Acute Decompensated Heart Failure: Can We Do Better In Improving
Outcomes?Barry Greenberg MDProfessor of Medicine
Director, Advanced Heart Failure Treatment ProgramUniversity of California, San Diego
Acute Decompensated Heart FailureMagnitude of the Problem
• 1 million admissions annually in the U.S. (↑ 50% over the past 10 years)
• Most common admitting diagnosis for patients ≥ 65 years
• Hospitalization costs are considerable ( >60% of amount spent on heart failure)
• Mean length of stay 5-6 days• In-hospital mortality 5%
Acute Decompensated Heart FailureHave We Made Progress?
• The good news:– In-hospital mortality 5% (↓ 40% in 10 years)– Mean length of stay 5-6 days (↓ 30% in 10 years)
• The bad news:– Readmission rates remain high
• 25% within 30 days• 50% within 6-12 months
– High mortality rates persist• 5-10% at 30 days• 20-40% at 6-12 months
Acute Decompensated Heart Failure:Patient Characteristics
ADHEREN = 105,388
OPTIMIZE-HF
N = 48,61272.4 73
ND
48ND8746
50
48727554
Euro-HFN = 11,327
Mean age (yrs) 71> 75 years (%) 30 men
51 womenMale (%) 53Caucasian (%) NDPrior HF history (%) 65Systolic dysfunction (%)
45
Adams KF, et al. Am Heart J. 2005;149:209-216.Gheorghiade M. Circulation. 2005;112:3958-3968.
Cleland JG, et al. Eur Heart J. 2003;24:442-463.
Acute Decompensated Heart Failure:Patient Symptoms
ADHEREN = 105,388
OPTIMIZE-HFN = 48,612
Any dyspnea (%) 89
34
Dyspnea on exertion (%) ND 61
31
68
66
Dyspnea at rest (%)
ND
44
ND
64
65
Fatigue (%)
Rales (%)
Peripheral edema (%)
Adams KF, et al. Am Heart J. 2005;149:209-216.Gheorghiade M. Circulation. 2005;112:3958-3968.
Which Patients Are At the Highest Risk For In-Hospital and Post-
Discharge Mortality?
ADHERE CART: Predictors of Mortality
SBP 115n = 24,933
SBP 115n = 7150
6.41%n = 5102
15.28%n = 2048
21.94%n = 620
12.42%n = 1425
5.49%n = 4099
2.14%n = 20,834
BUN 43N = 33,324
2.68%n = 25,122
8.98%n = 7202
SCr 2.752045
Greater thanLess than
Highest to lowest risk cohortOR 12.9 (95% CI 10.4–15.9)
< > < >
< >
CART, classification and regression treeFonarow GC, et al. JAMA. 2005;293:572-580.
Impact of Worsening Renal Function on Outcomes in Heart Failure
Outcome RF not worse RF worse OR (95% CI)
In-hospital mortality 3% 7% 2.7 (1.6–4.6)
30-day mortality 6% 10% 1.9 (1.3–2.8)
6-month mortality 19% 25% 1.6 (1.2–2.1)
LOS (days) 6.93 9.14
Krumholz H, et al. Am J Cardiol. 2000;85:1110.
6.3
14.5
11.4
7.8
42.2 3.5
0
10
20
N = 319 69 250 140 179 204 115(21.6%) (78.4%) (44%) (56%) (64%) (36%)
Variables Associated with Higher 60-day Mortality
Mor
talit
y (%
)
Overall < 136 ≥ 136 > 29 ≤ 29 Severe Not severe
* Edema, dyspnea, and jugular venous distention at baseline.
Gheorghiade M, et al. JAMA. 2004;291:1963-1971.
[Na+] BUN Congestion*
Fonarow GC, et al. Circulation. 1994;90:I-488.
High PCWP at Hospital Discharge Is Associated with Higher Long-term Mortality
Time (months)
N = 199
N = 257
PCWP > 16 mmHg
PCWP ≤ 16 mmHg
0 6 12 18 24
10
20
30
40
50
60
P = .001
Mortality (%)
CI > 2.6 L/min/m2
CI ≤ 2.6 L/min/m2
0 6 12 18 24
10
20
30
40
50
60
Atrial
Mortality (%)
N = 236
N = 220
Time (months)
Current Treatment of Acute Current Treatment of Acute DecompensatedDecompensatedHeart FailureHeart Failure
Diuretics
Reducefluid
volume
Vasodilators
DecreasePreload
AndAfterload
Inotropes
AugmentContract-
ility
Diuretics
Most Common IV MedicationsAll Enrolled Discharges (n=105,388) October 2001-
January 2004
0102030405060708090
100
Patie
nts
(%)
IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside
IV Vasoactive Meds
88%
6% 6% 10%3% 1%
10%
ADHERE data base
Loop Diuretics Impair Glomerular Filtration Rate
Circulation 2002;105:1348-53.
GFR
(% c
hang
e)
-25
-20
-15
-10
-5
0
5
10
15
Urine Output (mL) 0-8h
IV furosemide 80 mg
Placebo
0 500 1000 1500 2000 2500
SVRSVR LV filling pressureLV filling pressureHeart rateHeart rate
Acute Effects of IV Furosemide
Plasma norepinephrine levelsPlasma norepinephrine levels Plasma renin activityPlasma renin activity Plasma AVP levels Plasma AVP levels
1 h1 h
1800180017001700
1500150014001400
2 h2 h 3 h3 h 4 h4 hCC
****
TimeTime2020’’
16001600 ****
13001300
1 h1 h
3535
3030
2 h2 h 3 h3 h 4 h4 hCC
****
2020’’
2525****
2020 **
TimeTime1 h1 h
9595
9090
8585
80802 h2 h 3 h3 h 4 h4 hCC
****** **
TimeTime2020’’
****
TimeTime
900900
800800
700700
600600
****
CC1010’’
2020’’ 3 h3 h 4 h4 h1 h1 h 2 h2 h
**
TimeTime
1818
14141212
88
****
CC1010’’
2020’’ 3 h3 h 4 h4 h1 h1 h 2 h2 h
1616
1010
**
**
TimeTime
10.0010.00
8.008.007.007.00
5.005.00
CC1010’’
3030’’ 4 h4 h1 h1 h
9.009.00
6.006.00
****
* P < .05; ** P < .01.
Francis GS, et al. Ann Intern Med. 1985;103:1-6.
Diuretic Based Clinical Strategies Are Not Always EFFECTIVE in Reducing
Weight (n=25,799)
All Enrolled Discharges in the Last 12 Months (04.01.2003-03.31.2004) Who Were Discharged Home (including home with additional and/or outpatient care)
7% 6%13%
24%30%
16%
3% 2%0
10
20
30
40
50
Enr
olle
d D
isch
arge
s (%
)
(<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10)
Change in Weight (lbs)
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
21% discharged without weight loss or weight gain
ESCAPE: Relationship Between Diuretic Dose and Mortality
Maximum in-hospital diuretic dose (mg)Maximum in-hospital diuretic dose (mg)
PredictedPredicted ObservedObserved
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
00 100100 200200 300300 400400 500500 600600 700700
Mor
talit
yM
orta
lity
ESCAPE, Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness.
Hasselblad V, et al. J Cardiol Fail. 2005;11(6):S157. Abstract 250.
ESCAPE, Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness.
Hasselblad V, et al. J Cardiol Fail. 2005;11(6):S157. Abstract 250.
UNLOAD: Ultrafiltration vs Standard Diuresis
Ultrafiltration Diuresis P value
Mean weight loss (kg) 5 (n = 83) 3.1 (n = 84) .001
Rehospitalization (%)at 90 days
18 32 .022
Rehospitalization days (mean) at 90 days 1.4 3.8 .022
Unscheduled office/ED visits (%) at 90 days 21 44 .009
UNLOAD, Ultrafiltration vs IV Diuretics for Patients Hospitalized for Acute Decompensated CHF.UNLOAD, Ultrafiltration vs IV Diuretics for Patients Hospitalized for Acute Decompensated CHF.Costanzo MR, et al. J Amer Coll Cardiol. 2007;49:675-683.
UNLOAD Trial Safety EndpointsChange in Serum Creatinine
Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.
Ultrafiltration arm Standard care arm1.00.90.80.70.60.50.40.30.20.10.0
8 hrs 24 hrs 48 hrs 72 hrs Discharge 10 days 30 days 90 days
Seru
m c
reat
inin
e ch
ange
(mg/
dl)
N = 72 90 69 47 86 71 75 66N = 84 91 75 52 90 75 67 62
P > .05 for all time points
Improving Outcomes in Acute Decompensated Heart Failure
Patients
• Although diuretics (and ?ultrafiltration) are effective in relieving congestion they have adverse effects including worsening renal function that may adversely affect post-discharge outcomes.
Inotropic Agents and Vasodilators
Profiles and Therapies of Profiles and Therapies of Advanced Heart FailureAdvanced Heart Failure
YesNo
R. Bourge. Eur J Heart Failure 1999;1:251-257
Warm and DryPCW and CI
normal
Warm and WetPCW elevated
CI normal
Cold and WetPCW elevatedCI decreased
Cold and DryPCW low/normal
CI decreased
VasodilatorsNitroprussideNitroglycerine
Nesiritide
Inotropic DrugsDobutamine
MilrinoneCalcium Sensitizers
Nl SVR High SVR
Congestion at Rest
LowPerfusion
at Rest
No
Yes
Index hospitalization
Control (n = 472) Milrinone (n = 477)
Days of hospitalization for CV-related causes 5.9 (12.5) 5.7 (12.6)
Overall adverse events 2.1% 12.6% *
Sustained hypotension 3.2% 10.7% *
Adverse events within 60 days post-discharge
Rehospitalization or death 35.3% 35.0%
Death 8.9% 10.3%
OPTIME-CHF: Increase in Adverse Events in Milrinone-treated Patients
OPTIME-CHF, Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure. * P < .001.
Cuffe MS et al. JAMA. 2002;287:1541-1547.
Vasodilating Agents Currently Used to Treat ADHF
Agent HR BP CO PAW Side effects
NTG ↑ ↓ → ↓ ↓ Headache, ↓ BP,
tachyphylaxis
NP ↑ ↓ ↑ ↑ ↓ ↓ Thiocyanate toxicity,↓ BP
Nesiritide ↑ ↓ ↑ ↓ ↓ Sustained ↓ BP
# *#*
# *
# #
** # # #
#
##
*
# p < 0.05 versus placebo* p < 0.05 versus NTG
15 m
30 mBL
15 m
30 mBL
Mean observed value (mmHg)
Nitroglycerin
18
20
22
24
26
28
30
-10
-7
-4
-1
1 hr
2 hr
3 hr
1 hr
2 hr
3 hr
Mean change (mmHg)
Placebo Nesiritide
VMAC Primary Endpoint:VMAC Primary Endpoint:PCWP through 3 HoursPCWP through 3 Hours
Young JB et al. AHA Meeting 2000 Late Breaking Trials Session
*
Primary Endpoint
-100
102030405060708090
100Dyspnea at 3 hours
Nesiritide PlaceboNTG
Improved (%)
Worsened (%)
P=0.034
P=0.191
p-values are based on Van Elteren Test with 7-point ordinal scale
Young JB et al. AHA Meeting 2000 Late Breaking Trials Session
No change
Odds Ratios Of Worsening Serum Creatinine (>0.5 mg/dl) By Nesiritide Dose Group
Nesiritide Better
Nesiritide0.01 mcg/kg/min
Nesiritide0.015 mcg/kg/min
Nesiritide0.03 mcg/kg/min
Odds Ratio (and 95% confidence intervals)
P=0.17
P=0.02
P=0.001
0 1 2
Nesiritide Worse
3 4 5
Data on file, Scios Inc.
Improving Outcomes in Acute Decompensated Heart Failure
Patients
• Inotropic agents should be avoided unless there is evidence of hypoperfusion.
• Vasodilators unload the ventricle and are most useful in patients with well maintained blood pressure who remain symptomatic due to congestion.
• Nesiritide is effective in relieving congestion but has uncertain effects on renal function and long-term outcomes.
Emerging Therapies for Treating Acute Decompensated Heart Failure• AVP inhibitors• Continuous aortic flow augmentation
(CAFA-Cancion Device)
Vasopressin Effector Mechanisms
Vasopressin effects mediated by:• V1a receptors (blood vessels, myocardium)
– Peripheral and coronary vasoconstriction– Cell growth, increased intracellular calcium
• V2 receptors (renal tubules)– Water retention
Effect of Single Dose Conivaptanon Urine Output in Advanced HF
-50
0
50
100
150
200
250
0 5 10 15
Time (h)
Cha
nge
UO
(mL/
h)
Placebo10 mg20 mg40 mg
* P < .005
Change in Urine Output 0–4 h
*
*
*
Udelson JE, et al. Circulation. 2001;104:2417-2423.
SALT 1 and 2: Mean Sodium Concentration Over Time
SALT-2 and SALT-2, Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2.*P < .001 for tolvaptan vs. placebo; tolvaptan was discontinued on day 30.
Schrier RW, et al. N Engl J Med. 2006;355:2099-2112.
*** *
* * * *
****
* * * *
0 5 10 15 20 25 30 35 40Day
0 5 10 15 20 25 30 35 40Day
125
130
135
140
0125
130
135
140
0
Seru
m s
odiu
m (m
mol
/lite
r)
Number at riskTolvaptan 95 88 84 71 75 75 119 109 101 97 92 94Placebo 91 75 69 62 63 66 115 98 95 90 84 85
Physician-assessed Signs and Symptoms (% Patients with Improvement)
0
20
40
60
80
100
Day 1 Day 2 Day 3 Day 40
20
40
60
80
100
Day 1 Day 2 Day 3 Day 4
0
20
40
60
80
100
Day 1 Day 2 Day 3 Day 40
20
40
60
80
100
Day 1 Day 2 Day 3 Day 4
Dyspnea
Fatigue Edema
** * *
Orthopnea
** *
* * ** * *
* P<0.05
Tolvaptan Placebo
Konstam MA, et al. JAMA. 2007 Mar 28;297(12):1319-1331.
OutpatientInpatient
Changes in Renal Function
BUN (mg/dL)
Serum Cr(mg/dL)
-0.4
-0.2
0.0
0.2
0.4
0.6
Day1
Day 7 orDischarge
1 4 8 16 24 32 40 48 56
19121925
18641886
17551761
16201614
13811382
11681203
955978
813821
675677
525537
TLVPLC
-4
-2
0
2
4
6
8
Day1
Day 7 orDischarge
1 4 8 16 24 32 40 48 56
TLVPLC
19801987
18281820
16871674
14331434
12201247
10011014
851853
713706
558559
19401951
TolvaptanPlacebo
After Discharge (wk)InpatientKonstam MA, et al. JAMA. 2007;297:1319-31.
Continuous Aortic Flow AugmentationOrqis® Cancion®
Ax – Fem graft Cath : Fem:Fem
single Fem
• a – inflow (fem artery)• b – pump• c – pump motor• d – controller• e – flow sensor• f – outflow (desc
thoracic aorta)
aa
bb
cc
dd
ee
ff
Mechanism of ActionContinuous Aortic Flow Augmentation
Ventricular Unloading Vasodilation Renal Effects
DiuresisHemodynamic improvement
Clinical Benefit
Nitric OxideOther mediators
Effects of CAFA on Hemodynamics and Renal Function
Serum Creat n=20
1.0
1.1
1.2
1.3
1.4
1.5
BASELINE DAY 1 DAY 2 DAY 3
mg%
p=0.02
PCWGloba
1.7
1.8
1.9
2
2.1
2.2
2.3
2.4
2.5
15 20
L/m
in/m
2
P v CI l n=23
25 30
mmHg
24 hrs post
Baseline
72 hrs
24 hrs
Mohacsi P, et al: HFSA, Sept, 2003 Bohm M, et al: ESC HF Working Group, June, 2004Zile M et al: ACC Meeting March 2004 Czerska B et al: ESC HF Working Group June 2004
Hospital Readmission Is Reduced By HF Disease Management
ClineJaarsma
Rich
Naylor
Stewart
Rauh
Lasater
Ekman
Venner
Fonarow0.5
0.6
0.7
0.8
0.9
1
1.1RiskRatio
Summary RR = 0.76 (95% CI .68-.87)Summary RR for randomized only = 0.75 (CI = .60-.95)
Improved use of evidence-based therapy
Improved symptom status andfunctional capacity
Improved QOL
Reduction in hospitalization
Decrease in total medical costs
Improved survival suggestedin some studies
Benefits and Drawbacks of Heart Failure Disease Management Programs
Benefits Drawbacks
Usual Care96%
HF Disease HF Disease Management Management Program 4%Program 4%
Moser DK and Mann DL. Circulation. 2002;105:2810-2812.
Improving Care of Patients With Decompensated Heart Failure
• Diurese to reduce volume overload.• Vasodilators and inotropes useful in refractory
patients.• AVP antagonists correct hyponatremia and relieve
signs/symptoms of congestion.• CAFA improves hemodyanamics in
decompensated heart failure patients.• Disease management programs improve
outcomes.
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