0. 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

1. Baroreflex Activation Therapy (BAT) The CVRx Rheos® System
Programming
System
Baroreflex
Activation Leads
Implantable
Pulse Generator

2. Autonomic Nervous System
Baroreflex Activation Therapy (BAT)
Continuously Modulates the Autonomic Nervous System
Carotid Baroreceptor Stimulation
Brain
Autonomic Nervous System
Inhibited Sympathetic Activity
Enhanced Parasympathetic Activity
Heart
Vessels
Kidneys
↓ HR
↑ Vasodilation ↓ Stiffness
↑ Diuresis ↓ Renin
secretion 2

3. 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
Short Term Acute Response
Long Term Sustained Response
Short Term Procedural AEs
Short Term Hypertension Therapy AEs
Long Term Device AEs
Implant
Randomization
6-Month Blinded
Evaluation Period
6-Month Blinded
Evaluation Period
Long-Term Follow-Up
N = 181
Group A – Device ON
Group A – Device ON
N = 84
Group B – Device OFF
Group B – Device ON -1 3 6 9 12
(months) 3 3

4. 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

5. 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
Systolic BP (mean mmHg ± sd)
179
± 22
176
Diastolic BP (mean mmHg ± sd)
103
± 16
± 13
Heart Rate (mean bpm ± sd) 74
± 14 75

6. 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%
Minoxidil
14%
15% 6

7. 1st Endpoint – Short Term Acute Response 20% super-superiority – Responder rate device ON vs. device OFF
N = 84
65%
20%
A - B
45%
TRIAL ASSUMPTIONS
N = 181
54% 8%
N = 181
N = 84
46%
TRIAL RESULTS 70 60 50 40
% of Patients with ≥ 10mmHg
SBP Reduction at 6 Months 30
Goal Diff (A-B) >20% 20 10
Month-6 ON
Month-6
OFF
Month-6
ON - OFF 7

8. 2nd Endpoint – Long-term Sustained Response Percent of Sustained Responders at 12 Months
100 90
88% 80
p-value < 0.001
% of Sustained Responders at 12 months 70
OPC: 65% 60
N = 97
Month-12 ON 8

9. 3rd Endpoint – Short Term Procedure Adverse Events 30-Day Event Free rate90
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: 82% 80
75% 70
% of Patients Event Free at 30 days 60 50
N = 270
30-day
Groups A+B 9

10. 4th Endpoint – Short Term HTN Therapy Adverse Events 6-Month Event Free Rate
100
91.7
87.6 90 80
15% + C.I.
72.6
Goal Diff (A-B) < 15%
% of Patients Event Free at 6 Months 70 60
p-value < 0.001
N = 170
N= 85
Month-6
OFF
Month-6 ON
40% Reduction of Hypertensive Crises, 23% Reduction of Events 10

11. 5th Endpoint – Long Term Device Adverse Events 12-Month Event Free Rate
100
p-value < 0.001 90
88%
Types of Adverse Events
2% hypertension-related strokes
All other events < 2%
76% of all adverse events fully resolved 80
% of Patients Event Free at 12 Months
OPC: 72% 70 60
N = 265
12 Months
Groups A+B 11

12. Endpoint Summary Description 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 Events
30 days
1.00
Short Term BAT
Adverse Events
Long Term Device Adverse Events
7.7% 0%
20%
87.6
65%
100%
74.8
82%
100%
2.4%
-15% 0%
87.2
72%
100% 12 12 12 12

13. Pre-Specified Ancillary Efficacy Analysis % of Patients at SBP ≤ 140mmHg60
53%
p = 0.005
51%
N = 171
N = 81 45
42%
N = 172
SBP ≤ 140 mmHg
% of Patients 30
24%
N = 80 15
Month-6 ON
Group A
Month-6
OFF
Group B
Month-12 ON
Group A
Month-12 ON
Group B 13

14. Pre-specified Echo Sub-Study Long Term Regression in Left Ventricular Hypertrophy
120
117
p-value < 0.01
115
110
LV Mass Index (kg/m2)
105
Left Ventricular Mass Index
Red = severely abnormal
Lt green = mild to moderately abnormal
Dk green = reference range
102
100 95
N = 60
N = 60 90
Baseline
12 Months 14 14

15. Percent Patients at SBP Goal
Additional Observations – Post-Hoc Efficacy Analysis Results 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 mmHg
63% of responders reached blood pressure goal
Therapeutic efficacy continued to improve over time: 40
60% 35
54%
43% 30 26
45%
SBP Reduction (mmHg)
Percent Patients at SBP Goal 20
30% 10
15%
Month-6 ON
Month-12 ON
Month-6 ON
Month-12 ON

16. These data justify further development of BAT
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 16

17. Moving Forward: Miniaturization to Reduce Procedure Invasiveness
1st Generation CSL
New Generation CSL

18. Investigators and Participating CentersUS
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