Newer and Future (Device) Therapies for Heart Failure

William T. Abraham, MD, FACP, FACC, FAHA, FESC

Professor of Medicine, Physiology, and Cell Biology

Chair of Excellence in Cardiovascular Medicine

Chief, Division of Cardiovascular Medicine

Deputy Director, Davis Heart & Lung Research Institute

The Ohio State University

Columbus, Ohio

Dr. Abraham has received consulting fees and/or research grants from Abbott Vascular, Cardiokinetix Inc., CardioMEMS, CVRx, Impulse Dynamics, Medtronic, and St. Jude Medical,

and Sunshine Heart.

Current Evidence-Based Treatment of Chronic Systolic Heart Failure

Control Volume Reduce Mortality

Diuretics

Digoxin

-BlockerACEI

or ARB

AldosteroneAntagonist

or ARB

Treat Residual Symptoms

CRT an ICD*

Hyd/ISDN*

*For all indicated patients.

Abraham WT, 2005.

Current Evidence-Based Treatment of Chronic Diastolic Heart Failure

Recommended Therapies for Routine Use:

• Treating known risk factors (e.g., hypertension) with therapy consistent with contemporary guidelines

• Ventricular rate control for all patients with AF• Drugs for all patients

• Diuretics• Drugs for appropriate patients

• ACEI• ARBs• Beta-Blockers• Digitalis

• Coronary revascularization in selected patients• Restoration/maintenance of sinus rhythm in appropriate

patients

Guideline Recommendations* for the Management of Diastolic Heart Failure

*From ACC/AHA and HFSA heart failure guidelines; All of these recommendations based on consensus

Despite Current Therapies, Heart Failure Morbidity and Mortality Remain High

• 30% to 40% of patients are in NYHA class III or IV

• Re-hospitalization rates• 2% at 2 days • 25% at 1 month• 50% at 6 months

• 5-year mortality ranges from 15% to more than 50%• Asymptomatic LVD 15%• Mild-moderate HF 35%• Advanced HF >50%

Devices Under Investigation for the Treatment of Heart Failure

• Cardiac Contractility Modulation

• Cardiac Support Devices

• Ventricular Partitioning Devices

• Percutaneous Valve Repair

• Continuous Positive Airway Pressure Breathing (including ASV)

• Transthoracic Phrenic Nerve Pacing

• Ultrafiltration Devices

Devices Under Investigation for the Treatment of Heart Failure

• Newer Counter-pulsation Technologies

• Second and Third Generation LVADs

• Percutaneously-applied Ventricular Assistance

• Totally Implantable Artificial Hearts

• Fluid Monitors

• Implantable Hemodynamic Monitors

• Many others

Cardiac Contractility Modulation (CCM)

Detect localactivation

Apply electric signal during absolute refractory period

Delay

Durat

ion

Amplitude

CCM

MuscleForce

Optimizer II System

Early Studies of CCM

• Preclinical and early clinical studies showed that CCM:• Increases cardiac contractility• Reduces myocardial work• Produces LV reverse remodeling• Induces molecular changes (in genes, proteins

and phosphorylation) indicative of improved calcium handling and contractile function

• These observations led to pivotal trials in Europe (FIX-HF-4) and the U.S. (Fix-HF-5)

Results of the FIX-HF-4 andFIX-HF-5 Studies

• In NYHA class III-IV heart failure patients, CCM improves

• Exercise capacity• Quality of Life (MLWHFQ score)• NYHA

• A subgroup of patients (EF ≥ 25, NYHA III) appears to benefit most from CCM*

• A prospective randomized controlled trial to confirm these observations (FIX-HF-5b) is ongoing in the U.S.

*Abraham WT, et al. J Cardiac Failure 2011

Baroreflex Activation Therapy (BAT)

Kidneys

↓ HR ↑ Vasodilation↓ Stiffness

↑ Diuresis ↓ Renin secretion

Carotid Baroreceptor Stimulation

Reduced blood pressure

Reduced afterload, wave reflections and augmentation

Reduced myocardial work and oxygen consumption

Reduced neurohormonal stimulus

Increased venous capacitance

Heart Vessels

Brain

Autonomic Nervous SystemInhibited Sympathetic Activity

Enhanced Parasympathetic Activity

BaroreflexActivation

Lead

ImplantablePulse

Generator

Response to BAT is Prompt andDose-Related

~ 4 min

BAT for Heart Failure

• Heart failure shares similar underlying mechanisms and drug treatments with hypertension

• BAT technology will be applied in the same way to treat heart failure patients

• Initial studies targeting heart failure with preserved LVEF

5.8 Million Heart Failure Patients in U.S.

Drugs

Drugs + Devices

No Approved Therapies

Preserved EF

Low EF

HOPE-4-HF Study Overview

Enrollment uninterrupted

Data counts toward endpoint

First Phase Second Phase

Rheos + Medical Management

Implant/Activate

Medical Management Only

Ran

do

miz

e 2:

1

Spinal Cord Stimulation forHeart Failure

• SCS is approved for the treatment of chronic pain syndromes and has been used to treat intractable angina pectoris

• Current evidence suggests that thoracic SCS decreases sympathetic tone

• In a canine model, SCS caused vagal-like responses by slowing sinus rate and prolonging AV nodal conduction time and ventricular refractory period

• These effects may be beneficial in chronic heart failure

Clinical Response to SCS in a Canine Model of Heart Failure

Lopshire JC, et al. Circulation 2009

Echocardiographic Response to SCS in a Canine Model of Heart Failure

Lopshire JC, et al. Circulation 2009

Transvenous Phrenic Nerve Stimulation

Respiratory Rhythm Management

• Unilateral phrenic nerve stimulation of the diaphragm

• Implantable stimulator with proprietary algorithm

• Implantable proprietary transvenous leads

• Stimulation algorithm restores natural breathing pattern, stabilizes gas exchange and decreases hypoxic episodes

• Inserted by cardiologist or EP using techniques similar to existing cardiac devices

• Currently stand-alone device, but can be combined with other cardiac therapies

With Therapy

Acute Respiratory Rhythm Management Improves Sleep Indices

*t-test

Central Apnea Index

% change = -91.0p<0.0001*

% change = -49.0p=0.0006*

*t-test

% change = - 55.0p=0.001*

ODI 4 (%)

% change = -51.0p=0.0005*

Arousal Index

*t-test*t-test

Oxygen Desaturation Index 4%

Apnea Hypopnea Index

Ponikowski P, ….. Abraham WT. Eur Heart J 2011

Implantable Hemodynamic Monitors

LV Pressure Sensor

PA Pressure Sensors

RV Pressure Sensors

LA Pressure Sensor

The Pulmonary Artery Pressure Measurement System

Catheter-based delivery system MEMS-based pressure sensor

Home electronicsPA Measurement database

CHAMPION Trial: Cumulative HF Hospitalizations Over Entire Randomized Follow-Up Period

p < 0.001, based on Negative Binomial Regression

Cum

ulat

ive

Num

ber

of H

F H

ospi

taliz

atio

ns

Days from Implant

At RiskTreatment 270 262 244 209 168 130 107 81 28 5 1Control 280 267 252 215 179 138 105 67 25 10 0

Abraham et al., Lancet 2011

Secondary Efficacy Results

Treatment(n=270)

Control(n=280) p-Value

Change from Baseline in Mean Pulmonary Artery Pressure at 6 Months Mean AUC

-156 33 0.008

Subjects Hospitalized for Heart Failure at 6 Months# (%)

54 (20) 80 (29) 0.022

Days Alive Outside Hospital at 6 MonthsMean

174.4 172.1 0.022

Minnesota Living with Heart Failure Questionnaire at 6 MonthsMean

45 51 0.024

CHAMPION: Putting It Altogether

Pulmonary Artery Pressure

Medication Changes On Basis of Pulmonary Artery PressureP<0.0001

Pulmonary Artery Pressure ReductionP=0.008

Heart Failure Related Hospitalization ReductionP<0.0001

Quality of Life ImprovementP=0.024

P values for Treatment Vs Control Group

Implantable LA Pressure Monitor

Implantable Communications Module (ICM)

Lead

Sensor Module

Proximal Anchor

Distal Anchor

Sensor Diaphragm

~ 3 mm

Measures•LAP•IEGM•Core Temp

Implantable Sensor Lead (ISL)

PAMPowers implant by RF

Atmospheric reference

Stores telemetry

Alerts patient to monitor

DynamicRX™

Meds, activity, MD contact

Handheld Patient Advisor Module

(s) carvedilol(25mg),1 tab(s) lisinopril(20mg), 1 tab*(d) furosemide(40mg),1 tab

Physician-Directed, Patient-Self Management

PAM

LAP ≥28 … Very High… furosemide 80mg, call MDLAP 19-27 … High………. 40mgLAP 10-18 … Optimal…… 20mgLAP 6-9 … Low…………10mgLAP ≤ 5 … Very Low…. hold, increase fluid intake

Remote(patient’s home)

Direct USB (in-clinic)

RF Telemetry

Application SoftwareTrends, Waveforms, Prescriptions

PC or Web Based

Optimal LAP makes it easier to up-titrate β-Blockers and ACE-I/ARBs

HOMEOSTASIS Trial ResultsReduction in Heart Failure Hospitalizations

Period Annualized Event Rate

P-values

12-mo period before enrollment

1.4 (1.1-1.9) 0.054

First 3 moObservation Period

0.68 (0.33-1.4) <0.001 0.041

After mo 3 Titration/Stability Periods

0.28 (0.18-0.45)

Ritzema J, ..… Abraham WT. Circulation 2010

LAPTOP-HF, an adequately powered randomized controlled trial to assess clinical safety and effectiveness of this approach, is underway

New Approach to the Non-Invasive Assessment of Lung Water

• Proprietary RF monitoring and imaging technology

• As fluid replaces air, there is an increase in the dielectric coefficient

• Measurement is localized (lung-specific) as opposed to other modalities (e.g., bio-impedance)

• Enables non-invasive and continuous monitoring of lung fluid concentration

ReDS Correlation with CT and Pressure(Pre-Clinical Data)

Inferior (Dependent)

Lobes

Superior Lobes

Start of volume loading

Diuretics

CT + ReDS

LVEDP, PAP

Fluid concentration and pressures correlate during volume overload; a lag is observed

during diuresis

Interclass Correlation = 0.95

Left Ventricular Partitioning: Rationale

• Decrease LVEDV

• Decrease LVESV

• Reshape ventricle

• Decrease LV radius

• Reduce LV wall stress

• Increase contractility

• Prevent further remodeling/ reverse remodeling

Percutaneous Ventricular Partitioning Device:System Components

• 75mm & 85mm diameter• Deliver via 14/16 French Catheter• Nitinol struts• ePTFE membrane• Radiopaque Pebax polymer foot

Cardiokinetix, Inc., Menlo Park, California, USA

PARACHUTE

LV

ES

V (

ml)

0

50

100

150

200

Baseline 6 months 12 months

155.3

196.1

160.9

p<0.001

p<0.001

Efficacy Results:LVESV, Paired data, mean ± SEM

Abraham et al., HFSA 2010 LBCT Presentation

All 1yr, n=28

Cardiac Support Devices

• Primary goal is to reduces LV radius and transmural pressure, so that diastolic wall stress will fall

• Other properties (e.g., elasticity) of such devices may provide ancillary mechanisms of benefit

• First generation devices (e.g. CorCap™) required a major surgical procedure (i.e., sternotomy)

• Newer devices (e.g., HeartNet™) can be placed via a minimally invasive approach and has unique elastic properties

Minimally Invasive Approach to Ventricular Elastic Support Therapy

• Super elastic compliant nitinol structure

• Defibrillation, pacing compatible

• Delivered with special delivery system through minithoracotomy

• Self anchoring, self tensioning

• Pre sized based on echo measurements

Paracor HeartNet™ Compliance

Circumferential Compliance (lbf/in)

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100

Tensile Strain (%)

Lo

ad (

lbf/

in)

Paracor Myocardium CSD Pericardium 25% Stretch 45% Stretch

The elastic compliance allows the device to

stretch and return to its

original position

PEERLESS-HF CRT Subset Data

P=0.036HR=2.2

PEERLESS-HF CRT Subset Data

P=0.06HR=2.0

Extra-Aortic Counterpulsation

Heart Fills - Cuff Inflates Heart Ejects - Cuff Deflates

to body

to heartreduce workload

Increased Blood Flow: + 60% coronary flow; + 30% cardiac output; Reduced Heart Workload: - 30% pulmon. Pressure; -33% LV wall stress

C-Pulse for Moderate Heart Failure Patients

ECG Sense Lead

Extra-aortic Cuff

Battery Pack

Driver

Interface Lead

Ventricular Assist Devices

• AHA estimates that 250,000 patients could benefit from long-term circulatory support

• Potential Opportunities• Bridge to Transplant

• est. 7,000 patients annually

• Permanent Support or “Destination Therapy”• est. 40,000 patients annually

• Bridge to Recovery• est. > 200,000 patients annually

LVADs as Destination Therapy in End-Stage Heart Failure100

80

60

40

20

00 6 12 18 24 30

68 38 22 11 5 1

61 27 11 4 3 0

No. at Risk

LV Assist Device

Medical Therapy

Survival(%)

Months

LV Assist Device

Medical Therapy

Rose et al., NEJM 2001

LVADs as Destination Therapy in End-Stage Heart Failure100

80

60

40

20

00 6 12 18 24 30

68 38 22 11 5 1

61 27 11 4 3 0

No. at Risk

LV Assist Device

Medical Therapy

Survival(%)

Months

LV Assist Device

Medical Therapy

Rose et al., NEJM 2001

• Generation II Devices (axial flow pumps)

Characteristics:• small, simple designs• high rpm• easy insertion/removal (minimally invasive techniques)

• durability risk/bearing

Use (targeted):• temporary support• bridge to transplant• bridge to recovery • limited “permanent” use

Ventricular Assist Devices

Heartmate II Axial Flow LVAD

• Generation III Devices (magnetic bearings)

Characteristics:• high reliability• fewer mechanical parts• complex engineering• closed loop systems (?)

Use (targeted):• temporary support• bridge to transplant• bridge to recovery • “permanent” use

Ventricular Assist Devices

HeartWare Ventricular Assist System

• Small implantable centrifugal pump

• Designed to be implanted in the pericardial space

• ?High rate of thrombotic complications

Micro-pumps: Short-Term Use Impela 2.5

• Percutaneous Heart Pump

• Delivers 2.5 L/min of flow

• Unloads the ventricle

• Designed for Ease of Use (Cath Lab)

• 9 Fr Catheter

• 12 Fr micro-axial pump

Micro-pumps: Short-Term Use Impela 5.0

• Requires arterial cutdown

• Delivers 5.0 L/min of flow

• Unloads the ventricle

• Surgical insertion

• 9 Fr Catheter

• 21 Fr micro-axial pump

Micro-pumps: Long-Term Use CircuLite Synergy

• Provides up to 4.25 liters/min of flow

• Size of a AA battery

• Small enough to be implanted subcutaneously in a "pacemaker-like" pocket through a minimally-invasive procedure

• CE Mark trial ongoing

Total Artificial Heart: Syncardia

• Rate of survival to transplantation with TAH was 79% versus 46% in controls (P<0.001)

• 1-year survival rate among the patients who received the artificial heart was 70%, as compared with 31 percent among the controls (P<0.001)

Copeland JG, et al. NEJM 2004

Artificial Heart Driver

• Only FDA-approved driver for powering the artificial heart in the U.S. is the 418-lb hospital driver

• A portable driver, which would allow patients to be discharged from the hospital, is under investigation in an IDE study

The (Distant) Future of Heart Failure Therapies

• Xenotransplantation

• Gene therapies

• Cell therapies• Myoblasts

• Stem cells

• Others