Premieres preuves cliniques

Transcription

1 Premieres preuves cliniques Marc Sapoval, Michel Azizi Paris Descartes University Georges Pompidou European Hospital Hypertension Unit Clinical Investigation Center INSERM CIC9201 Cordis advisory Board, Paris, Sept 27, 2011

2 Conflits d intérêts Investigateur dans l essai Simplicity HNT2 Consultant ReCor, Cordis

3 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 Hypertrophy Arrhythmia Oxygen Consumption Heart Failure Renal Efferent Nerves Renal Ischemia Hypoxia Adenosine production BNP resistance Renin Release RAAS activation Sodium Retention Rightward Shift of Pressure- Natriuresis Curve Renal Blood Flow

4 Central Sympathetic Drive Assessed by MSNA Normotensives High Normals White Coat Borderline Htn Essential Htn Stage 1 Essential Htn Stage 2/3 Essential Htn with LVH Smith et al. AJH 2004; 17:

5 Renal sympathetic activity is increased in young an middle aged patients with untreated essential hypertension Di Bona et al. Am J Physiol Regul Integr Comp Physiol 2010; 298: R245.

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7 Surgical Sympathectomy: Historical perspective 1.Page I, Heuer GJ. A surgical treatment of essential hypertension. JCI 1934: Freyberg RH, Peet MM. The effect on the kidney of bilateral splanchnicectomy in patients with hypertension. J Clin Invest 1937;16: Smithwick RH. Surgical treatment of hypertension. Am J Med 1948; 4: Isberg EM, Peet MM. The influence of supradiaphragmatic splanchnicectomy on the heart in hypertension. Am Heart J 1948;35: Allen EV. Sympathectomy for essential hypertension. Circulation 1952;6: Smithwick RH. Hypertensive vascular disease: results of and indications for splanchnicectomy. J Chron Dis 1955;1:

8 Renal Sympathetic Denervation Delays or Prevents Development of Hypertension Models Demonstrating Benefit SHR (rat) Stroke Prone SHR (rat) New Zealand SHR (rat) BHR (rat) Goldblatt 1K, 1C (rat)* Goldblatt 2K, 2C (rat) Aortic coarctation (dog) Aortic nerve transection (rat) DOCA-NaCl (rat, pig)* Angiotensin II (rat, rabbit) Fat feeding - Obesity (dog) Renal wrap (rat) DiBona et. al. Physiol Rev. 1997, 77:75-197

9 Multiple Discrete Treatments maximize nerve coverage without applying circumferential energy in a single segment 40-minute catheter-based procedure Selective denervation of human kidney by delivery of 4 to 6 low power radiofrequency energy treatments (5-8W) are delivered along the length of both renal artery Focal ablations spaced along vessel allows healing Blood flow minimizes surface/endothelial injury

10 Focal medial and adventitial fibrosis with minimal intimal thicknening and disruption of the internal elastic lamina 6 monts 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

11 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

12 Reduction of Systemic Sympathetic Drive: MSNA in Resistant Htn Patient Baseline 1 M FU 12 M FU ECG BP /107 mmhg 141/90 mmhg 127/81 mmhg MSNA 1 0 s e c 56 bursts/min 41 bursts/min 19 bursts/min Improvement in cardiac baroreflex sensitivity after renal denervation (from 7.8 to 11.7msec/mmHg). Schlaich et al. NEJM. 2009; 36(9):

13 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

14 Symplicity HTN-2 Trial Inclusion Criteria: Office SBP 160 mmhg ( 150 mmhg type II diabetes) > 3 anti-hypertensive meds, no changes within 2 weeks prior to enrollment Age years egfr 45 ml/min/1.73m 2 Suitable renal artery anatomy Exclusion Criteria: No significant renal artery abnormalities or prior intervention Type I diabetes contraindications to MRI Stenotic valvular heart disease for which BP would be hazardous MI, unstable angina, or CVA in the prior 6 months Pregnancy Symplicity HTN-2 Investigators. The Lancet

15 Patient Disposition Assessed for Eligibility (n=190) Excluded Prior to Randomization (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%) Randomized (n=106) Allocated to RDN (n=52) No Six-Month Primary Endpoint Visit (n = 3) Reasons: Withdrew consent (n=1) Missed visit (n=2) Allocated to Control (n = 54) No Six-Month Primary Endpoint Visit (n = 3) Reasons: Withdrew consent (n=2) Lost to follow-up (n=1) Analyzed (n = 49) Analyzed (n = 51) Symplicity HTN-2 Investigators. The Lancet

16 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 ± ±

17 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

18 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 Office SBP <140 mmhg (%) 39% 3.6% < office SBP 10 mmhg (%) 84% 34% < office SBP = 0 (%) 10% 47% <0.0001

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

20 Procedural Safety 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

21 Other Safety RDN (n=49) Control (n=51) Composite CV Events Hypertensive event unrelated to non-adherence to medication 3 2 Other CV events 0 0 Other Serious AEs 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 Symplicity HTN-2 Investigators. The Lancet

22 Significant, Sustained BP Reduction BP change (mmhg) Simplicity HTN-1 investigators. Hypertension. 2011;57:

23 Procedure Detail & Safety 38 minute median procedure time Average of 4ablations per artery IV narcotics & sedatives used to manage pain during delivery of RF energy No catheter or generator malfunctions No major complications Adverse events 4/153: 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae 3 access site complications, treated without further sequelae Simplicity HTN-1 investigators. Hypertension. 2011;57:

24 Mid-term 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 sequelae) 2 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/1.73m 2 (n.s.) Simplicity HTN-1 investigators. Hypertension. 2011;57:

25 Critical Assessment 1. Internal validity: No ABPM to define resistant hypertension No work-up to exclude secondary hypertension Open label No marker/index of primary success No assessment of adherence to AHT during the trial No standardized AHT, therefore scoring of treatement is difficult No masked assessment of the primary endpoint which was office BP 2. Possibility of biases Expectation bias by patients and doctors Attrition bias (cointerventions, change in behavior ) Evaluation bias (office BP vs. ABPM)

26 Critical Assessment (II) 3. Results Timing for measuring BP is not reported Much larger office BP lowering effect than on ABPM No decrease in office BP in the control group whereas ABP decreased Uncontrolled changes in medical therapy during the trial in both groups 10% of patients do not respond to RD Safety cannot be assessed with certainty with 50 patients. A complication rate <5% would have been missed by the trial. Mid-term safety (2 years) is only known for a few number of patients 4. External validity Ineligible anatomy (n=30; 16%) Only half of highly selected patients who accepted to participate were finally included Majority of obese patients with mean BMI = 31 kg/m 2, (OSA?)

27 14-week BP lowering effects of Darusentan in patients with RH to a triple therapy including a diuretic Office BP ABPM 379 patients with SBP 140 mm Hg or 130 mm Hg if patient had diabetes or CKD Weber MA. Lancet 2009; 374: 1423

28 Baroreflex Activation Therapy in Patients With Resistant Hypertension: a double blind RCT 1. Resistant HTN: at least 1 office SBP> 160 mm Hg with DBP > 80 mm Hg 2. at least 1 month of maximally tolerated Rx with > 3 appropriate AHT, including a diuretic h ASBP >135 mm Hg As part of ongoing subject medical management, investigators were not prevented from changing antihypertensive medications during the course of the trial Bisognano et al. J Am Coll Cardiol 2011;58:765

29 Baseline characteristics Group A Group B (n 181) (n 84) Male 116 (64%) 46 (55%) Female 65 (36%) 38 (45%) Age, yrs 53.7 ± ±9.8 Caucasian 146 (81%) 59 (70%) SBP, mm Hg 169 ± ±24 DBP, mm Hg 101 ± ±14 Heart rate, beats/min 79 ±14 79 ±17 BMI, kg/m ± ±5.9 Diabetes 57 (31%) 29 (35%) Previous CAD 38 (21%) 18 (21%) Heart failure 12 (7%) 10 (12%) Previous stroke 24 (14%) 9 (11%) Number of BP medications 5.2 (1.6) 5.2 (1.8) Bisognano et al. J Am Coll Cardiol 2011;58:765

30 BP and MSNA decrease acutely and remained suppressed throughout each stimulation period Heusser et al. Hypertension. 2010;55:619

31 Primary endpoint : acute BP at 6 months % Responder pts Decrease in SBP (mmhg) % 46 % BAT on BAT off ±29 BAT on BAT off ±29 P = 0.97 proportion of subjects that achieve at least a 10 mm Hg drop in SBP at Month 6 P = 0.08 Bisognano et al. J Am Coll Cardiol 2011;58:765

32 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.

33 egfr changes in ACCOMPLISH trial Heerspink LH, De Zeeuw D. Lancet 2010;375:1140

34 Conclusions Catheter-based renal denervation in patients with treatmentresistant 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

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36 Perspectives 1. New catheters: RF, cryoablation, ultrasounds 2. New indications beyond resistant hypertension Hypertension Heart Failure Chronic Kidney Disease Type II Diabetes Obstrutive sleep apnea

37 Planned Trials in hypertension (clinicaltrials.gov) 1. Resistant hypertension only: 6 studies 1. Symplicity Catheter Simplicity program (HTN1, 2 and 3). HTN3: 530 patients open label randomized ReSET study: Sham Controlled RCT (Denmark) 2. Thermocool catheter (China) Feasibility, safety, single-arm, n= St Jude catheter Feasibility, safety, single-arm, n= Resistant hypertension + associated conditions : 1. Symplicity Catheter Obstructive sleep apnea, open label randomized, n= Cryoablation catheter Atrial fibrillation, Open RCT, Efficacy, n= Essential hypertension : 1. Thermocool catheter (China) Open RCT, Efficacy, n= 800

38 Planned Trials France: 1. DENER-HTN study: RD in patients with resistant hypertension: a multicenter PROBE study with medicoeconomic evaluation. PI: PrMarc Sapoval and PrMichel Azizi Funding: Ministry of health (STIC) 2. DERENEDIABstudy: RD patients with diabetic nephropathy and persistant proteinuria: a multicentre PROBE study PI: DrGuillaume Bobrieand PrMarc Sapoval Sponsor: APHP Funding: Ministry of health (PHRC)

39 Protocole DENER-HTN :Objectif et méthode 1. Objectif: Evaluer l efficacité, la sécuritéet l impact économique de la DR par RF par voie endovasculaire en complément d un traitement médical antihypertenseur optimisé standardisé(tmaos) chez des patients ayant une HTAR essentielle documentée 2. Méthodologie: Essai multicentrique, randomisé, contrôlé, ouvert, de supériorité, en groupes parallèles, comparant la DR+TMAOS contre le TMAOS seul Méthodologie: PROBE (avec analyse du critère de jugement àl insu des groupes de traitement) 3. Duréetotale de l étude: 27 mois (15 mois d inclusion et 12 mois de suivi)

40 Screening Plan expérimental Cs Interventionnaliste Cs pré-anesthésique Visite 0 Inclusion Consentement Visite 1 (MAPA 24 H) délai max: 4 semaines Trithérapie de base + DR + TMAOS 4 semaines Randomisation si: HTA résistante confirmée MAPA d 135 et/ou 85 Anatomie compatible Imagerie de moins d un an sinon àfaire Avis radiologue Anatomie compatible Trithérapie de base (TTT) HTA contrôlée: MAPA d <135 et 85 Sortie d étude Trithérapie de base + TMAOS

41 Critères de Jugement 1. Critère de jugement principal PAS diurne en MAPA, 6 mois post-randomisation. Critère de jugement principal associé: analyse coût-efficacité 2. Critères de jugement secondaires Score de traitement antihypertenseur EI de la DR (risques immédiats et tardifs) MAPA24h et nocturne: PAS/PAD/PP/FC PAS/PAD en mesure clinique et en AMT en particulier àv3 VOP et PAS et PP centrale % patients avec PAS <135 mmhg etpad <85 mmhg en MAPA diurne % patients avec PAS <140 mmhg etpad <90 mmhg en mesure clinique

42 Renal Denervation may improve glucose metabolism: non-randomized open label study Change in C-Pept. (ng/dl) Change in blood GLC (mg/dl) Change in HOMA-IR (ng/dl) Change in Insulin (µu/dl) Mahfoud F et al. Circulation 2011;123:1940

43 Effects of RD in patients with obstructive sleep apnea: an observational case-series AHI: apnea-hypopnea index Witowski et al. Hypertension. 2011;58

44 Planned Trials in other indications (clinicaltrials.gov) 1. Metabolic syndrome : 1. Thermocool catheter (China) Single-arm, n= Chronic renal failure: 4 studies 1. Symplicity Catheter (n=3) ESRD, Single arm, Open label feasibility and safety studies. n= 20 to Thermocool catheter (China) Non randomized open label, n= Heart failure: 1. Symplicity Catheter HF (II-III, EF < 45%) + renal dysfunction (egfr 45-60) Single arm, Open label feasibility and safety. n= Thermocool catheter (China) Non randomized open label, n= Mechanistic studies 1. Symplicity Catheter Biological parameters, sympathetic activity, n= 20-30

45 New RF balloons: V2 catheter

46 Cryoablation for renal denervation: Preclinical data Prochnau D. International Journal of Cardiology 2011

47 Consensus d expert 2012 HTA essentiellenon contrôlée (> 160 et/ou 100 mmhg) sous quadrithérapieou plus: avec un traitement comportant au moins un diurétique malgréla prescription de spironolactone25 mg/jour dans l association. Confirmation de l HTA non contrôlée par MAPAd/Automesure (> 135 et/ou 85 mmhg) DFG > 45 ml/min/1 73m² (MDRD) Anatomie des AR compatible avec la DR Présence de 2 reins fonctionnels de taille 90 mm Exploration des AR par angio TDM ou artériographie datant de moins d un an Absence d antécédent d angioplastie / stent AR avec une voie d abord ilio-fémoral et anatomie aortique compatibles Contre-indications: une sténose d une artère rénale > 30% la présence d'un stimulateur cardiaque ou d'un défibrillateur automatique implantable un âge de moins de 18 ans une grossesse en cours Indication posée par un groupe multidisciplinaire ayant une pratique et une compétence reconnue dans la prise en charge des patients avec HTA