Pr Patrick Rossignol - nephro-necker.org · Gambro, Novartis, Servier, Takeda • CardioRenal...
Transcript of Pr Patrick Rossignol - nephro-necker.org · Gambro, Novartis, Servier, Takeda • CardioRenal...
CIC-P Nancy
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
CIC-P Nancy
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
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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…
Brain
Autonomic Nervous System Reduce Sympathetic Activity
Enhance Parasympathetic Activity
Barostim
HEART: ↘heart rate and ↘ remodeling
ARTERIES:
↑ Vasodilation ↓ Elevated BP
KIDNEYS
↑ Diuresis ↓ Renin secretion
CVRx Barostim Platform
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in resistant hypertension
Heusser et al Hypertension 2010
Acute Baroreceptor Stimulation
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Wustmann et al Hypertension 2009
Chronic Baroreceptor Stimulation
in resistant hypertension
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1st generation Barostim: Rheos™
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J Am Coll Cardiol 2010;56:1254–8
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J Am Coll Cardiol 2010;56:1254–8
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De Leeuw, ESC 2013
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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
6-Month Blinded
Evaluation Period
6-Month Blinded
Evaluation Period
Long-Term
Follow-Up
Implant Randomization
Group A – Device ON Group A – Device ON
Group B – Device OFF Group B – Device ON
(months)
N = 181
N = 84
-1 0 6 3 9 12 Bisognano, Bakris et al. JACC 2011
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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/m2 ± 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
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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).
Bisognano, Bakris et al. JACC 2011
2) % of Patients at SBP ≤ 140mmHg
Group A (Rhéos ON): 42%
Group B (Rhéos OFF): 24% (p=0.005).
1st 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
2nd 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
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3rd Endpoint – Short Term Procedure Adverse Events
30-Day Event Free rate
75%
% o
f P
ati
en
ts E
ven
t F
ree a
t 3
0 d
ays
50
60
70
80
90
N = 270
OPC: 82%
30-day Groups A+B
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
Bisognano, Bakris et al. JACC 2011
(p=1).
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91.7
% o
f P
ati
en
ts E
ven
t F
ree a
t 6
Mo
nth
s
60
70
80
90
72.6
Goal Diff (A-B) < 15%
100
87.6
N = 85 N= 170
15% + C.I.
NON INFERIORITY
(15% margin)
p-value < 0.001
4th Endpoint – Short Term HTN Therapy Adverse Events
6-Month Event Free Rate
Month-6 OFF
Month-6 ON
Bisognano, Bakris et al. JACC 2011 16
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Long Term Device AEs
(5th 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).
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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
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5 Year Clinical Trial Results in Resistant Hypertension
Bakris et al, ASN 2014
§p<.001
Safety Events Years 2 - 5
Rate per Patient Year
System/Procedure 0.037%
Stroke 0.014%
Myocardial Infarction 0.0050%
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Peter W. de Leeuw et al. Hypertension. 2015;65:187-192
“In terms of normalization of blood pressure, there was again a
significant difference between the left-stimulated and the right-
stimulated group in favor of the latter (35% versus 54%; P=0.008).”
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Comparison Rheos™ vs. neo™
1st Generation 2nd Generation
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Hoppe et al. JASH, 2012
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Barostim Neo
(n=30)
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-30
-25
-20
-15
-10
-5
0
Ch
ange
in S
ysto
lic B
P (
mm
Hg)
neo System
-35
-40
3 Months BAT
6 Months BAT
Unilateral
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Rheos System
Immediate On Group
(n=181 patients)
Pivotal
Bilateral
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Barostim Neo TM (n= 30, 6-month single arm open label) vs. Rheos Efficacy
(Rhéos trial)
Hoppe et al. JASH, 2012
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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
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Hoppe et al. JASH, 2012
Safety profile
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TARGET ORGAN DAMAGE PROTECTION
….BEYOND BP REDUCTION ?
CIC-P Nancy HEART SINGLE –ARM STUDY (DEBuT, Rheos)
27 Bisognano JACC 2011
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(Neo)
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Wallbach et al J Hypertens 2014
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KIDNEY Non-RANDOMIZED STUDY (Neo)
29 Wallbach et al J Hypertens 2014
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KIDNEY Non RANDOMIZED STUDY
(Neo)
30 Wallbach et al J Hypertens 2014
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KIDNEY Non RANDOMIZED STUDY (Neo)
31 Wallbach et al J Hypertens 2014
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KIDNEY Non-RANDOMIZED STUDY (Neo)
32 Wallbach et al J Hypertens 2014
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ESC/ESH Guidelines 2013
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J Hypertens 2014
Modeling substudy
based on the Debut and Rheos trials data: from a German societal perspective over a
lifetime horizon.
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« 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)
Granted
by the French Ministry of Health
ClinicalTrials.gov Identifier: NCT02364310
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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 m2
• No carotid condition associated with a contra-
indication to use Barostim NeoTM
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PRIMARY OBJECTIVE
Medico economic assessment: cost-
effectiveness
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MAIN EVALUATION CRITERIA
• Clinical trial :
ICER: cost / diurnal SBP mm Hg on ABPM
after 12 months
• modelisation :
Incremental ratio: cost / living year saved
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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
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EXPERIMENTAL DESIGN: PROBE
N= 140
N= 64
N= 64
N= 26 ROLL-IN GROUP
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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
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
First patient in, May 11, 2015 in Nancy !
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