1. CVRx Baroreflex Activation Therapy:
Hypertension and Heart Failure Treatment
Robert S. Schwartz, MD
Minneapolis Heart Institute

2. Robert S. Schwartz, MD Consulting Fees MEDRAD Boston Scientific
Abbott Vascular
Edwards Lifesciences

3. The Baroreflex: a Therapeutic Target
Elements of the autonomic Nervous System
Floras, et al. JACC Vol. 54, No. 5, 2009 2 2

4. Resistant Hypertension Treated with Baroreflex Activation
Wireless Programming System
Baroreflex
Activation Lead
Implantable
Pulse Generator
>400 patients treated worldwide, +5 years
CE Marked for the treatment
of resistant hypertension 3

5. Stimulating Carotid Sinus Reduces Blood Pressure
63 yo awake female
~ 4 min
1 day postop, arterial line. Prompt changes w device. 4 4

6. Rheos Pivotal Trial (N=322)
Prospective, randomized, placebo-controlled clinical trial
Demonstrate safety and efficacy of Rheos BAT
Fully enrolled: 322 subjects implanted at 42 centers in the US & in Europe
Final Trial results expected in 2011
2:1 (Group A : Group B)
Implant
Randomization
6-Month Blinded Evaluation
6-Month Evaluation
Long-Term Follow-Up
Open Label – Device ON (N=55)
Group A – Device ON (N=181)
Group A – Device ON
Group B – Device OFF (N=84)
Group B – Device ON
Pivotal Trial. 6 mos. All have crosed 6 mo endpoint
ClinicalTrials.gov Identifier NCT 5

7. DEBuT 4-year Blood Pressure Reduction
Systolic
(Baseline = 193 ± 36 mmHg)
Diastolic
(Baseline= 111 ± 20 mmHg)
Heart Rate
(Baseline= 74 ± 13 bpm) -1 -4
-5°
-10 -5
-18*
-22 †
-21*
-20
Change in mmHg or bpm
Anti-hypertensive Medications
Baseline
5.0  1.3
1 year
-0.2  0.3 (p=0.51)
2 years
-0.7  0.4 (p=0.14)
3 years
-0.8  0.4 (p=0.06)
4 years
-1.6  0.5 (p=0.02)
-30 †
-30
-36 †
-38 †
-40 †
-40
1 year
2 years
-53 †
-50
3 years
(N=18)
4 years
°p < 0.05
*p < 0.005
†p < 0.001
Kroon et al, Journal of Hypertension 2010;28(e-suppl A):278 6 6 6

8. Office BP/HR Response 1 Year of Rheos Rx
Systolic BP
Diastolic BP
Heart Rate
200
193
179
175
150
155*
146*
125
111
Blood Pressure (mmHg) /
Heart Rate (BPM)
104
100
89*
88* 74 74 75 70
70† 50 25
DEBuT
(N = 18)
Pivotal
(N = 110)
DEBuT
(N = 18)
Pivotal
(N = 110)
DEBuT
(N = 18)
Pivotal
(N = 110)
Pre-Implant
*p value for change within study < 0.001
† p value for change within study < 0.005
12 Months of Therapy
12 month (Debut) and 12 mo Pivotal. Comparable reductions. Note: all pts on for at least 6 mos.
Kroon et al, Journal of Hypertension 2010;28(e-suppl A):278 7

9. Change in 6-Minute Hall Walk and QOL at 3 and 12 Months*
Baseline
500 #
100 *
3-Month
490 95
12-Month 93 92 *
480 90 #
p < 0.05,
p = 0.06
475
470 85 84
460 80
460
6-MHW Distance (meters)
450
SF-12 Total Score 75
440 70
438
430 65
420 60
410 55
400 50
6-MHW Distance
SF-12 Total
(N = 21)
(N = 18)
Bisognano et al, Journal of Cardiac Failure 2009: 15(6):S63 Abstract

10. ESC 2010 – What Happened?
“… data safety monitoring board told the company the pivotal trial of the device in 322 patients is unlikely to meet one of its end points, efficacy at six months.” 9 9

11. What Happened?
Problems with the 10 mmHg/6 mo endpoint: Placebo responded too well
Response in off mode was too good, and the 10 mmHg was too subtle. Thus endpoint missed.
However, data appear on a trajectory to meet 12 mo endpoint.
Full results due this year

12. Change in Plasma Renin: DeBut Trial
Expect the opposite
Heusser et al. Hypertension 2010;55: 11

13. Electrophysiologic Observations
240
700
53 yo male
639
220
202
Pre-Implant
600
200
3-Month
184
180
500
160
142
144
140
127
400
116
120
24-Hr PVC Count
100
300 80
200 60 44 40
100 20 6 6
Office SBP
BP effect? Therapy effect? Autonomic effect?
ABPM SBP
ATI
LVMi
PVC Count
Bisognano et al, Heart Rhythm 2009; 6(5): S327 Abstract 12 12

14. Summary Rheos Baroreflex Therapy in resistant HTN
Programmable device with ability to personalize therapy
Significant & sustained BP reduction with regression of LV Hypertrophy
Pivotal Trial for HTN fully enrolled, to be completed by 2011
Mechanisms suggested by observation
Reduced sympathetic nervous system activity
Increased parasympathetic nervous system activity
Potential therapy for HFNEF
Reductions in LV Mass Index
Pivotal Trial for HF underway 13

15. CVRx Baroreflex Activation Therapy:
Hypertension and Heart Failure Treatment
Robert S. Schwartz, MD
Minneapolis Heart Institute 14