New and Promising Management Strategies for Heart Failure ...€¦ · Barry Massie, M.D., UCSF • CLP = cross-linked polyelectrolyte, used to absorb water and electrolytes in the

New and Promising Management Strategies for Heart Failure, 2013

Including Highlights from 2012 Heart Failure Society of America, September 2012and Symposium on Cardiovascular

Regeneration – Integrated Regenerative Research Institute, SDSU

November, 2012

Educational Objectives 1

• Review briefly existing evidence-based therapies for heart failure

• Review a new volume management strategy

• Review a new therapy for HFpEF

Educational Objectives 2

• Review multiple strategies for improving myocardial function

• Review a strategy for enhancing cardiac output in advanced cardiomyopathy

• Review the current data for anticoagulation in heart failure

Traditional Evidence-based Therapies for Congestive Heart

Failure

• Management of volume to attain euvolemia (diuretics, sodium restriction and ultrafiltration) (not, strictly speaking, evidence-based)

• ACE-I or ARB for systolic dysfunction to stabilize or improve LV function

• Beta blocker for systolic dysfunction to stabilize or improve LV function

Traditional Evidence-based Therapies for Congestive Heart

Failure

• Aldosterone antagonists for systolic dysfunction to stabilize or improve LV function

• ISDN/Hydralazine in African-Americans with systolic dysfunction to stabilize or improve LV function

Some new (and revisited) Strategies for Congestive

Heart Failure1. Managing volume2. Treating HFpEF3. Improving myocardial function4. Augmenting Cardiac Output5. Preventing thromboembolism

Each of these new modalities is under development

and not yet ready for

“prime time”

Managing Volume

What can we do besides traditional sodium and water restriction, diuretics and ultrafiltration?

Current options for managing volume

• Sodium restriction• Water restriction• Oral or iv loop diuretic therapy

– Recall from DOSE-HF trial that continuous infusion and bolus dose loop diuretics showed no difference in outcomes

• Addition of a thiazide diuretic (e.g. metolazone)

• Ultrafiltration (Aquapheresis) therapy for patients with Stage III CKD– New NEJM study shows no further

benefit compared with loop diuretics

CLP vs Placebo in HF with CRF (from HFSA)

Barry Massie, M.D., UCSF

• CLP = cross-linked polyelectrolyte, used to absorb water and electrolytes in the GI track and eliminate in the GI track

• Not metabolized and not absorbed• Objectives of study:

– Measure effect of CLP on serum K+

– Ability to maintain aldosterone antagonists

CLP vs Placebo in HF with CRF

• Inclusion criteria:– K+ > 4.3 to <5.1– CKD Stage 3 or 4 (GFR > 15 to < 60)– Indication for aldosterone antagonist– CHF NYHA Class 3 or 4 with current symptoms of

CHF– ntProBNP > 2,000 (equivalent to BNP >600-1000)

• Exclusion criteria:– MI, Stroke, TIA or ACS– Unstable– H/O GI pathology– LFT’s > 3 x ULN


• Patients randomized to CLP + spironolactone, 25 mg./day or Placebo + spironolactone, 25 mg./day

• Exploratory phase II trial: 59 patients randomized to CLP and 52 to placebo

• 86 completed: 41 CLP and 46 placebo• 4 deaths, all in active arm!• Serum K+ not significantly changed

from baseline in either group


• Body weight decreased more with CLP than placebo (Not a primary endpoint)

• Dyspnea decreased more with CLP than placebo (Not a primary endpoint)

• NYHA improved more with CLP than placebo (Not a primary endpoint)

• No clinically relevant change in any electrolyte or serum aldosterone

• GI side effects more common in CLP group than in placebo

• 4 deaths all felt by primary investigator NOT to be caused by CLP

Mean Change in Body Weight CLP vs Placebo (P = NS)

% with disabling dyspnea – CLP vs Placebo – P = NS

6 Minute walk distance – CLP vs Placebo – P = NS

Kansas City Cardiomyopathy Questionnaire Score CLP vs. Placebo – P = NS

CLP vs Placebo in HF with CRF Commentary by Steven Gottlieb, M.D., U. of Maryland

• 10% of both CLP and placebo patients stopped treatment due to hyperkalemia (presumed due to spironolactone)

• No comparison of CLP with diuretics in head to head trial

• CLP doesn’t prevent hyperkalemia


• Stay tuned as to the ultimate clinical efficacy of CLP in CHF with CRF

White-faced (capuchin) monkey

HFpEF (Heart Failure with Preserved Ejection Fraction)

What therapies are available for heart failure with preserved

ejection fraction?

Current Evidence-based therapies for HFpEF

PARAMOUNT for HFpEF Scott Solomon, M.D., Boston

• Phase II study for evaluation of dual action agent which has both ARB and neprilysin inhibition activity (ARNI – angiotensin receptor/neprilysin inhibitor) - LCZ696

(Novartis) (Actually valsartan & AHU377 in 1:1 combination)

• Compared in head-to-head trial against valsartan

• Neprilysin inhibitors prevent breakdown of ANP and BNP (among many other actions).

• PARAMOUNT – 12 week trial of 308 patients randomized to LCZ696 or Valsartan

PARAMOUNT for HFpEF • Primary objective of PARAMOUNT:

NT-pro-BNP reduction• Secondary Measures:

– NYHA Class– LA width– LA volume– LA volume index– Inclusion criteria:

• NYHA class 2-3 heart failure • LVEF of at least 45%

• N-terminal-pro-BNP levels >400 pg/mL

PARAMOUNT for HFpEF • 134 in LCZ696 and 132 in valsartan arm

analyzed at 36 weeks• NT-proBNP decreased 23% (P=0.005) in

LCZ696 group and 15% (P=0.20) in valsartan group

• NYHA improved significantly with LCZ696 (P<0.05)

• Also improvement in LA width (P=0.03), LA volume (P=0.003) and LA volume index (P=0.007)

• Justifies Phase III trial

Albino Howler Monke

Improving Myocardial Function

What can we do to improve myocardial function in addition to neurohormonal

blockade?

Biological Approaches to improving Cardiac Function –• Stem Cell Therapies

– Allogeneic Mesenchymal Stem Cell Therapy

– Autologous Cardiac Stem Cell Therapy

• Gene Therapies– MYDICAR ® SERCA2a gene transfer

• Bioengineering strategies– Artificial bioengineered matrix

(scaffold) to allow orderly ingrowth of cardiomyocytes

Introduction to Regenerative Medicine for the Heart

Mark Sussman, PhDDistinguished Professor of Biology

Director of Integrated Regenerative Research InstituteSan Diego State University

Everybody wants answers (or claims to have answers)

Cell Therapy: How does it work?Cell Therapy: How does it work?

Relatively speaking, not very well

Most adoptively transferred cells are dead within a day or two

Remaining cells are few and far between

Difficult for cells to engraft, survive, proliferate, and differentiate

Functional improvements may be short lived

Efficacy in clinical settings needs to be improved

Target population for regenerative medicine likely to be aged with diminished regenerative potential

• Understand mechanistic basis of regeneration to improve the outcome

Restore Restore Healing to the Healing to the Aged HeartAged Heart

Super Stem Cell QualificationsSuper Stem Cell Qualifications

Telomeres hit Telomeres hit the Big Timethe Big Time

Putting the pieces togetherPutting the pieces together

Using Pim-1 to reclock your stem cells

•• promote cell cyclepromote cell cycle

•• fight senescencefight senescence

•• drive proliferationdrive proliferation

•• antagonize agingantagonize aging

•• maintain pluripotencymaintain pluripotency

A long way to humans...

...or closer than you think ?

NOT

Great Egret

Stem Cell Therapies for Heart Failure

What’s on the horizon right now?

Human Mesenchymal Stem Cells

Joshua Hare, M.D. University of MiamiInterdisciplinary Stem Cell InstituteMember, Integrated Regenerative

Research Institute

A Randomized, Double-Blind, Placebo-Controlled, Dose-

Escalation Study of Intravenous Adult Human Mesenchymal Stem

Cells (Prochymal) After Acute Myocardial Infarction

Joshua M. Hare, MD; Jay H. Traverse, MD; Timothy D. Henry, MD; Nabil Dib, MD; Robert K. Strumpf, MD; Steven P. Schulman, MD; Gary Gerstenblith, MD; Anthony N. DeMaria, MD; Ali E. Denktas, MD; Roger S. Gammon, MD; James B. Hermiller,

Jr, MD; Mark A. Reisman, MD; Gary L. Schaer, MD; Warren Sherman, MD

J Am Coll Cardiol. 2009;54(24):2277-2286. doi:10.1016/j.jacc.2009.06.055

Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction

• Phase II double-blind, placebo- controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs

• Primary end point: incidence of treatment-emergent adverse events within 6 months

• Exploratory efficacy endpoints: Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging

oad:

12/11/2012

Copyright © The American College of Cardiology. All rights reserved.

From: A Randomized, Double-Blind, Placebo-Controlled, Dose-

Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction


Time After MI to Infusion of Study Agent: Human mesenchymal stem

cells = solid bars; Placebo = open bars. MI = myocardial infarction.�





Increase From Baseline Values in Percent LVEF at 3 and 6 Months Post-Treatment in Patients With Anterior MI -

Human mesenchymal stem cells = solid bars (n = 17 at 3 months, n = 15 at 6 months); placebo = open bars (n = 10 at 3 months, n = 9 at 6 months). *p = 0.0436 at 6 months for human mesenchymal stem cell-treated patients versus baseline, analysis of variance. LVEF = left ventricular ejection fraction; MI = myocardial infarction.





Impact of hMSC Treatment on LVEF Evaluated by Cardiac MRI�Human mesenchymal stem cells (hMSCs) = green line (n = 21 at 3 months, n = 18 at 6 and 12 months); placebo = red line (n = 13 at 3 months, n = 11 at 6 and 12 months). *p = 0.003 by repeated measure analysis of variance; †p = 0.005 versus baseline. Abbreviations as in Figure 3.�

Human Mesenchymal Stem Cells

Placebo

Date of download: 2/21/2013

Copyright © The American College of Cardiology. All rights reserved.

From: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After

Acute Myocardial Infarction


Percentage of Patients With Improved Global Assessment�Human mesenchymal stem cells = green line; placebo = red line. *p = 0.027 between groups, Fisher exact test; †p = 0.016 versus day 10, Fisher exact test.�

Figure Legend:

SCIPIO: Phase 1, randomized, open-label trial of c-KIT-positive Cardiac Stem Cells

in

patients with left ventricular dysfunction (LVEF <40%) following an MI.

Roberto Bolli, M.D.Director, Institute of Molecular Cardiology

University of LouisvilleMember, Integrated Regenerative Research Institute

c-KIT Positive Cardiac Stem Cells

• In the human heart, mCSCs express stem cell antigen c-kit, which is a receptor for a stem cell factor.

• mCSCs are clustered in niches located in the myocardial

• Although mCSCs are present throughout myocardium, they are enriched at the atria and apex with low hemodynamic stress

SCIPIO Inclusion Criteria• LVEF < 40% (by any imaging modality:

echocardiography/SPECT/LV angiography)

• A history of Q-wave MI with a residual akinetic and nonviable scar

• Patients scheduled for surgical revascularization within few days (< 2 weeks) of the initial screening

SCIPIO Exclusion Criteria• Age >75 by time of infusion • Cardiogenic shock • Severe co-morbidities (e.g., renal failure,

liver failure) • Mini-CABG procedures • Pregnant/nursing women or women of

child-bearing potential • Inability to provide informed consent • Diabetic Hgb A1c > 8.5% • Patients with a history of hepatitis B,

hepatitis C, and HIV

SCIPIO Procedures• Open-label study, • Maximum of 20 patients to receive

intracoronary CSC transplantation. • These patients will have nonviable

myocardium/scar from prior MI and will undergo CABG for ICM.

• Surgeons will revascularize both viable and non-viable myocardium

• Cardiac cath one month after surgery with injection of CSCs into non-viable myocardial segments

SCIPIO – Aims and Goals

• To determine the feasibility of harvesting CSCs from RAAs of patients undergoing surgical revascularization

• To determine the safety of intracoronary infusion of CSCs

• To obtain initial evidence that CSC administration results in clinical improvement.

SCIPIO Results to date• c-KIT-positive cardiac stem cells (cells which

have the potential to regenerate) were harvested from the patient's right atrial appendage, isolated and expanded, and then infused to repair an infarction during coronary bypass surgery.

• Echocardiographic Results:Test Group EF Before

InfusionEF 4 mos EF 1 year EF 2 years

Cardiac Stem Cell Patients

29.0% 36.0% 37.8% 41.7%

Control Patients 29.2% 29.4% 31.7% 30.0%

SCIPIO

Completion scheduled for August, 2013

Ahninga (Snake bird)

Gene Therapy for Heart Failure

How can we influence cardiac function enzymatically in a positive fashion?

MYDICAR ® Gene Therapy for DCM

• MYDICAR®, SERCA2a (sarcoplasmic reticulum Ca2+-ATPase): genetically targeted enzyme replacement therapy designed to increase the level of SERCA2a via a single intracoronary dose

• Being studied in CUPID Phase 2bTrial • Design: multinational, multicenter,

double-blind, placebo-controlled, randomized study

CUPID Trial• Patients NYHA class 3-4 heart

failure and an LVEF <35%• Randomization: 25 / 14 (studied

vs. control) • 3 doses of gene therapy Low: 6 ×

1011 DNase-resistant particles

(DNP) (n = 8); Mid: 3 ×

1012

DNP (n = 8); High: 1 ×

1013 DNP (n = 9)

CUPID Trial• Studied endpoints: 7 efficacy

parameters across 4 domains: – Symptom: New York Heart Association

(NYHA) class and Minnesota Living With Heart Failure Questionnaire (MLWHFQ)

– Functional status: 6-minute walk test and peak maximum oxygen consumption (VO2)

– Biomarker: N-terminal prohormone brain natriuretic peptide (NT-proBNP)

– LV function/remodeling: ejection fraction and end-systolic volume

• Results expected in Mid-2015

Rafting on the Rio Balsa

3 generation men’s trip

Augmenting Cardiac Output

Improving on nature??

Synergy ® Micropump for chronic ambulatory CHF:

Daniel Burkhoff, M.D., CircuLite Medical Director

• Device size of AA battery – 25 gms. • Intake from subclavian• Output into RA• Targeted for patients in

INTERMACS Stages IV, V and VI (less ill than stages I, II and III)

• Only provides partial boost in cardiac output (~ 4.25 L/min)

Synergy ® CircuLite® Pump

Synergy ® Micropump for chronic ambulatory CHF: Daniel Burkhoff, M.D.

58 patients implanted in 5 years from 6/2007 – 8/2012

• Average duration 204 days; longest > 3 years

• Primary Indication: Class III and IIIb Patients• Still investigational

Swarming crocodil

Preventing Thromboembolism

Can we safely reduce hypercoagulability in patients

with CHF?

WARCEF Trial Results – Shunichi Homma, M.D., Columbia

• Warfarin vs Aspirin in Patients with Reduced Cardiac Ejection Fraction

• Sponsored by NINDS• 176 Centers – 11 Countries• Endpoint: Death, Ischemic Stroke or

Intracerebral Hemorrhage• 2,305 Patients with EF < 35% (Mean

~ 25%)• No significant difference in Primary

Endpoint between the two arms

WARCEF Trial Results• Death identical in two arms• Ischemic stroke 50% reduction• Patients < age 60 experienced greater

benefit from warfarin than aspirin (37% risk reduction) P = 0.006

• Patients > age 60 experienced increased bleeding

• So younger patients benefitted from warfarin and older patients benefitted from aspirin

WARCEF Trial ResultsCommentary by John Cleland, M.D.,

University of Hull, UK”• In a meta-analysis of four studies

incuding WARCEF: stroke reduced for 1 of 60 patients treated for two years but major bleeding increased (OR=2.02)

• Aspirin will be most widely used antithrombotic for patients with heart failure in NSR until trial including placebo is done

Summary• To the standard CHF

armamentarium of diuretics, ACE-I, ARB, Beta blocker, Aldosterone antagonist, digoxin, hydralazine/ISDN and ultrafiltration

• There is the potential to add:– CLP (Cross-linked polymer) for

volume control– Dual-agent ARB/Neprilysis inhibition

for HFpEF

Summary (continued)• Mesenchymal stem cell therapy for

LVSD• C-Kit positive cardiac stem cell therapy

for LVSD• SERCA2a enzyme replacement therapy

for LVSD• The Synergy ® micropump for

ambulatory heart failure• No evidence for benefit of

anticoagulation therapy for CHF patients in sinus rhythm

Stick Insect

Questions?

Documents

New and Promising Management Strategies for Heart Failure ...€¦ · Barry Massie, M.D., UCSF • CLP = cross-linked polyelectrolyte, used to absorb water and electrolytes in the