinical Data: Renal nerve injury at 6 mo. Normal nerve Renal nerve injury 6 mo. after RD Healing fibrosis causing a thickening of the surrounding perineurium No inflammatory component Kippy, R et al. Clin Res Cardiol DOI /s

15 Renal denervation with the Simplicity catheter

16 Effect of renal devervation on BP 200 Patient 1 One out of four AHT was stopped because of hypotension BP (mmhg) Days

17 Symplicity HTN-2 Trial Baseline 2 week observation Anatomical Screening (MRA, CTA, duplex or angiogram) 24-hr ABPM Baseline BP measure at end of baseline period Randomized 1:1 Control Group 6M Control Patients offered treatment Uncontrolled HTN SBP 160 mmhg ( 150 mmhg diabetics) 3 meds Primary Endpoint Treatment Group 6M 12-36M Baseline Drop-Outs Registry Suboptimal Anatomy Registry Symplicity HTN-2 Investigators. The Lancet

18 Patient Disposition Assessed for Eligibility (n=190) Excluded During Screening, Prior to Randomization (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%) Randomized (n=106) Allocated to RDN N=52 Treated N=49 Analyzable Allocated to Control N=54 Control N=51 Analyzable Crossover N=46 (2 LTFU) 12-month post-rdn N=47 Per protocol, 6-mo Post RDN, N=35 Not-per-protocol*, 6- mo Post RDN, N=9 * Crossed-over with ineligible BP (<160 mmhg)

19 Baseline Characteristics RDN (n=52) Control (n=54) p-value Age 58 ±12 58 ± Gender (% female) 35% 50% 0.12 Race (% Caucasian) 98% 96% >0.99 BMI (kg/m 2 ) 31 ±5 31 ± Baseline Systolic BP (mmhg) 178 ± ± Baseline Diastolic BP (mmhg) 97 ± ± Type 2 diabetes 40% 28% 0.22 Coronary Artery Disease 19% 7% 0.09 Hypercholesterolemia 52% 52% >0.99 egfr (MDRD, ml/min/1.73m 2 ) 77 ±19 86 ± egfr (% patients) 21% 11% 0.19 Serum Creatinine (mg/dl) 1.0 ± ± Urine Alb/Creat Ratio (mg/g) 128 ± ±

20 Baseline Medications RDN (n=52) Control (n=54) p-value Number Anti-HTN medications 5.2 ± ± % patients on HTN meds >5 years 71% 78% 0.51 % percent patients on 5 meds. 67% 57% 0.32 % patients on drug class: ACEi/ARB 96% 94% >0.99 Direct renin inhibitor 15% 19% 0.80 Beta-adrenergic blocker 83% 69% 0.12 Calcium channel blocker 79% 83% 0.62 Diuretic 89% 91% 0.76 Aldosterone antagonist 17% 17% >0.99 Vasodilator 15% 17% >0.99 Alpha-1 adrenergic blocker 33% 19% 0.12 Centrally acting sympatholytic 52% 52% >0.99

21 BP decrease at 6 months RDN (n=52) Control (n=54) p Office BP (mmhg) -32±23/-12±11 (n=49) +1±21/0±10 (n=51) < Self BP (mmhg) -20±17/-12±11(n=32) +2±13/0±7 (n=40) < h-ABPM (mmhg) -11±15/-7±11 (n=20) -3±19/-1±12 (n=25) 0.006/0.014 # Med Dose Decrease (%) 10 (20%) 3 (6%) 0.04 # Med Dose Increase (%) 4 (8%) 6(12%) 0.74

22 Distribution of Office SBP for the RDN Group 10% of patients did not respond to RDN % Patients Pre- RDN (18.3) 6 month (23.3) 12 month (21.9) 96.1 (15.5) 84.4 (17.0) 87.0 (16.1) Esler M. et al. Circulation; 126:2976

23 Distribution of office SBP for the crossover group (n= 35) Pre- RDN (19.6) 99.9 (15.1) 6 month (24.7) 91.5 (14.6) BP Change (27.5) -8.4 (12.1) % Patients Esler M. ACC 2012 Crossover (n=35) Decrease (# Meds or Dose) Increase (# Meds or Dose) 6 months post- RDN 18.2% (6/33) 15.2% (5/33)

24 Renal Function Over Time BL (N=49) 6 M (N=49) 12 M (N=45) BL (N=35) 6 M (N=35) 12 M (N=35) Esler M. ACC 2012 RDN Crossover

25 Procedural Safety 38 minute median procedure time Average of 4ablations per artery IV narcotics & sedatives used to manage pain during delivery of RF 1. No serious device or procedure related adverse events (n=52) 2. Minor adverse events 1 femoral artery pseudoaneurysm treated with manual compression 1 post-procedural drop in BP resulting in a reduction in medication 1 back pain treated with pain medications & resolved after one month 3. 6-month renal imaging (n=43, 37 Duplex echo, 5 MRI, 5 CT) No vascular abnormality at any RF treatment site progression of a pre-existing stenosis unrelated to RF treatment 4. 6-month renal function: No change Symplicity HTN-2 Investigators. The Lancet

26 Change in Office Blood Pressure over 36 months in a cohort study 0-5 BP change (mmhg) P<0.01 for from BL for all time points Systolic BP Diastolic BP 1 M (n=143) 3 M (n=148) 6 M (n=144) 12 M (n=130) 18 M (n=107) 24 M (n=59) 30 M (n=24) 36 M (n=24) Sobotka P. ACC 2012

27 Evolution of egfr over 36 months BL (N=143) 3 M (N=131) 6 M (N=141)12 M (N=128)18 M (N=53) 24 M (N=35) 30 M (N=11) Sobotka P. ACC 2012 Caution: The Symplicity Catheter System is an Investigational Device. Limited by U.S. law to investigational use. For OMA distribution only Medtronic, Inc. All rights reserved DOC_1A 03/2012

28 Critical appraisal of the results of the SIMPLICITY studies

29 Impact of non-blinded outcome assessors on estimated intervention effects in RCTs Hróbjartsson A. BMJ 2012;344:e1119

30 Relationship between changes in 24h ambulatory SBP and office SBP in patients treated with AHT A metaanalysis of 44 studies including 5842 patients Darusentan study Symplicity HTN2 29% 67% Mancia G. J Hypertens 2004; 22:435

31 BP lowering effects of SNB vs. SRASB in the PHARES study Mean difference in dabp SBP: 10 mmhg (95% CI, 7 14 mmhg) DBP: 4 mmhg (95% CI, 2 7 mmhg) BP control rates in RH patients SNB strategy: 58% SRASB strategy: 20% Bobrie G et al J Hypertens. 2012; 30(8):1656

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33 Critical Assessment of the Simplicity HTN2 trial 1. Internal validity Open label No ABPM to define resistant hypertension at baseline No work-up to exclude secondary hypertension No marker/index of primary success No assessment of adherence to AHT during the trial No standardized AHT (treatment scoring is difficult) No masked assessment of the primary endpoint (office BP) 2. List of possible biases Expectation bias by both patients and doctors Performance bias (cointerventions, change in behavior ) Evaluation bias (office BP vs. ABPM) Azizi M et al. Eur J Vasc Endovasc Surg. 2012;43:293.

34 Critical appraisal of the renal effects

35 Change in egfr from baseline to 6 weeks by quartile of change in SBP Mann JE et al. Ann Intern Med. 2009;151:1-10.

36 Renal denervation increases glomerular hyperfiltration in the obesity-induced hypertension in dogs Lohmeier TE.Hypertension 2012;59:331

37 RDN and the kidney: preliminary data in humans RDN decreases ultrasound renal resistive index with no change in egfr or UAER in patients with RH and baseline egfr 45 ml/min Mahfoud F et al. Hypertension 2012; 60:419 RDN preserves renal perfusion in presence of reduced systemic BP: decreases renal vascular resistance without changing renal bloodflow (MRI) or GFR suggesting that autoregulation of renal perfusion is maintained Ott C et al. cjasn 2013 RDN does not change makers of acute kidney injury (NGAL, KIM-1) Dorr O et al. JACC 2013; 61:479 RDN reduces safely office BP in pts with RH and stage 3-4 CKD Hering D et al. JASN 2012; 23:1250

38 Long term safety With the increasing use of RDN, such complication may occur more often: Long term follow-up necessary Vonend O et al. Lancet 2012; 380: 778 Kaltenbach B et al. JACC 2012, Oct 24.

39 64 y women During RDN procedure 6 months after RDN

40 External validity

41 Eligibility for RDN in real-life patients with RH referred to a tertiary hypertension unit during year patients hospitalized in patients with RH (20%) 113 patients with secondary hypertension (57%) 87 patients with essential RH (43%) 15/1034 patients (1.5%) of all hospitalized patients eligible for RDN 15/87 (17.2%) of patients with essential RH eligible for RDN Azizi M. et al. JACC 2012, Oct 25

42 Conclusions Catheter-based renal denervation in patients with treatment-resistant essential hypertension, resulted in significant reductions in office BP, much less marked when using ABPM. The technique was applied without major complications in the short term. The technique needs still to be evaluated to : assess its efficacy against the best optimal care using predefined and validated algorhythm of antihypertensive treatments Find out a method indicating the primary success of the denervation assess its long term safety Symplicity HTN-2 Investigators. The Lancet

43 1. Objective : The French DENER-HTN trial To assess efficacy, safety and cost-effectiveness of the radiofrequency based renal denervation (RD, Symplicity catheter, Medtronic ) in 120 patients with proven resistant hypertension. 2. Methodology : Multicentre, randomized, controlled, open-label, parallel, superiority trial, comparing RD + standardized optimal antihypertensive treatment (SOAT) vs. SOAT alone with blind assessment of the primary endpoint (ABPM, PROBE design) 3. Total duration of the trial: 27 months (enrollment : 15 months, follow up : 12 months) Azizi M. The DENERHTN study.