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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