Transcript Newer and Future Therapies for Heart Failure

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
Diuretics
Reduce Mortality
ACEI
or ARB
-Blocker
Aldosterone
Antagonist
or ARB
CRT 
an ICD*
Hyd/ISDN*
Treat Residual Symptoms
*For all indicated patients.
Abraham WT, 2005.
Digoxin
Current Evidence-Based Treatment of
Chronic Diastolic Heart Failure
Guideline Recommendations* for the
Management of 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
*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)
CCM
Amplitude
Muscle
Force
Apply electric signal
during absolute refractory
period
Detect local
activation
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 and
FIX-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)
Carotid Baroreceptor Stimulation
Brain
Autonomic Nervous System
Inhibited Sympathetic Activity
Enhanced Parasympathetic Activity
Heart
↓ HR
Baroreflex
Activation
Lead
Implantable
Pulse
Generator
Vessels
Kidneys
↑ Vasodilation
↓ Stiffness
↑ Diuresis
↓ Renin secretion
Reduced blood pressure
Reduced afterload, wave reflections and augmentation
Reduced myocardial work and oxygen consumption
Reduced neurohormonal stimulus
Increased venous capacitance
Response to BAT is Prompt and
Dose-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
 Drugs +
Devices
 Drugs
No Approved
Therapies
• Initial studies targeting
heart failure with
preserved LVEF
5.8 Million Heart Failure Patients in U.S.
Randomize 2:1
HOPE-4-HF Study Overview
Implant/
Activate
Rheos + Medical Management
Medical Management Only
First Phase
≤ 100 patients at 15 sites
FDA review on 30 Rheos
patients followed for 3 mo
Second Phase
540 patients at 70 U.S. sites and
20 OUS sites
Primary endpoint: CV death / HF
event
Enrollment uninterrupted
Data counts toward endpoint
Follow-up until 270 primary endpoint
events reached
Spinal Cord Stimulation for
Heart 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
Central Apnea Index
% change = -91.0
p<0.0001*
Apnea Hypopnea Index
% change = -49.0
p=0.0006*
*t-test
*t-test
Oxygen ODI
Desaturation
Index 4%
4 (%)
% change = - 55.0
p=0.001*
Arousal Index
% change = -51.0
p=0.0005*
*t-test
Ponikowski P, ….. Abraham WT. Eur Heart J 2011
*t-test
Implantable Hemodynamic Monitors
LV Pressure Sensor
RV Pressure Sensors
PA Pressure Sensors
LA Pressure Sensor
The Pulmonary Artery Pressure
Measurement System
Catheter-based delivery system
MEMS-based pressure sensor
Home electronics
PA Measurement database
Cumulative Number of HF Hospitalizations
CHAMPION Trial: Cumulative HF Hospitalizations
Over Entire Randomized Follow-Up Period
260
Treatment
240
Control
220
p < 0.001, based on Negative
Binomial Regression
200
180
160
140
120
100
80
60
40
6 Months
15 Months
20
0
0
At Risk
Treatment 270
Control
280
90
262
267
180
244
252
270
360
450
540
630
720
810
209
215
168
179
130
138
107
105
81
67
28
25
5
10
Days from Implant
Abraham et al., Lancet 2011
900
1
0
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
Months
Mean
174.4
172.1
0.022
45
51
0.024
Minnesota Living with Heart Failure
Questionnaire at 6 Months
Mean
CHAMPION: Putting It Altogether
Pulmonary Artery Pressure
Medication Changes On Basis of Pulmonary Artery Pressure
P<0.0001
Pulmonary Artery Pressure Reduction
P=0.008
Heart Failure Related Hospitalization Reduction
P<0.0001
Quality of Life Improvement
P=0.024
P values for Treatment Vs Control Group
Implantable LA Pressure Monitor
Implantable
Sensor
Lead (ISL)
Lead
Sensor
Module
Distal
Anchor
Proximal
Anchor
Implantable
Communications
Module (ICM)
Sensor
Diaphragm
~ 3 mm
Measures
•LAP
•IEGM
•Core Temp
Handheld Patient Advisor Module
(s) carvedilol(25mg),1 tab
(s) lisinopril(20mg), 1 tab
*(d) furosemide(40mg),1 tab
PAM
Powers implant by RF
Atmospheric reference
Stores telemetry
Alerts patient to monitor
DynamicRX™
 Meds, activity, MD
contact
Physician-Directed, Patient-Self Management
LAP ≥28 … Very High… furosemide 80mg, call MD
LAP 19-27 … High………. 40mg
LAP 10-18 … Optimal…… 20mg
LAP 6-9 … Low…………10mg
LAP ≤ 5 … Very Low…. hold, increase fluid intake
Optimal LAP makes it easier
to up-titrate
β-Blockers and ACE-I/ARBs
Direct USB
(in-clinic)
RF
Telemetry
Remote
(patient’s home)
Application Software
Trends, Waveforms, Prescriptions
PC or Web Based
PAM
HOMEOSTASIS Trial Results
Reduction in Heart Failure Hospitalizations
Period
Annualized Event
Rate
12-mo period before
enrollment
1.4 (1.1-1.9)
First 3 mo
Observation Period
0.68 (0.33-1.4)
After mo 3
Titration/Stability
Periods
0.28 (0.18-0.45)
P-values
0.054
<0.001
0.041
LAPTOP-HF, an adequately powered randomized controlled trial to
assess clinical safety and effectiveness of this approach, is underway
Ritzema J, ..… Abraham WT. Circulation 2010
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., bioimpedance)
•
Enables non-invasive and
continuous monitoring of lung
fluid concentration
ReDS Correlation with
CT and Pressure
(Pre-Clinical Data)
Superior
Lobes
Inferior
(Dependent)
Lobes
Start of volume loading
Diuretics
Interclass Correlation = 0.95
CT + ReDS
LVEDP, PAP
Fluid concentration and pressures correlate
during volume overload; a lag is observed
during diuresis
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
Efficacy Results:
LVESV, Paired data, mean ± SEM
All 1yr, n=28
p<0.001
200
p<0.001
LVESV (ml)
196.1
150
155.3
160.9
100
50
0
Baseline
6 months
Abraham et al., HFSA 2010 LBCT Presentation
12 months
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)
The elastic
compliance
allows the
device to
stretch and
return to its
original
position
Load (lbf/in)
1
0.8
0.6
0.4
0.2
0
0
20
40
60
80
100
Tensile Strain (%)
Paracor
Myocardium
CSD
Pericardium
25% Stretch
45% Stretch
PEERLESS-HF CRT Subset Data
P=0.036
HR=2.2
PEERLESS-HF CRT Subset Data
P=0.06
HR=2.0
Extra-Aortic Counterpulsation
Heart Fills - Cuff Inflates
Heart Ejects - Cuff Deflates
to body
to heart
reduce
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
Extra-aortic Cuff
ECG Sense Lead
Interface Lead
Battery Pack
Driver
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 Failure
100
80
Survival
(%)
60
LV Assist Device
40
20
Medical Therapy
0
0
6
12
18
24
30
Months
No. at Risk
LV Assist Device
68
38
22
11
5
1
Medical Therapy
61
27
11
4
3
0
Rose et al., NEJM 2001
LVADs as Destination Therapy in
End-Stage Heart Failure
100
80
Survival
(%)
60
LV Assist Device
40
20
Medical Therapy
0
0
6
12
18
24
30
Months
No. at Risk
LV Assist Device
68
38
22
11
5
1
Medical Therapy
61
27
11
4
3
0
Rose et al., NEJM 2001
Ventricular Assist Devices
• 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
Heartmate II Axial Flow LVAD
Ventricular Assist Devices
• 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
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 418lb 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