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