results from the rheos pivotal trial baroreflex activation therapy sustainably lowers blood pressure...
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Results from the Rheos Pivotal Trial
Baroreflex Activation Therapy Sustainably Lowers Blood Pressure in Patients with Resistant Hypertension
John Bisognano, Domenic Sica, Mitra Nadim, Luis Sanchez, George Bakris, On Behalf of the Rheos Pivotal Trial Investigators
Baroreflex Activation Therapy (BAT) The CVRx Rheos® System
2
ImplantablePulse Generator
BaroreflexActivation Leads
ProgrammingSystem
Baroreflex Activation Therapy (BAT) Continuously Modulates the Autonomic Nervous System
Kidneys
↓ HR ↑ Vasodilation
↓ Stiffness
↑ Diuresis
↓ Renin secretion
Carotid Baroreceptor Stimulation
Heart
Vessels
Brain
Autonomic Nervous SystemInhibited Sympathetic Activity
Enhanced Parasympathetic Activity
Prospective randomized double-blind trial 322 patients at 49 sites 55 roll-in patients / 265 randomized (2:1)
Co-primary endpoints1. 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
Rheos Hypertension Pivotal Trial Design
6-Month BlindedEvaluation Period
6-Month BlindedEvaluation 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 63 9 12
Key Inclusion Criteria
SBP ≥ 160 mmHg
DBP ≥ 80 mmHg
24 hour ABPM ≥ 135 mmHg
At least one month of maximally tolerated therapy with at least three appropriate antihypertensive medications, including a diuretic
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
Pivotal Trial Baseline Medications
Group A(N = 181)
Group B(N = 84)
Diuretic 96% 92%
Beta Blocker 86% 83%
Calcium Channel Blocker 65% 71%
ACE Inhibitor 57% 54%
ARB 47% 43%
Alpha Blocker 12% 18%
Sympatholytic 44% 54%
Minoxidil 14% 15%
1st Endpoint – Short Term Acute Response20% super-superiority – Responder rate device ON vs. device OFF
% o
f P
atie
nts
with
≥ 1
0mm
Hg
SB
P R
educ
tion
at 6
Mon
ths
0
10
30
40
60
20
50
70
54%
8%N = 181 N = 84
46%
Goal Diff (A-B) >20%
Month-6ON
Month-6OFF Month-6
ON - OFF
2nd Endpoint – Long-term Sustained Response Percent of Sustained Responders at 12 Months
88%
60
70
80
90
OPC: 65%
100
p-value < 0.001
% o
f S
usta
ined
Res
pond
ers
at 1
2 m
onth
s
Month-12ON
N = 97
3rd Endpoint – Short Term Procedure Adverse Events30-Day Event Free rate
75%
% o
f P
atie
nts
Eve
nt F
ree
at 3
0 da
ys
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
91.7
% o
f P
atie
nts
Eve
nt F
ree
at 6
Mon
ths
60
70
80
90
72.6
Goal Diff (A-B) < 15%
100
87.6
N = 170 N= 85
15% + C.I.
p-value < 0.001
4th Endpoint – Short Term HTN Therapy Adverse Events 6-Month Event Free Rate
Month-6OFF
Month-6ON
40% Reduction of Hypertensive Crises, 23% Reduction of Events
5th Endpoint – Long Term Device Adverse Events12-Month Event Free Rate
% o
f P
atie
nts
Eve
nt F
ree
at 1
2 M
onth
s
88%
60
70
80
90
100p-value < 0.001
OPC: 72%
12 MonthsGroups A+B
Types of Adverse Events
2% hypertension-related strokes
All other events < 2%
76% of all adverse events fully resolved
N = 265
Endpoint SummaryDescription Timeframe N p-value
Short Term Acute Efficacy
6 months 265 0.97
Long Term Sustained Efficacy
12 months 97 <0.001
Short Term Procedure
Adverse Events30 days 265 1.00
Short Term BATAdverse Events
6 months 265 <0.001
Long Term Device Adverse
Events12 months 265 <0.001
0% 20%
7.7%
0%-15%
2.4%
87.6
65% 100%
87.2
72% 100%
74.8
82% 100%
N = 81N = 171N = 172 N = 80
Pre-Specified Ancillary Efficacy Analysis% of Patients at SBP ≤ 140mmHg
42%
0
15
30
45
60
Month-6ON
Group A
53%
Month-12ON
Group A
24%
51%p = 0.005
p = 0.70
% o
f P
atie
nts
SB
P
≤ 14
0 m
mH
g
Month-6OFF
Group B
Month-12ON
Group B
Pre-specified Echo Sub-Study Long Term Regression in Left Ventricular Hypertrophy
LV M
ass
Inde
x (k
g/m
2 )
p-value < 0.01
N = 60
95
105
110
115
Baseline
102
12 Months90
100
120
117
N = 60
Additional Observations – Post-Hoc Efficacy AnalysisResults at 12 Months and Beyond
81% of patients were responders (SBP ≥ 10 mmHg relative to pre-implant)The average SBP drop at 12 months among responders was 44 mmHg63% of responders reached blood pressure goal
26
0
10
20
30
40
Month-6ON
43%
35 54%
SB
P R
educ
tion
(mm
Hg)
Month-12ON
Therapeutic efficacy continued to improve over time:
0
15%
30%
45%
60%
Per
cent
Pat
ient
s at
SB
P G
oal
Month-6ON
Month-12ON
Conclusions
3 primary endpoints achieved: long term efficacy, long term device safety, and short term therapy safety
2 primary endpoints not achieved: short term efficacy and procedure adverse events
Weight of overall evidence suggests long term efficacy of BAT to reduce blood pressure in resistant hypertension
These data justify further development of BAT
Moving Forward: Miniaturization to Reduce Procedure Invasiveness
1st Generation CSL
New Generation CSL
Investigators and Participating Centers
US Mark Passman; University of Alabama, AL
Mason Weiss; Apex Cardiology Consultants, CA
Fred Weaver; University of Southern California, CA
Preston Flanigan; VISOC, CA
Fadi Matar; Florida Cardiovascular Institute, FL
Harischandra Karunaratne; Florida Hospital Cardiovascular Institute, FL
Peter Wassmer; Heart & Vascular Institute, FL
Jeffrey Travis; Southeast Regional Research Group, GA
Michael Park; Iowa Heart Center, IA
George Bakris; University of Chicago, IL
Sibu Saha; University of Kentucky, KY
Mitchell Weaver; Henry Ford Health System, MI
Marcus Rothstein; Washington University, MO
Paul van Bemmelen; Temple University, PA
Gregory Roberts; Baptist Hospital of East Tennessee, TN
Eric Peden; The Methodist Hospital System, TX
Paul Kramer; Liberty Hospital, TX
Stephen Motew; Novant Clinical research Inst, NC
Vasilios Papademetriou; Veteran’s Affairs Medical Center, DC
Branislav Schifferdecker; Oklahoma Cardiovascular Research, OK
Gregory Trachiotis; GW Medical Faculty Associates, DC
James Fogartie; Rex HealthCare, NC
Deepak Gangahar; Nebraska Heart Institute, NE
Massimo Napolitano; Hackensack University Medical Center, NJ
Daichi Shimbo; Columbia University Medical Center, NY
John Bisognano; University of Rochester, NY
Anthony Comerota; Jobst Vascular Center, OH
Eugene Chung; The Lindner Clinical Trial Center, OH
Jean Starr; Ohio State University Medical Center, OH
Satish Muluk; Allegheny General hospital, PA
Paul Casale; Lancaster General Hospital, PA
William Todd Bohannon; Scott & White Memorial hosp, TX
William Edwards; St Thomas Research Institute, TN
James Hermiller; St Vincent Medical group, IN
Pat Kelly; Sanford research, SD
Michael Koren; jacksonville Center Clinical research, FL
Todd Reil; U of Minnesota, MN
Europe Peter De Leeuw; University of Maastricht, Netherlands
Hermann Haller; University of Hannover, Germany