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

CIC-P Nancy

CIC-P Nancy

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

CIC-P Nancy

CIC-P Nancy

in resistant hypertension

Heusser et al Hypertension 2010

Acute Baroreceptor Stimulation

CIC-P Nancy

Wustmann et al Hypertension 2009

Chronic Baroreceptor Stimulation

in resistant hypertension

CIC-P Nancy

1st generation Barostim: Rheos™

CIC-P Nancy

J Am Coll Cardiol 2010;56:1254–8

CIC-P Nancy

J Am Coll Cardiol 2010;56:1254–8

CIC-P Nancy

De Leeuw, ESC 2013

CIC-P Nancy

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

CIC-P Nancy

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

CIC-P Nancy

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

CIC-P Nancy

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).

15

CIC-P Nancy

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

CIC-P Nancy

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).

17

CIC-P Nancy

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

CIC-P Nancy

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%

CIC-P Nancy

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).”

CIC-P Nancy

Comparison Rheos™ vs. neo™

1st Generation 2nd Generation

CIC-P Nancy Barostim Neo TM (n= 30, single arm open label)

Hoppe et al. JASH, 2012

CIC-P Nancy

Barostim Neo

(n=30)

-26

-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

-26

Rheos System

Immediate On Group

(n=181 patients)

Pivotal

Bilateral

-26

Barostim Neo TM (n= 30, 6-month single arm open label) vs. Rheos Efficacy

(Rhéos trial)

Hoppe et al. JASH, 2012

CIC-P Nancy

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

CIC-P Nancy Barostim Neo TM (n= 30, single arm open label)

Hoppe et al. JASH, 2012

Safety profile

CIC-P Nancy

TARGET ORGAN DAMAGE PROTECTION

….BEYOND BP REDUCTION ?

CIC-P Nancy HEART SINGLE –ARM STUDY (DEBuT, Rheos)

27 Bisognano JACC 2011

CIC-P Nancy VASCULAR SINGLE –ARM STUDY

(Neo)

28

Wallbach et al J Hypertens 2014

CIC-P Nancy

KIDNEY Non-RANDOMIZED STUDY (Neo)

29 Wallbach et al J Hypertens 2014

CIC-P Nancy

KIDNEY Non RANDOMIZED STUDY

(Neo)

30 Wallbach et al J Hypertens 2014

CIC-P Nancy

KIDNEY Non RANDOMIZED STUDY (Neo)

31 Wallbach et al J Hypertens 2014

CIC-P Nancy

KIDNEY Non-RANDOMIZED STUDY (Neo)

32 Wallbach et al J Hypertens 2014

CIC-P Nancy

ESC/ESH Guidelines 2013

33

CIC-P Nancy

J Hypertens 2014

Modeling substudy

based on the Debut and Rheos trials data: from a German societal perspective over a

lifetime horizon.

CIC-P Nancy

« 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

CIC-P Nancy

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

CIC-P Nancy

PRIMARY OBJECTIVE

Medico economic assessment: cost-

effectiveness

CIC-P Nancy

MAIN EVALUATION CRITERIA

• Clinical trial :

ICER: cost / diurnal SBP mm Hg on ABPM

after 12 months

• modelisation :

Incremental ratio: cost / living year saved

CIC-P Nancy

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

CIC-P Nancy

EXPERIMENTAL DESIGN: PROBE

N= 140

N= 64

N= 64

N= 26 ROLL-IN GROUP

CIC-P Nancy

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 !

CIC-P Nancy

43

www.inicrct.org