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

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

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

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

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

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 -1 0 6 12 Pivotal Trial. 6 mos. All have crosed 6 mo endpoint ClinicalTrials.gov Identifier NCT00442286 5

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

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

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

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

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

Change in Plasma Renin: DeBut Trial Expect the opposite Heusser et al. Hypertension 2010;55:619-626 11

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

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

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