Ventricular Assist Devices for Chronic Heart...

Ventricular Assist Devices for Chronic Heart Failure

Σ.Γ.Δράκος, Επικ. Καθ/τής

Medical Director, Cardiac Mechanical Support Program

Investigator, Molecular Medicine Program

University of Utah

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1980 1990 2000

Coronary Deaths

Coronary deaths are down by half But heart failure has almost tripled

Heart Failure

Source: National Hospital Discharge Survey data. Centers for Disease Control and Prevention/National Center for

Health Statistics and National Heart, Lung, and Blood Institute.

Enhanced survival in other CV diseases leads to expansion of HF Population

Heart Failure: The Final Cardiovascular DiseaseChronic Heart Failure: Global Epidemic

- 2.5% of population

- 1 in 5 over 40

- Most common hospital admission diagnosis

322 670 1,2

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Stehlik J et al. ISHLT Registry; J Heart Lung Transpl 2011

Advanced Heart Failure Therapies:

Heart Transplantation cannot meet the need

Chronic Mechanical Circulatory Support

1. Βridge to Transplant (BTT)

2. Destination Therapy (DT)

3. Bridge to Recovery (BTR)

Bridge to Heart Transplant

Proportion of patients surviving to Transplant

Frazier O, et al, JTCS 2001

Aaronson K, et al, JACC 2002

LVAD

Medical

Therapy

Drakos S, …, Renlund D. J Thorac Cardiovasc Surg 2006


VAD effects Prior to Transplant: HLA sensitization

Drakos S, …, Renlund D. J Heart Lung Transpl 2007

IVIG

No IVIG

Drakos SG, et al. J Heart Lung Transpl 2009

Pulsatile

flow VAD

Continuous

flow VAD


Survival After Transplant – UTAH program

Drakos SG, et al. J Heart Lung Transpl 2006

Bridged to Tx with LVAD

Bridged to Tx with Medical Therapy

n=278

2nd Era Continuous LVAD

2nd Era Pulsatile LVAD

Nativi JN, Drakos SG, et al. J Heart Lung Transpl 2011

Survival After Transplant – ISHLT Registry


Bridged to Tx with LVAD

Bridged to Tx with Medical Therapy

- N=130 end stage HF patients

- Randomization: LVAD (1st generation) vs Optimal Medical

Therapy

- Too old or too sick for heart transplant- Age 68

- NYHA Class IV

- LVEF 17%

- Wedge 25mmHg

- Cardiac Index 1.9

- IV Inotrope dependent 72%

REMATCH 2001

Disadvantages of 1st Generation, Pulsatile LVADs

2. Engineering Malfunctions after 12-15 months

1. Large Size – Morbidity / Infections

Destination Therapy (DT): Landmark Trials

Medical therapy

LVAD – Pulsatile, 1st generation

Landmark REMATCH Trial:

Late VS. Early Results: UTAH contribution

Park S, et al, J. Thor Cardiovasc Surg 2005

Advantages of 2nd Generation, Continuous-flow LVADs

2. Small Size – Decreased Perioperative Morbidity / Infections

1. No Engineering Malfunctions – Extended Durability (>10 years)

LVAD 2nd generation,

Continuous-flow

LVAD 1st generation,

Pulsatile-flow

“REMATCH II” 2009

Destination Therapy (DT): Landmark Trials

http://content.nejm.org/content/vol361/issue23/images/large/08f2.jpeg

• Meta to Quality of Life tha akolouthisoun ta

complications – “Not everything is perfect”

“REMATCH II” Trial: Complications

Medical Therapy Arm of

REMATCH

TRANSPLANT

ISHLT Registry

n>40,000

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

VAD Arm of

REMATCH 2001

(1st generation)

2ndgeneration VAD

INTERMACS 2011,

n=1936

6 12 18 24

Months post LVAD implant

The Field Is Evolving…

3rd generation VAD

1. Technological Advances

2. Patient Management

3. Patient Selection

Su

rviv

al




Technology evolves…

2. Wireless energy transfer = elimination of percutaneous

abdominal exit site (3-5 years away from clinic)

1. Size matters!

Balance Anticoagulation Between…

Wever O, Drakos SG. Pharmacol & Ther 2011

“…the optimal time for referral in an individual patient’s course of

progressive HF is an art and a science…”

James Fang, NEJM 2009

The Right Time for LVAD Implantation

“Optimal Window”

Operative Risk

Right heart failureEnd-organ dysfunction

Cachexia

Too earlyToo late

AHA statement, Circ 2012

Referred to HF program for VAD/ Tx evaluation if:

a) NYHA III or IV

and

b) two of the following:

- Serum sodium < 136 mmol/L

- Creatinine > 1.8mg/dl

- Intolerant or refractory to ACE/ARB/BB

- Diuretic dose > 1.5 mg/kg/d

- Heart failure-related hospital admissions

- QRS > 140 ms refractory to CRT therapy

- Hematocrit < 35%

Russell S, Miller L , Pagani F. Congestive Heart Failure 2010

Moderate Indication

Strong Indication

Aaronson K, et al. Eur J Heart Fail 2010

Patient Selection to Prevent Post LVAD

Implantation Right Ventricular Failure

Drakos SG, et al. Am J Cardiol 2010

Right Ventricular Failure Risk Score

Quality of Life

Dick Cheney

Who has LVAD?

Πρόγραμμα Χρ. Mητ. Υποβ.

Noζοκ. Eσαγγελιζμoύ -

Γ’ Καρδιολογικής Κλινικής

Παν/μίοσ Αθηνών

HF=2.6 % Population* or6.24 Million

~50 % Preserved Systolic Function

3.12 Million

~240 Million Population≥ age 20 years old

Advanced Stage C and Stage D ≥ age 20 years old

280,800

Theoretical No. of Adults With Advanced HF in US -Potential LVAD candidates for BTT or DT

Advanced Stage C / NYHA class IIIB

124,800

Stage D / NYHA functional class IV

156,000

~50 % Systolic HF

3.12 Million

80-85% Stage A-B

0.5-5 % Stage D

15-20% Stage C (3-4% advanced Stage C)

~ 30% = ~ 90,000 accessible patients

30 BTT or DT LVADs / 100,000 population

Modified after permission from:

Starling R, O’ Connell J

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20082007 2010 20112009

U.S. VAD Implants for currently approved indications (BTT, DT)

Load Drives Cardiac Remodeling and

HF progression

LV

F

un

cti

on

T

LOAD

Initial Insult

LV

LV

LV

Cardiac Remodeling Trajectory

LV Structure

Hypothesis:

Load ‘Removal’ via LVAD=

Reverse Remodeling?

Cardiac Recovery?

Pre LVAD Post LVADwhen

postdurpre

Mean

value

100,00

90,00

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what: edd

par

kaz

ax

al

who

LV End-diastolic Diameter (mm)

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Drakos S, ..., Yacoub M, Nanas J. Eur Heart J 2007;28: 143Drakos S, …, Yacoub M, Nanas J. Ann Thor Surg 2008; 91: 764

QRS

QTc

Drakos SG, …, Yacoub MH, Nanas JN. JACC Imaging 2008: 3: 64

Pre LVAD Post LVAD

Sympathetic innervation MIBG imaging

Harefield Athens Recovery Program (HARP)

LVAD Unloading: Reverse Remodeling?

Dimopoulos S,…, Nanas S. J Heart Lung Transpl 2010

Drakos S, et al, Circulation 2012

Cardiac Recovery? LVAD Weaning?

Fascinating and Rare Anecdote?

Vs.

Consistent and ‘Real’ Phenomenon?

Harefield Athens Recovery Program

LVAD Induced Cardiac RecoveryFascinating Anecdote Vs. ‘Real’ Phenomenon?

Circulation, July 2012

Reasons for Variable ResultsStudy Design Issues

1. Small Numbers, Retrospective Design

2. Heart Function Monitoring

3. Concurrent Drug Therapy

4. Variable Explantation Criteria (Recovery ‘definition’)

5. Patients Diversity in Recovery Propensity - HF etiologies - extent of pre-LVAD pathologic changes

Drakos SG, et al. Circulation 2012

What Does the Field Need to Advance?

Large- scale, Prospective, Translational Programs:

1. Evaluate Extent of functional Recovery

2. Investigate mechanisms of Recovery

Molecular Medicine Program

HF/ Tx/ VAD Programs

Basic ScienceComponent

Clinical Component

Utah LVAD Recovery Program

Two-phase Translational Program Started in 2008

Hypertrophy Evaluation

Drakos, …, Li DY. JACC 2010; 56: 382-91

1st Phase (Years 1 and 2): Standardization of Tissue Protocols

Microvascular EvaluationFibrosis Evaluation


Post LVAD echo

Post LVAD ‘Turn-Down’ echo

Pre LVAD echo

1st Phase (Years 1 and 2): Imaging Protocols Standardization


2nd Phase (Year 3): Apply Protocols at Full Scale

Prospective Translational Program:




1. Infrastructure / Recruit Patients

2. Control for Confounders & Limitations

3. Serial Monitoring of Functional Recovery

Evaluate Extent of functional Recovery


Infrastructure/ Recruit Patients

Utah

Progress so far (Tissue & Clinical data):

- 171 LVAD pts prospectively enrolled

- 26 Donors (not allocated for Tx)




- Concurrent drug therapies

- Duration of unloading



Determine Extent of functional Recovery



- Concurrent drug therapies

- Duration of unloading


- Echo evaluation

- Hemodynamic evaluation

Determine Extent of functional Recovery


Pre LVAD Post LVAD (‘Turn-Down’ echo)

Patient “A” Improved Cardiac Function= RESPONDER


Patient “B” DID NOT Improve= NON RESPONDERDespite Same Unloading duration, HF duration, HF etiology


Pre LVAD Post LVAD (‘Turn-Down’ echo)


Drakos SG, et al. JACC In Press

LV Functional ‘Responders’: 19% of pts

Relative LVEF Increase: 50-350%

(echo results on 90 prospectively enrolled pts)

Drakos SG, et al. JACC In Press

Drakos SG, et al. JACC in press


Time Course of Unloading- induced Functional Response

LVAD Induced Recovery?Fascinating Anecdote Vs. ‘Real’ Phenomenon?

- Single-program, large-scale

Utah LVAD Preliminary Data

- LVEF degree of improvement superior Pharmac./Regenerative trials

- ‘Burned-out’ HF… exciting implications for less advanced HF

LVAD Induced Recovery?Fascinating Anecdote Vs. ‘Real’ Phenomenon?

- Single-program, large-scale

Utah LVAD Preliminary Data

- LVEF degree of improvement superior Pharmac./Regenerative trials

- ‘Burned-out’ HF… exciting implications for less advanced HF

- Revisit view: human heart incapable of repair/ recovery

- Opportunity understand human heart’s potential to respond to injury/death


1. Determine Extent of functional Recovery



Recovery Mechanisms: More Energy Efficient Metabolism?


unpublished data

Cell cycle reentry

Recovery Mechanisms: Regeneration?

unpublished data


Opportunity to Transform HF Biology and HF Clinical Practice

HF patients

Optimal Medical Therapy

LVADBridge to

Heart Recovery


Heart Transplant

Stem cells

Surgical Therapies

Basic ScienceClinical

Research Fellows

Nikos Diakos

Omar Wever

Abdul Saidi

Div Verma

Chi Yen

LVAD Unloading & RecoveryWhat are the Future Research Targets?

Drakos SG, et al. Circulation 2012

Guest Faculty

David Kass, MD, Johns Hopkins

Douglas Mann, MD, Washington Univ.

Joseph Hill, MD, PhD, Univ. Texas Southwestern

Michael Givertz, MD, Harvard Univ.

Joseph Rogers, MD, DUKE Univ.

Roger Hajjar, MD, Mount Sinai

Simon Maybaum, MD, Albert Einstein College of Medicine

Evangelia Kranias, PhD, Univ. of Cincinnati

Mark Slaughter, MD, Univ. of Louisville

Francis Spinale, MD, MUSC

Evgenij Potapov, MD, Berlin Heart Institute, Germany

John V. Terrovitis, MD, University of Athens, Greece

Summary

- Bridge to Transplant, Destination Therapy:

1st line therapeutic options for selected HF patients

- Room for Improvement / Decrease Complications:

1. Technological Advances,

2. Patient Management,


Summary

Research in LVAD Recovery field:

- Transform role of LVAD from BTT to enabler of cardiac recovery?

- Revisit view: human heart incapable of repair/ recovery

- Redirect Basic Science of cardiac recovery by focusing

the field on basic pathways relevant to humans (i.e. biomarkers derived

from LVAD ‘Responders’)

Funding Sources for UTAH Recovery Program

1. VA Merit Award

2. American Heart Association

3. CTSA/NIH Award

4. Deseret Foundation

5. U of U Molecular Medicine (U2M2)

6. Intermountain Health Care

Importance of Pulse in Flow both for the

Peripheral Organs and the Heart ?

2nd Generation, Continuous-flow VADs: Concerns due to non- pulsatile/ non- physiologic

blood flow pattern

Coronary Flow

Cardiac

Output

Aortic Pressure

Right Atrial Pressure

Non-Pulsatile flow

Pulsatile flow

Drakos S, Ntalianis A, …, Nanas J. ASAIO J 2002

Short-term Support: Pulse in Flow Does Matter!Porcine model of ACUTE HF

Animal data suggested adaptation to the non–physiologic/ non-pulsatile flow over a period of few weeks

Jett, et al, ASAIO J 1999Saito, et al, Ann Thor Surg 2002

Tominaga, et al, J Thorac Cardiovasc Surg 1996

Long-term Support: Pulse Less Crucial ?

Long-term support: Human Peripheral Organs Adapt to Non Pulsatile flow

Increased GI Bleeding with

Non-Pulsatile LVADs?

Crow et al. J Thorac Cardiovasc Surg 2009

LVAD Unloading & Recovery: Future DirectionsOptimal Type of Unloading ?

Drakos, Kfoury, ..., Li. Circulation 2012, In Press

Ventricular Assist Devices for Chronic Heart...

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