Pr Patrick Rossignol Inserm 1433 Clinical Investigation Center Hypertension and Heart Failure Unit Association Lorraine pour le Traitement de l Insuffisance Rénale (ALTIR) CHRU, Lorraine University Nancy, France Carotid barostimulation in resistant hypertension
Disclosures Honoraria: Astra-Zeneca, CVRx, Daichii-Sankyo, Fresenius, Gambro, HAC-Pharma, Novartis, Relypsa, Sanofi, Servier, Stealth peptides Research grants: Astra-Zeneca, BG Medicine, BMS, Roche Travel grants: Astra-Zeneca, Daichii-Sankyo, Gambro, Novartis, Servier, Takeda CardioRenal co-founder
Barostim Brain CVRx Barostim Platform CVRx Programmable Barostim Platform Designed to electronically activate baroreceptors which signal the brain to orchestrate a multi-systemic response to address chronic, progressive diseases: hypertension, heart failure, arrhythmia Autonomic Nervous System Reduce Sympathetic Activity Enhance Parasympathetic Activity HEART: heart rate and remodeling ARTERIES: Vasodilation Elevated BP KIDNEYS Diuresis Renin secretion
Acute Baroreceptor Stimulation in resistant hypertension Heusser et al Hypertension 2010
Chronic Baroreceptor Stimulation in resistant hypertension Wustmann et al Hypertension 2009
1 st generation Barostim: Rheos
J Am Coll Cardiol 2010;56:1254 8
J Am Coll Cardiol 2010;56:1254 8
De Leeuw, ESC 2013
Rheos Hypertension Pivotal Trial Design Prospective randomized double-blind trial 322 patients at 49 sites 55 roll-in patients / 265 randomized (2:1) Co-primary endpoints 1. Short Term Acute Response 2. Long Term Sustained Response 3. Short Term Procedural AEs 4. Short Term Hypertension Therapy AEs 5. Long Term Device AEs Implant Randomization 6-Month Blinded Evaluation Period 6-Month Blinded Evaluation Period Long-Term Follow-Up N = 181 N = 84 Group A Device ON Group B Device OFF Group A Device ON Group B Device ON -1 0 6 3 9 12 Bisognano, Bakris et al. JACC 2011 (months)
Pivotal Trial Baseline Characteristics Group A (N = 181) Group B (N = 84) Gender 64% Male 55% Male Race 73% Caucasian 78% Caucasian Age (mean years ± sd) 54 ± 11 53 ± 10 BMI (mean kg/m 2 ± sd) 33 ± 5 32 ± 6 Antihypertensive Meds (mean # ± sd) 5.2 ± 2 5.2 ± 2 Systolic BP (mean mmhg ± sd) 179 ± 22 176 ± 22 Diastolic BP (mean mmhg ± sd) 103 ± 16 103 ± 13 Heart Rate (mean bpm ± sd) 74 ± 14 75 ± 16 Bisognano, Bakris et al. JACC 2011
1 st Endpoint Short Term Acute Response Responder rate i.e. at least -10 mm Hg M6/M0 for device ON vs device OFF: Group A (Rhéos ON): 54% Group B (Rhéos OFF): 46 %, p= 0.97 2 nd Endpoint Long-term Sustained Response Percent of Sustained Responders at 12 Months among responders at month 6 i.e. at least -10 mm Hg at M12 AND 50 % of M6 response : 88% (vs. OPC 65%) : p<0.001 Pre-Specified Ancillary Efficacy Analyses (double blind) at month 6 1) Systolic blood pressure changes between M0 and M6 Group A (Rhéos ON): -16 ± 29 mmhg Group B (Rhéos OFF): -9 ± 29 mmhg (p= 0.08). 2) % of Patients at SBP 140mmHg Group A (Rhéos ON): 42% Group B (Rhéos OFF): 24% (p=0.005). Bisognano, Bakris et al. JACC 2011
% of Patients Event Free at 30 days CIC-P Nancy 3 rd Endpoint Short Term Procedure Adverse Events 30-Day Event Free rate 90 OPC: 82% 80 70 60 50 N = 270 30-day Groups A+B isognano, Bakris et al. JACC 2011 (p=1). 75% Types of Adverse Events 4.4% permanent nerve injury (numbness, dysphagia, dysphonia) 4.8% transient nerve injury 4.4% general surgical complications (86% resolved) 2.6% respiratory complaints (100% resolved) 76% of all adverse events fully resolved OPC: Objective Performance Criteria 15
% of Patients Event Free at 6 Months CIC-P Nancy 4 th Endpoint Short Term HTN Therapy Adverse Events 6-Month Event Free Rate 100 90 87.6 91.7 80 70 60 15% + C.I. 72.6 Goal Diff (A-B) < 15% NON INFERIORITY (15% margin) p-value < 0.001 N = 85 N= 170 Month-6 OFF Month-6 ON 16 Bisognano, Bakris et al. JACC 2011
Long Term Device AEs (5 th endpoint): J30-J365 Long-term safety of 87.2%, with a lower bound of the unilatéral CI 95% of 83.8%, i.e better than the prespecified Objective Performance Criteria of 72% (p<0.001). 17
Long-term follow-up (22-53 months) Nb of BP Meds at last follow-up visit in BP responders : 5 (vs. 5.3 pre implant) Bakris et al. JASH, 2012 18
5 Year Clinical Trial Results in Resistant Hypertension Safety Events Years 2-5 Rate per Patient Year System/Procedure 0.037% Stroke 0.014% Myocardial Infarction 0.0050% p<.001 Bakris et al, ASN 2014
In terms of normalization of blood pressure, there was again a significant difference between the left-stimulated and the rightstimulated group in favor of the latter (35% versus 54%; P=0.008). Peter W. de Leeuw et al. Hypertension. 2015;65:187-192
Comparison Rheos vs. neo 1 st Generation 2 nd Generation
Barostim Neo TM (n= 30, single arm open label) Hoppe et al. JASH, 2012
Barostim Neo TM (n= 30, 6-month single arm open label) vs. Rheos Efficacy (Rhéos trial) 0 neo System Unilateral Rheos System Bilateral -5 Change in Systolic BP (mmhg) -10-15 -20-25 -30-26 -26-26 3 Months BAT 6 Months BAT -35-40 Barostim Neo (n=30) Pivotal Immediate On Group (n=181 patients) Hoppe et al. JASH, 2012
BAT successfully lowered BP and heart rate in a subset of patients with still resistant hypertension who had previously undergone renal nerve ablation Hoppe et al. JASH, 2012
Barostim Neo TM (n= 30, single arm open label) Safety profile Hoppe et al. JASH, 2012
TARGET ORGAN DAMAGE PROTECTION.BEYOND BP REDUCTION?
HEART SINGLE ARM STUDY (DEBuT, Rheos) Bisognano JACC 2011 27
VASCULAR SINGLE ARM STUDY (Neo) Wallbach et al J Hypertens 2014 28
KIDNEY Non-RANDOMIZED STUDY (Neo) 29 Wallbach et al J Hypertens 2014
KIDNEY Non RANDOMIZED STUDY (Neo) 30 Wallbach et al J Hypertens 2014
KIDNEY Non RANDOMIZED STUDY (Neo) Wallbach et al J Hypertens 2014 31
KIDNEY Non-RANDOMIZED STUDY (Neo) 32 Wallbach et al J Hypertens 2014
ESC/ESH Guidelines 2013 33
Modeling substudy based on the Debut and Rheos trials data: from a German societal perspective over a lifetime horizon. J Hypertens 2014
Granted by the French Ministry of Health «ESTIM-rHTN» medicoeconomic evaluation of baroreceptor STIMulation for the treatment of Resistant HyperTensioN A multicenter randomized, PROBE design trial of baroreceptor stimulation with Barostim Neo TM vs. usual care Sponsor: Nancy University Hospital (CHRU) ClinicalTrials.gov Identifier: NCT02364310
MAIN INCLUSION CRITERIA 18-75 y old men or women Resistant hypertension on 4 medications incl. thiazide or thiazide-like at appropriate doses + spironolactone (unless spiro intolerance) Essential hypertension egfr 30 ml/min/1,73 m 2 No carotid condition associated with a contraindication to use Barostim Neo TM
PRIMARY OBJECTIVE Medico economic assessment: costeffectiveness
MAIN EVALUATION CRITERIA Clinical trial : ICER: cost / diurnal SBP mm Hg on ABPM after 12 months modelisation : Incremental ratio: cost / living year saved
SECONDARY OUTCOME CRITERIA Efficacy : Comparison with usual care SBP, DBP, mean BP 24h, diurnal, nocturnal on ABPM: 6 months, 12 months Casual BP, PWV, PPc, LVM, LV function on echocardiography: 6 months, 12 months Evolution of egfr (MDRD) and of microalbuminuria: 6 months, 12 months Antihypertensive regimen : 6 months, 12 months EuroQol5D 6 months, 12 months Compliance Cardiovascular, cerebrovascular events Global cardiovascular risk : 6 months, 12 months Tolerance : morbidity at 1 month post surgery
EXPERIMENTAL DESIGN: PROBE N= 140 N= 64 N= 64 N= 26 ROLL-IN GROUP
Steering committee: chair: Pr Patrick Rossignol, Nancy Co-chair: Pr Michel Azizi, Paris Methodologist, statistician: Pr Gilles Chatellier, Paris Medico-economic assessment : Dr Karine Chevreul (URC-Eco, Paris) Dr Jean-Marc Alsac, Paris Pr Faiez Zannad, Nancy Advisor : Pr George Bakris, Chicago, USA DSMB: Pr Pascal Desgranges, vascular surgeon, Hôpital Henry Mondor, Créteil Pr Pascal Bousquet, cardiologist, pharmacologist, Université de Strasbourg Dr Catherine Cornu, methodologist, CIC, CHU de Lyon First patient in, May 11, 2015 in Nancy!
www.inicrct.org 43