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.