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First Generation BAT Results in Resistant Hypertension

First Generation BAT Results in Resistant Hypertension Baroreflex Activation Therapy Sustainably Lowers Blood Pressure in Patients with Resistant Hypertension. Baroreflex Activation Therapy (BAT) Continuously Modulates the Autonomic Nervous System. Carotid Baroreceptor Stimulation. Brain.

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First Generation BAT Results in Resistant Hypertension

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  1. First Generation BAT Results in Resistant Hypertension Baroreflex Activation Therapy Sustainably Lowers Blood Pressure in Patients with Resistant Hypertension

  2. 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 ↑ Natriuresis ↓ Renin secretion

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

  4. Immediate Dose Response ≈ 4 min

  5. Acute Muscle Sympathetic Nerve Activity After 3 Months of Therapy Blood Pressure (mmHg) MSNA (%) Time (mins) Heusser et al, HTN 2010

  6. Feasibility Study Results Sustained Reduction of SBP over 4 years Systolic (Baseline = 193 ± 36 mmHg) Diastolic (Baseline= 111 ± 20 mmHg) -10 0 -18 -21 -50 -22 Change in BP (mmHg) -20 -30 -36 -38 -30 -40 N = 18 1 year 2 years 3 years -53 -40 4 years Note: Unpublished results confirm sustained reduction 5 years out Kroon et al, ESH 2010

  7. Feasibility Study ResultsAcute Reduction of Aortic Augmentation Pressure 60 yo female Radial Aortic Control BAT Georgakopoulos et al, JCF 2010

  8. Feasibility Study ResultsBaroreflex Sensitivity is Chronically Maintained PRE-implant ChronicON Acute OFF 33° 32° 38° No evidence for impaired baroreceptor sensitivity No evidence for chronic baroreflex resetting during therapy

  9. Barostim Reduces Left Ventricular Mass Index at 3 and 12 Months 100% 80% 60% Severely Abnormal Range Women: > 122 g/m2 Men: > 149 g/m2 40% 20% P < 0.01 Moderately Abnormal range Women: 96 – 122 g/m2 Men: 116 – 149 g/m2 P < 0.01 Reference Range Women: <96 (g/m2) Men: <116 (g/m2) 0% Baseline 3 Months 12 Months (N=21) (N=21) 8 Bisognano et al, J Clinical Hypertension 2009

  10. 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 Rheos Hypertension Pivotal Trial Design 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 0 3 6 9 12 (months)

  11. 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

  12. Pivotal Trial Baseline Characteristics

  13. Pivotal Trial Baseline Medications

  14. 1st Endpoint – Short Term Acute Response20% super-superiority – Responder rate device ON vs. device OFF TRIAL ASSUMPTIONS TRIAL RESULTS 65% 70 N = 181 54% 60 N = 181 46% 45% 50 N = 84 A - B 40 % of Patients with ≥ 10mmHg SBP Reduction at 6 Months 30 20% Goal Diff (A-B) >20% N = 84 20 8% 10 0 Month-6 ON Month-6 OFF Month-6 ON - OFF

  15. 2nd Endpoint – Long-term Sustained ResponsePercent 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 OPC: Objective Performance Criteria

  16. 3rd Endpoint – Short Term Procedure Adverse Events30-Day Event Free rate 90 • 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 OPC: Objective Performance Criteria

  17. 4th Endpoint – Short Term HTN Therapy Adverse Events6-Month Event Free Rate 100 91.7 87.6 90 15% + C.I. 80 72.6 Goal Diff (A-B) < 15% % of Patients Event Free at 6 Months 70 60 p-value < 0.001 N = 85 N= 170 Month-6 OFF Month-6 ON 40% Reduction of Hypertensive Crises, 23% Reduction of Events

  18. 5th Endpoint – Long Term Device Adverse Events12-Month Event Free Rate 100 p-value < 0.001 90 88% 80 % of Patients Event Free at 12 Months OPC: 72% 70 60 N = 265 12 Months Groups A+B OPC: Objective Performance Criteria

  19. Pre-Specified Ancillary Efficacy Analysis% of Patients at SBP ≤ 140mmHg p = 0.70 60 53% p = 0.005 51% N = 171 N = 81 45 42% N = 172 % of Patients SBP ≤ 140 mmHg 30 24% N = 80 15 0 Month-6 ON Group A Month-6 OFF Group B Month-12 ON Group A Month-12 ON Group B

  20. Pre-specified Echo Sub-Study Long Term Regression in Left Ventricular Hypertrophy 120 117 p-value < 0.01 115 110 LV Mass Index (g/m2) 105 102 100 95 N = 60 N = 60 90 12 Months Baseline

  21. Additional Observations – Post-Hoc Efficacy AnalysisResults at 12 Months and Beyond 81% of patients were responders (SBP ≥ 10 mmHg relative to pre-implant) • Therapeutic efficacy continued to improve over time: 40 60% 54% 35 43% 30 26 45% SBP Reduction (mmHg) Percent Patients at SBP Goal 20 30% 10 15% 0 0 Month-6 Month-12 Month-6 Month-12

  22. Summary Baroreflex Activation Therapy in resistant hypertension Programmable device with ability to personalize therapy Significant & sustained BP reduction with regression of LV Hypertrophy MSNA measurements suggest sympathetic drive reduction is the mechanism of action Pivotal Trial results suggest long-term efficacy of BAT to reduce blood pressure in resistant hypertension 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 These data justify further development of BAT

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