Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

William Pierce, MD What ever happened to the ? MechanicalMechanical supportsupport ofof thethe failingfailing heart:heart: WillWill heartheart transplantationtransplantation becomebecome obsolete?obsolete?

Dan M. Meyer, MD The 20thth Annual Donald and Lois Roon Visiting Lectureship Scripps Green Hospital September 28, 2011

Jack Copeland, MD Surgical treatment of advanced heart disease Charles Lindbergh

Heart Transplantation History History

 Lower + Shumway  James Hardy  Stanford Univ USA, 1918-2003  First long term successful heart transplant (4th) Univ Mississippi  Surg Forum 11:18 1960 1964 First Human  5 dogs survived 6-21 d Orthotopic HTx  N=97 HTx 1968-1975 Xenograft (Chimp)  Surv-1 yr = 49%   1968 Surv-1 = 22% JAMA 188:1132-40,  1974 Surv-1 = 62% 1964  Surv-5 yr = 23% Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Heart Transplantation Life Magazine – Dec. 15, 1967 History

 1968  102 heart transplants worldwide  17 countries  52 medical centers  median survival = 29 days  1969  Fewer than 50 heart transplants  1970-1975  Fewer than 20 heart transplants per year  Stanford (Shumway)  Medical College of Virginia (Lower)

Life Magazine - Sept. 17, 1971

HeartMate IP LVAD Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

LVADs as Destination Therapy REMATCH Update

1.00  1 year LVAD vs. 0.90 VE LVAS (n=71) OMM survival = 0.80 OMM (n=61) 0.70 P=0.0012 53.5% vs. 26.5% 0.60  2 year LVAD vs. 0.50 P=0.0004 0.40 OMM survival = 0.30 P=0.0063 32% vs. 8.2% 0.20 0.10  3 year LVAD vs. 0.00 0 6 12 18 24 30 36 42 48 54 OMM survival = Months Post Enrollment 15.9% vs. 2% (NS)

REMATCH Update (as of April 2004) – Source Thoratec Registry

Improving Outcomes BEYOND REMATCH The Problem

100 Half-life =9.1 years HTx Conditional Half-life = 11.6 years  The number of patients with end-stage CHF 80 Actuarial Survival (1982-2000) increasing (Stage D), ~500,000 in the US LVAD 60 “ IMPROVEMENTS with: LDSH  ~ 10% of patients >65yo LV dysfunction - DEVICES N=52,195 40 - MANAGEMENT  LVAD  This number is expected to double in 25 yrs

Survival (%) Survival LESS ADVANCED Illness 20 (Patient Selection)  The number of available donors are not OMM expected to increase, numbering 2200 in US 0 01234567891011121314151617 Years Post-Transplantation

Heart Failure Expected to Become More Treatment Options Common as Population Ages Common as Population Ages End-Stage

 Medical management - limited by poor outcomes

 Cardiac transplantation - limited by donor shortage

 Mechanical circulatory support devices Left ventricular assist device (LVAD) Heart Failure‐Epidemiology Forecasts to 2015. Datamonitor 2002 Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Congestive Heart Failure HEART TRANSPLANTATION Medical Rx Survival Kaplan-Meier Survival (1/1982-6/2008)

100 Half-life = 10.0 years Conditional Half-life = 13.0 years 80

60 HEARTN=80,038 TRANSPLANTATION

Kaplan-Meier40 Survival (1/1982-6/2005) N at risk at 23 years = 124 Survival (%) (%) Survival

20

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Years

ISHLT 2010 Gorodeski et al. Circ Heart Fail 2009;2:320-324 J Heart Lung Transplant. 2010 Oct; 29 (10): 1083-1141

Loss of Pulsatility with Increased RPM Thoratec HeartMate II LVAD Pump

Worldwide Clinical Experience HeartMate II BTT Long-term Results (n=281)

More than 8,000 patients worldwide have now been implanted with the HeartMate II LVAS.

. Patients supported ≥ 1 year: 2978 . Patients supported ≥ 2 years: 1108 . Patients supported ≥ 3 years: 300 . Patients supported ≥ 4 years: 136 . Patients supported ≥ 5 years: 33 . Patients supported ≥ 6 years: 9

As of Sept 2011 23 25 JAAC 2009;54(4):312-21. Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Kaplan-Meier Survival (n=281) HeartWare LVAD

 HVAD miniaturized implantable blood pump

 Provides up to 10 L/min of flow

 Centrifugal design, continuous flow

 Hybrid magnetic / hydrodynamic impeller suspension

 Optimizes flow, pump surface washing, and hemocompatibility

Pagani F, Miller L, Russell S, JAAC: Vol 54, No 4, 2009.

ADVANCE Trial Secondary Outcome: Survival Indications for LVAD Placement 100  Bridge to Decision HVA  Bridge to Transplant 90 D  Destination Therapy Control  Bridge to Recovery 80 Days Post Treatment Control Implant p = .39 30 98.6% 96.6% % Survival % 90 95.6% 93.6% 70 Event: Death (censored at 180 93.9% 90.2% transplant or recovery)

360 90.6% 85.7% ITT Population

60 0 60 120 180 240 300 360 Days Post Implant

Patients Treatment 140 128 108 92 63 36 26 at Risk Control 499 440 370 305 228 176 127

Patient Selection/Stabilization Timing of LVAD is Key to Survival

Too Late

Futile Implants 1-Year Survival Operative 19% Risk Death Successful 1-Year Survival Implants 69%

Worsening nutritional, end-organ, and RV function

Lietz et al. Circulation. 2007;116(5):497 Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

INTERMACS Profiles Level Key feature of level Descriptive label 1 Critical cardiogenic shock “Crash and burn” 2 Progressive decline Inotropes, slipping 3 Stable but inotropic dependent Inotropes, stable 4 Recurrent decompensations “Frequent flyer” 5 Exertion intolerant Housebound 6 Exertion limited “Walking wounded” (fatigue within minutes) 7 NYHA IIIA Too well for VAD/Transplant

Stevenson L, et al JACC, 2007

Clinical Outcomes National Shift in Timing of Implants INTERMACS Profile

Length of Stay Post-VAD Actuarial Survival Post-VAD

Less acutely ill, ambulatory patients in INTERMACS profiles 4–7 had better survival and reduced length of stay compared to patients who were more accurately ill in profiles 1–3.

Group 1: INTERMACS 1 Group 2: INTERMACS 2–3 Group 3: INTERMACS 4–7 Boyle, Ascheim, Russo, et al. JHLT. 2011;30:4.

Current research efforts

 Assessment of sympathetic nerve activity in non-pulsatile systems  Non-invasive monitoring of the LVAD patient  Clinical studies LVAD and ventricular arrythmias LVAD and renal recovery LVAD and gastrointestinal bleeding Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Study Protocol Study Protocol Phase 1 Phase 2 Instrumentation ECG/HR BP Instrumentation cuff (Korotkoff /Doppler) ECG/HR beat-by-beat finger arterial BP (Nexfin) BP cuff (Korotkoff /Doppler) TCD recording from a non-pulsatile LVAD beat-by-beat finger arterial BP (Nexfin) patient Microneurography (MSNA) Sympathetic multiunit activity occurs as “bursts” peroneal nerve Transcranial Doppler (TCD) burst recordings Sitting/Standing Maneuvers – 0.05 Hz Head up tilting supine, 30°, and 60° Transfer function estimation – cross spectral method of gain, phase, Cardiac output and coherence acetylene rebreathing technique TCD recording from a pulsatile LVAD patient

An LVAD patient undergoing head up tilting

Total study time: approximately 6-7 hours involving about Total study time is approximately 6-7 hours involving about 15 investigators

Sympathetic and Cardiovascular Responses During Bolus Injection of Nitroprusside and Phenylephrine in a Nonpulsatile Patient

130 120 110 HR 100 HR 90 80 70 Nitroprusside Phenylephrine 30 s 120 110 100 90 80

BP (mmHg) BP 70 60 50

0.2

0.0

-0.2

MSNA -0.4

-0.6

-0.8

Conclusions Clinical Implications

 Non-pulsatile LVAD patients have dramatically higher sympathetic activity than pulsatile patients and controls,  Higher sympathetic activity could lead to adverse presumably due to greater baroreceptor unloading (impaired baroreceptor function) events in these patients over time: CV events, stroke, high blood pressure, renal effects  Cerebral autoregulation does not seem to be significantly affected in nonpulsatile devices, at least at  It may be possible to develop surrogate measures of the frequency of normal activity sympathetic activity to guide therapy in these  Variability in CBFV and BP during sit-stand is relatively low in nonpulsatile devices compared to pulsatile patients  There may need to be some “built in” pulsatility in  More data and larger studies are needed to further define devices that are primarily non-pulsatile: the physiology of nonpulsatility with change in speed, devices that are primarily non-pulsatile: position, exercise, and device optimization  How to do that? What frequency? What duration? Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Nexfin - Blood pressure measurement Nexfin integrative hemodynamics

One screen:

Blood pressure + Cardiac Output Brachial pressure + Hemodynamics + ECG

Touch screen user interface

Finger pressure Brachial pressure

9/28/2011 43 9/28/2011 44

A Study of Blood Pressure Measurement in Patients Increased LVAD Utilization with Non-pulsatile Left Ventricular Assist Devices

 Findings: In the first 10 subjects, correlation of BMEYE with A-line measurements is stronger than Doppler with A-line measurements.

Doppler and A- BMEYE and A- line line Pearson’s 0.8 0.9 coefficient

Interclass 0.861 0.911 correlation

LVAD Program Growth Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Quality Program Details Intermacs Quality Assurance Report Performance Measures Adverse Events

Baylor University Medical Center INTERMACS Adverse Events #%#% Bleeding 104 23 4317 17.5 Cardiac Arrhythmia 15 3.3 1591 6.4 Death 14 3.1 747 3 Device Malfunction 37 8.2 712 2.8

NeurologicInfection 30 6.6 3472 14 Dysfunction 14 3.1 687 2.7 Psychiatric Episode 24 5.9 396 1.6 Rehospitalization 81 17.9 4774 19.3 July 2011

CMS Eligibility Criteria DT Gaining Popularity Destination Therapy

 Class III-IV CHF  EF < 25%  Significant functional limitations despite OMM for at least 60 days

 VO2max < 12 ml/kg/min or inotrope dependent

 Inability to tolerate OMM  No conditions which limit life expectancy  Acceptable surgical risk (nutrition, organ function)

Stewart G, et al Circ 2011;123:1559-68.

Destination Therapy Centers Destination Therapy Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Heartmate II in patients > 70 years of age Heartmate II in patients > 70 years of age

J Am Coll Cardiol 2011;57:2487-95 J Am Coll Cardiol 2011;57:2487-95

HeartMate II LVADs as Destination Therapy Improvement in DT Outcomes Patient Management It’s a collaborative effort  The total heart treatment team includes: Referring physician Heart failure cardiologist VAD NP/coordinator Cardiovascular surgeon Other implanting center team members/social services, financial, psychiatry, nutritionist, rehabilitation services Patient and family

Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist  device. N Engl J Med. 2009;361:2241-51. Community Park SJ. AHA Scientific Sessions, November 2010.

LVAD DT vs Extended Criteria LVAD DT vs Extended Criteria Cardiac Transplant Cardiac Transplant

Ann Thorac Surg2010;89:1205-10 Ann Thorac Surg 2010;89:1205-10 Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Heart transplant vs LVAD in heart Heart transplant vs LVAD in heart transplant –eligible patients transplant –eligible patients

Williams et al. Ann Thorac Surg 2011;91:1330-4 Williams et al. Ann Thorac Surg 2011;91:1330-4

Heart transplant vs LVAD in heart 2011 Hospital Medicare Inpatient transplant –eligible patients Reimbursement

DRG-1 Payment Over Time

Williams et al. Ann Thorac Surg 2011;91:1330-4

Myocardial recovery with continuous Myocardial recovery with continuous flow pumps flow pumps

Birks et al. Circulation.2011;123:381-390 Birks et al. Circulation.2011;123:381-390 Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Felt plug with video

Conclusions Quality of Life  Landscape of chronic HF has changed due to emerging advanced therapies

 LVAD utilization is gaining increased acceptance as device technology improves

 Placement of LVADs earlier in the spectrum of advanced heart failure (INTERMACS PROFILES) is associated with better outcomes

 Efforts to improve DT LVAD outcomes, perhaps not transplantation, represents the greatest hope for addressing end stage heart failure Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

INTERMACS Profiles Patient Selection Level Key feature of level Descriptive label CMS Patient Selection Criteria for Bridge to Transplantation: 1 Critical cardiogenic shock “Crash and burn” A. Patient approved/listed for heart transplantation B. Implanting site needs written permission from patient’s 2 Progressive decline Inotropes, slipping transplant center CMS Patient Selection Criteria for Destination Therapy: 3 Stable but inotrope dependent Inotropes, stable NYHA Class IV ≥ 90 days & life expectancy < 2 yrs: 4 Recurrent decompensations “Frequent flyer” A. Not heart transplant candidate 5 Exertion intolerant Housebound B. NYHA Class IV heart failure symptoms failed to respond to OMT 6 Exertion limited “Walking wounded” for at least 60 of the last 90 days (fatigue within minutes) C. LVEF < 25% 7 NYHA IIIA Too well for D. Peak oxygen consumption of < 12 ml/kg/min or continued need VAD/Transplant for IV inotropes E. BSA ≥ 1.5 m² if a first generation VAD is used Stevenson L, et al JACC, 2007 CMS National Coverage Determination 2007

Indications for LVAD Placement Charles Lindbergh • Bridge to Tranplant • Destination Therapy • Bridge to Candidacy • Bridge to Recovery Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

Making an impact….. Sample Individual MSNA Recordings During HUT

Pulsat Non- ile Pulsatile

Supine

30 HUT

60 HUT

10 sec 10 sec

Timeframe for Definitive Interventions based on INTERMACS classifications

AHA/ACC Stage C Stage D classification

NYHA Class III Class IIIb/IV Class IV classifications

INTERMACS levels 7 6 5 4 3 2 1

Brief Advanced Exertion Exercise Recurrent Stable but Progressive Critical descriptions NYHA Class limited/ intolerant/ decompen- inotrope- decline/ cardiogenic III “Walking “House- sation/ dependent/ “Sliding on shock/ “Crash wounded” bound” “Frequent “Dependent inotropes” and burn” flyer” stability” Timeframe for Transplan- Variable, Variable, Elective over Elective over a Needed within Needed within definitive tation or depends upon depends upon weeks to few weeks a few days hours intervention circulatory nutrition, organ nutrition, organ months as long support not function, and function, and as treatment of currently activity activity episodes indicated restores stable baseline, including nutrition

Sources: “Heart Failure”. NEJM 2003; 348:2007-18. “On the Fledgling Field of Mechanical Circulatory Support”. JACC 2007; (50) 8. “Characteristics of Stage D heart failure: Insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM)”. Am J Heart 2008; 155:341-9. INTERMACS Manual of Operations version 2.2, User’s Guide

Natural History of Heart Failure

Class III

100 10  25% of HF Patients

 Frequent 75 hospitalizations

year 

Worsening symptoms / despite drug therapy Rate

50 1  Significant opportunity for new therapies Survival 25 Survival Rate Hospitalizations Hospitalizations

Annual .1 0 I II III IV Deceased NYHA CLASS

Adapted from Bristow, MR Management of Heart Failure, Heart Disease: A Textbook of Cardiovascular Medicine, 6th edition, ed. Braunwald et al. Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

System Components HeartMate II LVAS Pump

. HM II Components: . Flexible inflow conduit  Implantable titanium blood . Textured surfaces pump  Inlet cannula, inflow and  System Controller outflow elbows  Thrombo-resistant . Shared Components: . Outflow graft with bend  System Monitor relief .  Display Module . Anastomosed to LV apex and ascending aorta  Power Sources . Pump output varies over  Power Base Unit cardiac cycle  Batteries & Clips  Follows native pulse  Emergency Power Pack  Afterload sensitive  Accessories

Lower INTERMACS Score Associated With Decreased Survival

HR 2.7 (1.1–7) P < 0.005 80% N = 54 72% 62% INTERMACS 3-4 54% 41% 27% INTERMACS 1-

Alba AC. J Heart Lung Transplant 2009; 28:827-33. Dan M. Meyer, MD 2011 Donald and Lois Roon Visiting Lectureship Wednesday, Sept. 28, 2011

A Team Effort A Study of Blood Pressure Measurement in Patients with Non-pulsatile Left Ventricular Assist Devices.

 Background: The most accurate technique for measuring blood pressure in patients with non-pulsatile assist devices is currently unknown.  Goal: Compare various techniques of blood pressure measurement in LVAD patients with the gold standard of an a-line measurement  Methods: Measurements are made with a non-invasive finger beat-to- beat plethysmography (BMEYE device), a Doppler ultrasound machine, and an arterial line in the post-op ICU setting.  Measurements are made in the below three scenarios to validate the accuracy of each device when blood pressure is expected to change. 1. Orthostatic blood pressure measurements 2. Before, during and after the subject performs the valsalva maneuver 3. Change in LVAD pump speed – higher than baseline and lower than baseline.