Safety and Efficacy in Patients With and Without Cardiac - - PowerPoint PPT Presentation

Baroreflex Activation Therapy for the Treatment of Heart Failure with a Reduced Ejection Fraction: Safety and Efficacy in Patients With and Without Cardiac Resynchronization Therapy

Michael Zile, MD, William Abraham, MD, Fred Weaver, MD, Christian Butter, MD, Anique Ducharme, MD, Marcel Halbach, MD, Didier Klug, MD, Eric Lovett, PhD, Jochen Müller-Ehmsen, MD, Jill Schafer, MS, Michele Senni, MD, Vijay Swarup, MD, Rolf Wachter, MD, William Little, MD;

• n behalf of the BAT for HFrEF Study Group

HFrEF

 Adverse Cardiovascular Remodeling  Morbidity & Mortality

Autonomic Nervous System Imbalance

HFrEF

Baroreflex Activation

Sympathetic Parasympathetic

Integrated Autonomic Nervous System Response

Inhibits Sympathetic Activity Enhances Parasympathetic Activity

Carotid Baroreceptor Stimulation Afferent Signaling

↓ HR ↓ Remodeling ↑ Vasodilation ↓ Elevated BP ↑ Diuresis ↓ Renin secretion

Baroreflex Activation: Mechanism of Therapy in CHF

Abraham et al, JACC-HF, 2015. In Press: BAT safe and effective, improves clinical status and outcomes in patients with HFrEF

HFrEF

Sympathetic Parasympathetic

Cardiac Resynchronization

“CRT Restores Sympathetic- Vagal Balance By Altering Vagal Signal Transduction”

Demazunder et. al., Circ Res 2015

• Purpose: Define the differences in treatment

effect produced by BAT in protocol pre-specified groups of patients, those with CRT versus those without CRT.

• Design: Multi-national, prospective, randomized

controlled trial

• Randomized 1:1 to receive BAT plus optimal medical

and device therapy (“BAT Patients”) or optimal medical and device therapy alone (“Control patients”)

• Enrollment in US, Germany, Italy, France and Canada

Study Purpose and Design

• NYHA Functional Class III
• Left ventricular ejection fraction ≤ 35%
• Six-minute hall walk distance 150 - 400 m
• On stable optimal medical therapy for at least 4

weeks prior to baseline assessment and if indicated, device therapy for at least 6 months

• No restriction on QRS, concomitant devices, or AF

Key Enrollment Criteria

Variable No-CRT (n=95) CRT (n=45)

Age (years) 63 ± 12 68 ± 9 * Gender: Female 17% 9% Race: Caucasian 83% 91% NYHA: Class III 99% 100% MLWHF QOL Score 48 ± 21 44 ± 24 6 Minute Hall Walk Distance (m) 302 ± 81 303 ± 84 HR (bpm) 74 ± 12 72 ± 10 SBP (mmHg) 117 ± 18 118 ± 19 DBP (mmHg) 73 ± 11 70 ± 10 LVEF (%) 25 ± 7 24 ± 6 NT-pro BNP (pg/mL, Median [IQR]) 1144 [534, 3529] 1457 [472, 4603] eGFR (mL/min) 60 ± 20 55 ± 19 History of Coronary Artery Disease 71% 60% History of Atrial Fibrillation 41% 51% HF hospitalizations (over 6 Mo prior to enrollment, days/pt/year) 6.3 ± 19 1.8 ± 5.0

Baseline Demographics

* = p < 0.05 CRT vs. No-CRT

Variable No-CRT (n=95) CRT (n=45) Number of Meds 4.6 ± 1.7 4.7 ± 2.0 ACE/ARB 83% 75% Beta-Blocker 86% 86% MRA 58% 48% Diuretic 85% 86% Ivabradine 3% 2% Digitalis 13% 23% Calcium Channel Blocker 9% 5% ICD 85% 91%

Baseline Medications and Devices

System or Procedure Related Major Adverse Neurological or Cardiovascular Events (MANCE) at 6 months: CRT: 100% Event-Free Rate 24 Subjects Implanted No-CRT: 96% Event-Free Rate 47 Subjects Implanted

Primary Safety Endpoint

• MLWHF Quality of Life Score
• Six-Minute Hall Walk Distance
• Serum Biomarker: NT-proBNP
• Echo Structure / Function
• Left Ventricular Ejection Fraction
• LV Volume
• Hospitalizations for Worsening Heart Failure
• Number of Hospitalizations
• Days Hospitalized

Efficacy Endpoints

Two sets of statistical comparisons: 1- Differences in the changes from baseline to 6 months in BAT compared with Control. CRT analyzed separately from no-CRT patients. 2- Differences in the response to therapy with BAT in CRT compared with the no-CRT patients.

Statistical Analysis

• 40
• 30
• 20
• 10

10

6 Month Change from Baseline

BAT Control

no-CRT

BAT Control

CRT

• 21.6

3.5

• 9.3
• 0.9

Improvement

MLWHF QoL Score

p < 0.001 p = 0.23 p = 0.04

6-MHW Distance

• 80
• 40

40 80 120

6 Month Change from Baseline Meters

BAT Control

no-CRT

BAT Control

CRT

85.5 3.6 16.4

• 3.5

Improvement

p = 0.003 p = 0.38 p = 0.01

NT-proBNP

• 400
• 200

200 400 600

6 Months Change from Baseline pg/mL

BAT Control

no-CRT

BAT Control

CRT

• 97

[-505, 93] 116.0 [-74, 700] 79.8 [-452, 402] 433 [64, 537]

p = 0.03 p = 0.16 p = 0.59

LV Ejection Fraction

• 6
• 4
• 2

2 4 6

6 Month Change from Baseline %

BAT Control

no-CRT

BAT Control

CRT

4.3

• 0.1
• 1.2
• 0.1

Improvement

p < 0.03 p = 0.71 p = 0.02

• 20
• 15
• 10
• 5

5 10

6 Month Change from Baseline Days

BAT Control

no-CRT

BAT Control

CRT

• 8.9

0.18

• 1.05
• 0.13

Improvement

Heart Failure Hospitalization Days

p = 0.05 p = 0.75 p = 0.09

Differences in the response to therapy with BAT in No-CRT compared with CRT patients Measure Estimate P-value Favors QoL Score

• 12.31

0.040 No-CRT 6MHWD (meters) 69.05 0.010 No-CRT NT-proBNP (pg/mL)

• 841.32

0.59 No-CRT LVEF (%) 5.51 0.022 No-CRT # HF Hospitalization Days

• 8.08

0.09 No-CRT

Summary

• Baroreflex Activation Therapy is safe in HFrEF.
• BAT significantly improves quality of life score,

exercise capacity, NT-proBNP, and possibly the burden of HF hospitalizations.

• Results were most pronounced and statistically

significant in No-CRT patients.

• Each of these observations should be confirmed

in an adequately powered, prospective, randomized clinical outcome trial.