11

Treating Decompensated Treating Decompensated and Stage D Heart Failureand Stage D Heart Failure

Ronald S. Freudenberger, M.D.

Medical Director, Center for Advanced Heart Failure, Lehigh Valley Hospital& Health Network and Lehigh Valley

Heart Specialists Professor of Medicine

Penn State College of Medicine

DecongestionDecongestion

DrugsDrugs Monitoring devicesMonitoring devices UltrafiltrationUltrafiltration

Devices for decompensation or end Devices for decompensation or end stagestage

TransplantationTransplantation

Inadequate Diuresis During Inadequate Diuresis During ADHF TreatmentADHF Treatment

Note: For the chart, n represents the number of patients who have both baseline and discharge weight, and the percentage is calculated based on the total patients in the corresponding population. Patients without baseline or discharge weight are omitted from the histogram calculations.ADHERE® Database

All Enrolled Discharges in Over 12 Months (01.01.2003–12.31.2003)Who Were Discharged Home (including home with additional and/or outpatient care)

The Nationn=26,757, 68%

Change in Weight From Admission to Discharge

7% 6%13%

24%30%

15%

3% 2%

0

10

20

30

40

50

E

nro

lled

Dis

char

ges

(%

)

(<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10)

Change in Weight (lb)

20 % discharged20 % discharged

without Wt Loss or with Wt gainwithout Wt Loss or with Wt gain

−−2525

−−2020

−−1515

−−1010

−−55

00

55

1010

1515

00 500500 10001000 15001500 20002000 25002500

Urine Output (mL) 0Urine Output (mL) 0––8 hours8 hours

GF

R (

% C

han

ge)

GF

R (

% C

han

ge)

PlaceboPlacebo

IV furosemideIV furosemide

Gottlieb SS, Brater DC, Thomas I, et al. Circulation. 2002;105:1348-1353.

Change in GFR After IV Furosemide 80 mg in HFChange in GFR After IV Furosemide 80 mg in HFClass III CHF n=16 mean age 61 LVEF .28 CAD 63 % Class III CHF n=16 mean age 61 LVEF .28 CAD 63 %

Furosemide Monotherapy Furosemide Monotherapy Causes Significant Decline in Causes Significant Decline in

GFRGFR

A1 Adenosine Antagonists in A1 Adenosine Antagonists in CHF* CHF*

*Renal Function and Renal Output in Edematous Heart Failure Patients Treated with Furosemide (80 mg IV) and/or BG9719.

Gottlieb SS et al. Circulation. 2002;105:1348-1353.

-25

-15

-5

5

15

0 500 1000 1500 2000 2500

Placebo

BG9719 BG9719 +FurosemideGFR

(% change)(1-8 hours)

FurosemideAlone

Urine Output (mL)(0-8 hrs, Day 1 – Baseline)

Vasopressin Levels in CHFVasopressin Levels in CHF

0

3

6

9

12

pA

VP

(p

g/m

l)

CHF Age-matched NLS

n = 75 n = 50

Goldsmith et al, JACC 1983

p<0.01

Arginine VasopressinArginine Vasopressin

V1a Blood vesselsMyocardium

V2 Renal tubules

TolvaptanTolvaptan

0

1

2

3

4

Median Plasma AVP (pg/mL) in SOLVD Trial1

Control Prevention Treatment (1.4-2.3) (1.7-3.0) (2.3-4.4)

Francis et al. Circulation 1990;82:1724-1729.

Conivaptan

Effects of Tolvaptan and Furosemide Effects of Tolvaptan and Furosemide on GFR, ERPF and RBFon GFR, ERPF and RBF

-15

-10

-5

0

5

10

GFR (mL/min) ERPF (mL/min) RBF (mL/min)

TLV

FURO

% C

han

ge v

s P

lace

bo

*

*

*

**

* p<0.05 vs Placebo; **p<0.001 vs Placebo

Burnett et al, AHA 2003

Effect of Tolvaptan in HF With Effect of Tolvaptan in HF With Hyponatremia Hyponatremia (Serum Na(Serum Na++ < < 136 mEq/L)136 mEq/L)

131

132

133

134

135

136

137

138

139

0 1 4 7 11 18 25

Day

mEq/L

Placebo Tolvaptan

*

**

* **

* p<0.01

low

Gheorghiade M et al, Circulation 2003

Composite Components Composite Components (Day 7 or Discharge)(Day 7 or Discharge)

Change in Body Weight

Trial A Trial B

mm

0

5

10

15

20P=nsP=ns

Change in Global Clinical Status

No significant difference in GCS improvement

Additional weight loss

0.6 kg 0.9 kg

Trial A Trial B

kg

-5

-4

-3

-2

-1

0

1P<0.0001 P<0.0001

n=997 n=1007 n=1031 n=1008

n=903 n=910 n=931 n=900

Tolvaptan Placebo

Gheorghiade M, et al. JAMA. 2007;297:1332-1343.

TLV

PLC

Peto-Peto Wilcoxon Test: P=0.68

TLV 30 mgPLACEBO

Pro

po

rtio

n A

liv

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months In Study0 3 6 9 12 15 18 21 24

2072 1812 1446 1112 859 589 404 239 97

2061 1781 1440 1109 840 580 400 233 95

HR 0.98; 95%CI (.87-1.11)Meets criteria for non-inferiority

Peto-Peto Wilcoxon Test: P=0.55

TLV

PLC

Pro

po

rtio

n W

ith

ou

t E

ve

nt

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24

2072 1562 1146 834 607 396 271 149 58

2061 1532 1137 819 597 385 255 143 55

HR 1.04; 95%CI (.95-1.14)

TLV 30 mgPLACEBO

Months In Study

Konstam MA, et al. JAMA. 2007;297:1319-31.

CV Mortality or HF HospitalizationAll-Cause Mortality

EVEREST: Primary End PointsEVEREST: Primary End Points

IstaroximeIstaroxime

New combined inotropic and lusiotropic New combined inotropic and lusiotropic agentagent

Mechanism of action: inhibition of Na+/K+ Mechanism of action: inhibition of Na+/K+ ATPase (digoxin-like) and stimulation of SR ATPase (digoxin-like) and stimulation of SR Ca++ ATPase (increase SERCA 2a activity)Ca++ ATPase (increase SERCA 2a activity)

Hemodynamic properties: lowers PCWP; Hemodynamic properties: lowers PCWP; increases CI; decreases HR and increases increases CI; decreases HR and increases BPBP

Lowers LVED volumes and improves Lowers LVED volumes and improves diastolic acceleration timediastolic acceleration time

Gheorghiade M et al. JACC 2008;51:2276-85

Hemodynamic effects of Istaroxime

Gheorghiade M et al. JACC 2008;51:2276-85

Gheorghiade M et al. JACC 2008;51:2276-85

Echocardiographic descriptions of IstaroximeEffects on LV parameters

Ultrafiltration and Renal Ultrafiltration and Renal FunctionFunction

Jaski et alJaski et al reported no difference in mean creatinine reported no difference in mean creatinine before UF (1.6mg/dL +/- 0.6mg/dL) and 24 h after UF before UF (1.6mg/dL +/- 0.6mg/dL) and 24 h after UF (1.7 mg/dL +/- 0.6 mg/dL)(1.7 mg/dL +/- 0.6 mg/dL)

Bart et alBart et al reported an average pre-UF creatinine of reported an average pre-UF creatinine of 1.6 mg/dL and 48 h post-UF creatinine of 1.9 mg/dL, 1.6 mg/dL and 48 h post-UF creatinine of 1.9 mg/dL, which was not statistically significantwhich was not statistically significant

Costanzo et alCostanzo et al reported no change in creatinine pre- reported no change in creatinine pre- and post-UF in both the EUPHORIA and UNLOADand post-UF in both the EUPHORIA and UNLOAD trialstrials

Marenzi et alMarenzi et al reported no change in creatinine when reported no change in creatinine when utilizing UF in volume-overloaded patientsutilizing UF in volume-overloaded patients

Costanzo MR, et al. J Amer Coll Cardiol. 2007;49:675-83.

6

5

4

3

2

10

Ultrafiltration Arm Standard Care Arm

m =5.0, CI ± 0.68 kg

(N = 83) m =3.1, CI ± 0.75 kg(N = 84)

p = 0.001W

eig

ht

Lo

ss

(k

g)

A

6

5

4

3

2

1Ultrafiltration Arm

Dy

sp

ne

a S

co

re

B

Standard Care Arm

m =6.4, CI ± 0.11 kg(N = 80) m = 6.1, CI ± 0.15

(N = 83)

p = 0.357

UNLOAD Primary Efficacy Endpoints: UNLOAD Primary Efficacy Endpoints: UltrafiltrationUltrafiltration

Costanzo MR, et al. J Amer Coll Cardiol. 2007;49:675-683.

Ultrafiltration arm (16 events)100

80

60

40

20

00 10 20 30 40 50 60 70 80 90

Days

#of patients at risk

Ultrafiltration arm 88 85 80 77 75 72 70 66 64 45

Standard care arm 86 83 77 74 66 63 59 58 52 41

Standard care arm (28 events)

P = 0.037

Pat

ien

ts f

ree

fro

m

re-h

osp

ital

izat

ion

(%

)

UNLOAD: Freedom from Re-hospitalization

RVDP

ePAD

RVSP

PEI

STI

HR

RV Pressure

RV dP/dt

Timing intervals

V. Sense V. Sense

EGM

REducing Decompensation events Utilizing intraCardiac prEssures in patients with

chronic HF

CONFIDENTIAL- Medtronic, Inc.

HYPERVOLEMICHYPERVOLEMIC

Monitoring-Monitoring-CHAMPIONCHAMPIONCCardiomems ardiomems HHeart sensor eart sensor AAllows llows

MMeasurement of easurement of PPressure to ressure to IImprove mprove OOutcomes in NYHA Class III HF Patientsutcomes in NYHA Class III HF Patients

Cancion System for Aortic Flow Therapy

Aortic Flow Therapy

Backflow against the aortic wall

Forward flow in the center of the aorta

Early Diastole Early DiastoleWith AFT

1) 1) TechnicalTechnical (device group only)- (device group only)- insertion and attainment of flow 1 L/min for 24 insertion and attainment of flow 1 L/min for 24 hourshours2) 2) HemodynamicHemodynamic-mean PCWP decrease from -mean PCWP decrease from baseline of 5 mm Hg calculated as the average baseline of 5 mm Hg calculated as the average of values at 72 to 96 hoursof values at 72 to 96 hours3) 3) ClinicalClinical any of the following: 10 consecutive any of the following: 10 consecutive days alive out of hospital, no alternative days alive out of hospital, no alternative mechanical support, absence of death, and mechanical support, absence of death, and

absence of readmission for HF.absence of readmission for HF. ( (days 1 to 35 after randomization) days 1 to 35 after randomization)

Primary end point overall success Primary end point overall success compositecomposite

Copyright ©2008 American Heart Association

Greenberg, B. et al. Circulation 2008;118:1241-1249

Percentage of patients with PCWP and clinical success

13.6% of the control group and 17.4% of the device group patients (P=0.45 )

Copyright ©2008 American Heart Association

Greenberg, B. et al. Circulation 2008;118:1241-1249

PCWP and CI at baseline (prerandomization) and at sequential postrandomization time points (mean{+/-}SEM)

Kaplan-Meier: Mortality

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60

Days since randomization

Pro

po

rtio

n e

ve

nt-

fre

e

Standard Therapy

Orqis CRS

HR 1.05 (0.60, 1.82)

Number at risk:Orqis 109 100 90 85 75 72 70Std 59 51 49 45 43 41 37

Kaplan-Meier: Death or HF Hospitalization

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60

Days since randomization

Pro

po

rtio

n e

ven

t-fr

ee

Standard Therapy

Orqis CRS

HR: 0.87 (0.57, 1.33)

Number at risk:Orqis 109 99 82 68 57 52 47Std 59 49 43 34 28 23 22

*Use as an alternative to transplant is currently under clinical investigation in the US.

The HeartMateThe HeartMate®® Left Left Ventricular Assist System Ventricular Assist System

(LVAS)(LVAS) Bridge to Bridge to

TransplantTransplant Destination* Destination*

Therapy for Non-Therapy for Non-Transplant Transplant CandidatesCandidates

HeartMateHeartMate®® XVE LVAD XVE LVAD

REMATCH Inclusion REMATCH Inclusion CriteriaCriteria

Original Criteria (124/129 pts)Original Criteria (124/129 pts)

Ineligible for cardiac transplantationIneligible for cardiac transplantation NYHA Class IV NYHA Class IV >> 90 days (70% on 90 days (70% on

inotropes)inotropes) Intensive medical therapyIntensive medical therapy LVEF LVEF << 25% 25% VOVO22max max <<12 ml/kg/min12 ml/kg/min

Cardiac MortalityCardiac Mortality0

.00

.20

.40

.60

.81

.0

months from randomization

Su

rviv

al

0 6 12 18 24 30

REMATCH, cardiac mortality

LVASOMM

Improved Outcomes in 2-Improved Outcomes in 2-Year LVAD SurvivalYear LVAD Survival

LVAD SurvivalLVAD Survival

Mechanical Circ Support Registry ISHLT 2005

CMS DecisionCMS Decision

One year following REMATCH CMS One year following REMATCH CMS approved the use of the HeartMate LVAD approved the use of the HeartMate LVAD as an alternative to heart transplant.as an alternative to heart transplant.

Required the patient have been evaluated Required the patient have been evaluated and rejected for transplantand rejected for transplant

Have Stage D HF for over 90 daysHave Stage D HF for over 90 days Presumed survival of less than 50% at 1 Presumed survival of less than 50% at 1

yearyear Expected benefit from LVAD therapyExpected benefit from LVAD therapy

NUMBER OF HEART TRANSPLANTS NUMBER OF HEART TRANSPLANTS REPORTED BY YEARREPORTED BY YEAR

189 317665

1182

2158

2710

31373362

4001 4171 4197 4365 4439 4399 4263 41673833

3563 3410 3367 3269 3180 3026 3095

0

500

1000

1500

2000

2500

3000

3500

4000

4500

Nu

mb

er

of

Tra

ns

pla

nts

ISHLT 2007

NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as evidence that the number of hearts transplanted worldwide has declined in recent years.

J Heart Lung Transplant 2007;26: 769-781

HEART TRANSPLANTATIONHEART TRANSPLANTATION Kaplan-Meier SurvivalKaplan-Meier Survival (1/1982-6/2005)(1/1982-6/2005)

0

20

40

60

80

100

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

Years

Su

rviv

al

(%)

Half-life = 10.0 yearsConditional Half-life = 13.0 years

N=70,702

ISHLT 2007

N at risk at 22 years: 33

HEART TRANSPLANTATION Kaplan-Meier Survival (1/1982-6/2005)

J Heart Lung Transplant 2007;26: 769-781

The Randomized Trial The Randomized Trial

We think that everyone might benefit the most if the Most radical protagonists of evidence based medicineOrganized and participated in a double blind,Randomized, placebo controlled, crossover trial of the parachute.

OptimalMedicalTreatment

Transplant

Dead

Class I CHF

Class II CHF

Class III CHF

Class IV CHF

Post-Transplant Well

PT-CAD

PT-Malignancy

PT-Renal Failure

PT-CAD+Malignancy

PT-CAD+Renal Failure

PT-Malignancy+Renal Failure

PT-CAD+Malignancy+Renal Failure

Medical Subtree

Post-transplant Subtree

MarkovNode

LVAD

MarkovNode

Dead

Dead post-LVAD

Postop_Hemorrhage

Postop_Thrombotic_CVA

Postop_Hemorrhagic_CVA

Post_LVAD_Well

Post-LVADsubtree

Modified from Freudenberger,RS Circulation. 2006 Jul 4

Gain from LVAD vs. OMT

-40

-20

0

20

40

60

80

100

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Relative mortality after LVAD

Gain

in L

ife-e

xpecta

ncy (m

onth

s)

Threshold Class IV-A

Threshold Class IV-B

LVADFavored

OMTFavored

Baseline

Modified from Freudenberger,RS Circulation. 2006 Jul 4

Gain of LVAD over HT

-100

-80

-60

-40

-20

0

20

40

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Relative mortality after LVAD

Gain

in life-e

xpecta

ncy

Threshold Class IV-A

Threshold Class IV-B LVAD

Favored

OMTFavored

Baseline

Modified from Freudenberger,RS Circulation. 2006 Jul 4