decompensated heart failure - cecity · comorbidities: diabetes 20-25% renal insufficiency:...

Decompensated Heart Failure:

Focusing on Early and Aggressive Treatment to

Improve Patient and Economic Outcomes

Clyde W. Yancy, M.D.University of Texas Southwestern Medical Center

Dallas

Adapted from HFSA. Pharmacotherapy. 2000;20:495.

Evolution to Cardiovascular Events; What causes heart failure?

SNS-RAS SNS-RAS

MetabolicSyndrome

(Insulin resistance, diabetes)

HTN

MI Cardio-myopathy

HF

Heart FailureHeart Failure--How does it How does it happen?happen?

Myocardial injuryMyocardial injury Fall in LV performanceFall in LV performance

Activation of RAAS, SNS, ET,Activation of RAAS, SNS, ET,and othersand others

Myocardial toxicityMyocardial toxicity Peripheral vasoconstrictionPeripheral vasoconstrictionHemodynamicHemodynamic alterationsalterations

Remodeling andRemodeling andprogressiveprogressiveworsening ofworsening ofLV functionLV function Heart failure symptomsHeart failure symptomsMorbidity and mortalityMorbidity and mortality

ANPANPBNPBNP

-

-

Acute MI(hours)

Infarct expansion(hours to days)

Global remodeling(days to months)

Example of Post-MI Remodeling

• Apical infarction from total occlusion LAD,remainder of coronaries without obstruction

Reversal of Remodeling With Pharmacologic Treatment

Cardiac adrenergic,RAS signaling

Myocytedysfunction

Improved myocyte function

Antiadrenergictherapy

Remodeledventricle

Relatively normal chamber size &

geometry

Survival Benefit: ACEIs and ß-Blockers-is mortality still an issue?

15.6

11.9

7.8

12.4

0

2

4

6

8

10

12

14

16

Placebo Active treatment

% SOLVD-TMERIT-HF +CIBIS II

Death at 1 Year

Adapted from McMurray JJV. Heart. 1999;82(suppl IV):IV14–IV22.

? Additional benefit Of aldosterone antagonism

*annual mortalityRate in Val-HeFT:6%*

Congestive Heart Failure:A New Problem Emerges

• Nearly 900,000 annual hospital admissions(increased 90% in past 10 years)1

• Most common discharge diagnosis for patients older than 65 years2

• 6.5 million hospital days per year1

• Single largest expense for Medicare1

• 0.9% of members with HF incur 4% of health plan costs with mean annual charges of $6,0263

1. Hunt SA et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult.2001.

2. Graves EJ, Gillum BS. 1994 Summary: National Hospital Discharge Survey. National Center for Health Statistics; 1996.

3. DeLissovoy G et al. Treatment Charges & Resource Use Among Patients with HF Enrolled in an MCO.Managed Care Interface, May, 2002.

Heart Failure HospitalizationsThe Number of Heart Failure Hospitalizations Is Increasing

in Both Men and Women

CDC/NCHS: hospital discharges include patients both living and dead.

Ann

ual D

isch

arge

s

0

100,000

200,000

300,000

400,000

500,000

600,000

'79 '81 '83 '85 '87 '89 '91 '93 '95 '97

WomenMen

Year'99

American Heart Association. 2002 Heart and Stroke Statistical Update. 2001.

Rates of Hospital Re-admission

0

10

20

30

40

50

60

Within 2Days

Within 1Month

Within 6Months

Patie

nts

Rea

dmitt

ed (%

)

2%

20%

50%

Aghababian RV. Rev Cardiovasc Med. 2002;3(suppl 4):S3–S9.

Outcomes of Heart Failure Hospitalizations

• Median length of hospital stay: 6 days1

• Hospital readmissions– 20% at 30 days1

– 50% at 6 months1

• Mortality– 11.6% at 30 days2

– 33.1% at 12 months2

– 50% at 5 years1

1. Aghababian RV. Rev Cardiovasc Med. 2002;3(suppl 4):S3–S9.2. Jong P et al. Arch Intern Med. 2002;162:1689–1694.

ADHERE-An Acute Decompensated Heart Failure Registry

Gaps in Knowledge Before ADHEREGaps in Knowledge Before ADHEREClinical Trials:

Age: 50-60’s years old

Sex: 70-80% Men

Comorbidities: Diabetes 20-25%Renal Insufficiency: infrequent (mean Cr 1.1-1.3)

Ventricular Function: 75-80% Systolic Dysfunction (LVEF < 0.40)

PAC use: 30-40%

In-hospital Mortality: 1.5-2.5%

Goals of the ADHERE RegistryGoals of the ADHERE Registry

• Describe demographics and clinical characteristics of patients hospitalized with acutely decompensatedheart failure (AHF)

• Characterize current management of hospitalized patients with AHF

• Define treatment strategies associated with best clinical outcomes and most efficient use of resources

• Assist in evaluating and improving the quality of care

Cumulative Patient Enrollment

38,31044,240

51,06956,805

63,321

70,55976,491

31,00036,00041,00046,00051,00056,00061,00066,00071,00076,00081,00086,000

12/30/02 2/28/03 4/29/03 6/28/03

Cumulative Patient Enrollment

As of 10/03, >100,000 entries are in the ADHERE Database

Executive SummaryAll Enrolled Discharges in the Last 12 Months (07.01.2002-06.30.2003)

The Nationn=58919Demographics/Patient Characteristics

557 (n=33572)

46

Chronic Renal Dialysis (%)LVEF Measured In-hospital (%)

LVEF <40% or Mod/Sev Impairment (%)

4852

GenderMale (%)Female (%)

75.348

Median Age (yrs)Patients >75 Years (%)

Indented percentages are calculated based on the number of patients presented in the preceding row, rather than the number of patients for the column.

Utilization of Evidence-based Therapies in Heart Failure

2300/7883 Patients hospitalized with HF; prior known dx of systolic dysfunction HF; outpatient medical regimen.ADHERE Registry Report Q1 2002 (4/01-3/02) of 180 US HospitalsPresented at the Heart Failure Society of America Satellite Symposium, September 23, 2002.

50.8

12.8

57.4

80.8

41

0102030405060708090

100

Outpatient HF Medication

Patie

nts

Trea

ted

(%)

History of HF and LVEF Documented and ≤ 0.40*

*Excludes patients with documented contraindications.

ACE Inhibitor ARB β -Blocker Diuretic Digoxin

Most Common IV Medications

0102030405060708090

100

% o

f Pat

ient

s

IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside

IV Vasoactive Meds

88%

6% 6% 10%3%

All Enrolled Discharges (n=105388) from October 2001 to January 2004

1%10%

4.04.75.41.4

In-hospital Mortality (%)Mechanical Vent (%)Renal Dialysis (%)Defibrillation or CPR (%)

Adverse Outcomes

4.35.0 (n=46835)

4.1 (n=58919)

2.5 (n=11074)

Median Total Hospital LOS (days)Median ED and/or Obs LOS (hrs)Median Inpatient Hospital LOS (days)

Median ICU LOS (days)

The Nation n=58919

LOS

All Enrolled Discharges in the Last 12 Months (07.01.2002-06.30.2003) Executive Summary (Continued)

Indented percentages are calculated based on the number of patients presented in the preceding row, rather than the number of patients for the column.

INTRODUCING A NEW PARADIGM IN

CARDIOVASCULAR DISEASE:

Heart Failure and Mortality in the

ADHERE Database:What Have We

Learned?

Mortality Data Mining ProcessMortality Data Mining ProcessMortality Data Mining ProcessStep 1Step 1

Defining Covariate Adjusted Odds Ratios of Death

Defining Covariate Adjusted Defining Covariate Adjusted Odds Ratios ofOdds Ratios of DeathDeath

All Covariates

Risk Stratification Modeling

Predictors of Death (i.e.)• BUN• CREATININE• SPBP• SODIUM• AGE• SEX

All Covariates

Propensity Modeling Software

Predictors of Treatment (i.e.)• BUN• CREATININE• SPBP• SODIUM• AGE• SEX

Step 2Step 2Defining Covariate Adjusted

Probability of Treatment“propensity score”

Defining Covariate Adjusted Defining Covariate Adjusted Probability ofProbability of TreatmentTreatment

“propensity score”“propensity score”

Risk and Propensity

Adjusted OR of Death

CART CART

AgeAge Qualitative LVEF / PreQualitative LVEF / Pre--hosp/init hosp/init evalevalLength of stayLength of stay--inpatientinpatient GenderGenderTime in careTime in care Race / ethnicityRace / ethnicity DyspneaDyspnea categorycategoryHF: preHF: pre--hospitalhospital Primary InsurancePrimary Insurance FatigueFatigueFirst weightFirst weight Ischemic EtiologyIschemic Etiology RalesRalesFirst heightFirst height HF: Baseline NYHA classHF: Baseline NYHA class Peripheral EdemaPeripheral EdemaFirst systolic BPFirst systolic BP CADCAD NYHA Class IV / PresNYHA Class IV / PresFirst diastolic BPFirst diastolic BP CAD: Prior MICAD: Prior MI Congestion / 1Congestion / 1stst xx--rayrayheart rateheart rate CAD: Prior revascularizationCAD: Prior revascularization QRS duration >120 msQRS duration >120 msSodiumSodium AtrialAtrial fibrillationfibrillation Cardiac enzymesCardiac enzymesCreatinineCreatinine DiabetesDiabetes HBG < 12HBG < 12BUNBUN HypertensionHypertension Duration of symptomsDuration of symptomsBUN / BUN / CreatinineCreatinine ratioratio HyperlipidemiaHyperlipidemia Tachycardia >100Tachycardia >100HemoglobinHemoglobin Stroke / TIAStroke / TIA HypertensiveHypertensive--SBP >140SBP >140BNPBNP Ever smokedEver smokedKirk Adams HF scoreKirk Adams HF score DyspneaDyspnea typetype

ADHERE: Potential Predictors of ADHERE: Potential Predictors of InIn--Hospital MortalityHospital Mortality

AgeAge Qualitative LVEF / PreQualitative LVEF / Pre--hosp/init hosp/init evalevalLength of stayLength of stay--inpatientinpatient GenderGenderTime in careTime in care Race / ethnicityRace / ethnicity DyspneaDyspnea categorycategoryHF: preHF: pre--hospitalhospital Primary InsurancePrimary Insurance FatigueFatigueFirst weightFirst weight Ischemic EtiologyIschemic Etiology RalesRalesFirst heightFirst height HF: Baseline NYHA classHF: Baseline NYHA class Peripheral EdemaPeripheral EdemaFirst systolic BPFirst systolic BP CADCAD NYHA Class IV / PresNYHA Class IV / PresFirst diastolic BPFirst diastolic BP CAD: Prior MICAD: Prior MI Congestion / 1Congestion / 1stst xx--rayrayheart rateheart rate CAD: Prior revascularizationCAD: Prior revascularization QRS duration >120 msQRS duration >120 msSodiumSodium AtrialAtrial fibrillationfibrillation Cardiac enzymesCardiac enzymesCreatinineCreatinine DiabetesDiabetes HBG < 12HBG < 12BUNBUN HypertensionHypertension Duration of symptomsDuration of symptomsBUN / BUN / CreatinineCreatinine ratioratio HyperlipidemiaHyperlipidemia Tachycardia >100Tachycardia >100HemoglobinHemoglobin Stroke / TIAStroke / TIA HypertensiveHypertensive--SBP >140SBP >140BNPBNP Ever smokedEver smokedKirk Adams HF scoreKirk Adams HF score DyspneaDyspnea typetype

3 Greatest Predictors of IHM3 Greatest Predictors of IHMVariable Predictors of IHMVariable Predictors of IHMNonNon--Predictors of IHMPredictors of IHM

ADHERE: Potential Predictors of ADHERE: Potential Predictors of InIn--Hospital MortalityHospital Mortality

ADHERE CART Analysis• Best single predictor for in-hospital mortality was high

admission BUN (>43 mg/dL)

• Next most useful predictor was low admission SBP (<115 mmHg)

• Third best predictor was a high admission creatinine (>2.75 mg/dL)

• These branch points allowed identification of patients with mortality rates as low as 2.14% and as high as 21.94%, odds ratio 12.9 (95% CI 10.4-15.9)

ADHERE CART Analysis

SYS BP 115n=24,933

SYS BP 115n=7,147

6.41%n=5,102

15.28%n=2,048

21.94%n=620

12.42%n=1,425

5.49%n=4,099

2.14%n=20,834

BUN 43N=32,324

GreaterGreaterthanthan

LessLessthanthan

2.68%n=25,122

8.98%n=7,202

Cr 2.75n=2,045

Fonarow et al., Accepted HFSA 2003Fonarow et al., Accepted HFSA 2003

%’s = mortality rates%’s = mortality rates

ADHERE Mortality AnalysisPatients Receiving IV Vasoactive Medications

• In ADHERE, therapies rendered were determined based on clinician judgment and not by a study protocol

• Imbalances between groups in baseline characteristics that both predicted mortality as well as the likelihood of receiving a given therapy were adjusted using multivariable regression and propensity analysis

Effects of IV Vasoactive Medications on Mortality in ADHERE

Abraham et al., Accepted HFSA 2003

0.41*0.57*0.83†Adjusted for covariates and propensity score

0.51*0.58*0.85§Adjusted for covariates

sex, age, BUN, SBP, DBP, CR

0.36*0.53*1.62*Unadjusted

Nesiritidevs.

dobutamine

Nesiritide vs.

milrinone

Nesiritide vs. NTG

Analysis

** pp<<0.0002, 0.0002, §§ p=0.24, p=0.24, ††p=0.19 p=0.19 Nesiritide n=2,128; NTG n=3,457; milrinone n=1,205; Nesiritide n=2,128; NTG n=3,457; milrinone n=1,205; dobutaminedobutamine n=2,211n=2,211

ADHERE Mortality Analysis

Nesiritide N = 2,128

Favors NesiritideFavors Nesiritide

NitroglycerinNitroglycerinN = 3,457N = 3,457

MilrinoneMilrinoneN = 1,205N = 1,205

DobutamineDobutamineN = 2,212N = 2,212

Favors Other AgentFavors Other Agent

0 1 2Hazard Ratio

P P = 0.186= 0.186

P P < 0.0002< 0.0002

P P < 0.0002< 0.0002

Utilization of inotropic agents versus nesiritide

Based on cumulative national benchmark report data

* Inotropes: Dobutamine, Dopamine, and milrinone

ADHERE National Benchmark Data

17%16%

15% 15%

7%

9%10%

12%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Q4 2002 Q1 2003 Q2 2003 Q3 2003

Inotrope Use*Nesiritide Use

ADHERE CM- LESSONS LEARNED: RENAL

DYSFUNCTION

Prevalence of Renal Insufficiency in Hospitalized Heart Failure

5.0%

14.0%

20.0%

0.0%

5.0%

10.0%

15.0%

20.0%

Source: Scios ADHERE Registry April 2003. Note: P- values for categorical variables from Mantel-Haenszel Chi-square statistic.

SCr < 2.0mg/dL

N = 52,047

SCr 1.5- 2.0mg/dLChronic Dialysis

5.7%

3.5%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%P-value = < 0.0001

Outcomes - Mortality

Summary of Patient Characteristics Renal Insufficiency vs. Without Renal Insufficiency

Renal Insufficiencyn = 765

Without Renal Insufficiencyn = 1,151

Source: Scios ADHERE Registry April 2003. Note: P- values for categorical variables from Mantel-Haenszel Chi-square statistic.

6.6

5.6

5.05.25.45.65.86.06.26.46.6

P-value = < 0.0001

Outcomes - Total Hospital LOS (days) Mean

Renal Insufficiencyn = 13,466

Without Renal Insufficiencyn = 33,125

Summary of Patient Characteristics Renal Insufficiency vs. Without Renal Insufficiency

Source: Scios ADHERE Registry April 2003. Note: P- values for categorical variables from Mantel-Haenszel Chi-square statistic.

Risk of Mortality in Relation toDecreasing LVEF and GFRc

HillegeHillege HL et al. Circulation 2000; 102: 203HL et al. Circulation 2000; 102: 203--1010

Baughman, et al. N Engl J Med 2002;347:158–159

Natriuretic peptides: ‘the opposition’

Pharmacologic Actions of Human BNP

RenaldiuresisnatriuresisGFR

Neurohormoralaldosterone, renin, AIIendothelinnorepinephrine

Hemodynamic(balanced vasodilation)• preload (veins)• afterload (arteries)• coronary arteries

DR IMKRG

S SSSGLGF

C CS SG

SGQVMK V L RR

H

KPS

Cardiac lusitropic anti-fibroticanti-remodeling

RAP = right arterial pressure.

Hemodynamic Effects ofNesiritide in CHF Patients

*P < 0.01 vs. baseline†P < 0.05 vs. placebo ‡P < 0.05 vs. baseline

–60

–40

–20

0

20

40

60

HR RAP PCWP SVR CI SVI

Placebo (n = 4)Nesiritide (n = 10)

Cha

nge

From

Bas

elin

e (%

)

* ‡

‡

* †

A Randomized, Double-Blind, Placebo-Controlled Trial

Abraham WT et al. J Cardiac Fail. 1998;4:37–44.

Plasma Aldosterone Plasma Norepinephrine

Nesirit

ide

0.015

µg/kg

/min

Nesirit

ide

0.030

µg/kg

/min

Placeb

o

- 2.5 ng/dL - 1.6 ng/dL 0.6 ng/dL

Nesirit

ide

0.015

µg/kg

/min

Nesirit

ide

0.030

µg/kg

/min

Placeb

o

- 75 pg/ml 8 pg/ml 36 pg/ml

Figure adapted from data published in Colucci WS et al. N Engl J Med 2000:343:246-53

Effects on Neurohormones at 6 Hours

P = 0.03P = ns

Effects of nesiritide vs. dobutamine on heart rate, premature ventricular beats (PVB),

and repetitive beats

Burger AJ, et al. Am Heart J 2002;144:1102–1108

PRECEDENTPRECEDENT

-20

0

20

40

60

80

Mean change from baseline in events/hour or average HR

(bpm)

P<0.001

P=0.001

P<0.001

Heart rate PVB Repetitive beats

Dobutamine (n=83)

Nesiritide 0.015 µg/kg/min (n=84)

Nesiritide 0.030 µg/kg/min (n=79)

Treatment Duration (h)0

Months6

Eligible Patients(N = 489)

Catheterized(n = 246)

Noncatheterized(n = 243)

Stratified Randomized

Nitroglycerin (n = 60)

Placebo (n = 62)

NES fixed dose (n = 62)

NES adjustable dose (n = 62)

Nitroglycerin (n = 92)

NES fixed dose (n = 92)

NES adjustable dose (n = 62)

3-Hour Placebo-Controlled Period

Active-Controlled Period

1 2 3

Nitroglycerin (n = 124)

Placebo (n = 80)

NES fixed dose (n = 119)

Nitroglycerin (n = 83)

NES fixed dose (n = 80)

End of Study Drug

Added to standard therapy

VMAC: Study Design

Scios Inc. NDA 20-920 Cardiovascular and Renal Drugs Advisory Committee Briefing Document: Natrecor (nesiritide) for Injection. Sunnyvale, CA: Scios Inc; May 25, 2001.

Nesiritide Hemodynamic Effects vs. IV NTGC

hang

e fr

om B

asel

ine

in P

CW

P (m

mH

g)

End of Placebo-Controlled Period

Time on Study Drug (Hours)

During 3-hour Placebo Period:Placebo, n = 62 IV NTG, n = 60Nesiritide, n = 124

After 3-hour PeriodIV NTG, n = 92Nesiritide, n = 154

† P ≤ 0.05 vs. IV NTG* P ≤ 0.05 vs. Placebo

†*

Publication Committee for the VMAC Investigators. JAMA 2002: 287(12); 1531-1540

0 0.25 0.5 1 2 3 6 9 12 24 36 48

-9

-8

-7

-6

-5

-4

-3

-2

-1

0PCWP - Placebo

PCWP - IV NTG

PCWP - Nesiritide

†*

†* †

** †

* †

†††

*

Pharmacoeconomics of Heart Failure Treatment

Loma Linda Experience

• Review of 130 consecutive patients discharged from the CCU

• Data on patient demographics, medication usage and outcomes

• Patients divided into two groups, 58 nesiritide and 72 controls

Effect of Nesiritide on Length of Hospital Stay in Decompensated Heart Failure. Chang R et al. ACC Poster Presentation April 2003.

Loma Linda Experience: Baseline Characteristics

Age 58±22 66 ±22 .07EF 18±11 24 ±16 .023SBP 115 ±21 126 ±25 .011SCr 1.97±1.14 1.57 ±.85 .023BUN 50±39 40 ±27 .067

Nesiritide No Nes P-value

Loma Linda Experience: Results

2.81

1.971.86

3.88

1.57 1.56

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Nesiritide No Nes

LOS (p<0.001)Admit SCrDischarge SCr

Days or mg/dl

ADHERE: Loma Linda Experience

LomaLinda

Like Hospital

HospIn

Region

AllHospitals

Inpatient LOS

U of Kentucky (UK) Experience

• Retrospective study of 55 ADHF patients admitted to University of Kentucky HF service (29 nesiritide, 26 milrinone)– Primary outcomes

• Length of Stay (Overall, ICU, Floor)• Hospital readmission at 30 days

– Secondary outcomes• Length of medication infusion• Change in hemodynamics• Overall cost of therapy• Overall diuresis

Effect of Nesiritide vs. Milrinone on Patient Outcomes in the Treatment of Acute Decompensated Heart Failure. Lewis DA et al. To be presented at ACCP Spring Forum April 2003

Univ of KY Experience:Baseline Characteristics

0.71753 +/- 3.7055 +/- 3.59PAS

0.08322 +/- 1.5026 +/- 1.72PCWP

0.5641271 +/- 1061357 +/- 101SVR

0.65214 +/- 1.5215 +/- 1.69RAP

0.5232.2 +/- 0.162.4 +/- 0.22CI

0.40759 +/- 2.7462 +/- 2.37DBP

0.097114 +/- 3.77124 +/- 4.33SBP

0.001116.6 +/- 10.950.1 +/- 5.3Duration (hrs)

0.0481.42 +/- 0.171.87 +/- 0.14SCr (mg/dl)

0.30189 +/- 4.6296 +/- 4.96Weight (kg)

0.09357 +/- 2.9663 +/- 2.36Age

P-valueMilrinone (n=26)Nesiritide (n=29)

Effect of Nesiritide vs. Milrinone on Patient Effect of Nesiritide vs. Milrinone on Patient Outcomes in the Treatment of acute HFOutcomes in the Treatment of acute HF

Parameters Nes (N=29) Milrinone (N=25) P-v aluesBaseline SrCr 1.87 1.42 0.048Duration of Tx (hr) 50.1 116.6 0.001LOS (days) 7 8.2 0.328 ICU LOS 3.9 5.9 0.007 Floor LOS 3.1 2.3 0.46330-day readmit 16% 28% 0.306Dec PCWP/ 48 hrs 10.5 mmHg 4 mmHg 0.026

Lewis DA, PharmD et al. ACCP Spring Forum April ,2003

Univ of KY Experience: Secondary Outcomes

2985 ml2205 ml48 hours0.101823ml1067 ml24 hours

P-valueNesiritideMilrinoneDiuresis

$4,155$746$3,409Nesiritide$4,553$280$4,273Milrinone

Overall CostDrug CostHospital Cost(LOS)

Costs

Cleveland Clinic Experience

Hospital Floor• 159 admissions

• 22 Natrecor

– LOS 3.7 days

• 137 other therapy

– LOS 5.5 days

Observation Unit• 48 admissions

• 18 Natrecor

– 16 (89%) DC Home

• 30 other therapy

– 14 (47%) DC Home

Peacock WF. Rev Cardiovasc Med 2002;3(suppl 4):S41-S48.

LOS = length of stay; SC = standard care; ED/OU = emergency department/observation unit; APC = ambulatory payment classification; DRG = diagnosis-related group.Data on file. Scios Inc. August 2002.

Eligible CHF Patients(n = 250)

Nesiritide + SC(n = 120)

Standard Care (SC)(n = 117)

Outpatient Care(APC Code)

Inpatient Care(DRG Allowed)

53 Remain Stable After Discharge

64 Patients Admitted

49 Remain Stable After Discharge

51% Discharged (n = 61)

45% Discharged(n = 53)

59 Patients Admitted 6 Rehosp w/in 30 Days

4.6-Day LOS (index + readmit)

15 Patients Rehosp w/in 30 Days

8.3-Day LOS (index + readmit)

Readmission w/in 30 Days(No DRG Allowed)

ED/OU

≥12 hours

PROACTION: Emergency Medicine Pilot Trial

PROACTION: Outcomes

Index Admissions:

• 11% ↓ in all cause index admissions– 55% standard therapy, 49% nesiritide

• 21% ↓ in CHF index admissions– 38% standard therapy, 30% nesiritide

• 29% ↓ in Class III/IV index admissons– 42% standard therapy, 30% nesiritide

PROACTION: Outcomes

Re-admissions After Index:

• 57% ↓ in all cause readmissions– 23% standard therapy, 10% nesiritide

• 45% ↓ in total LOS (index + readmit)– 8.3 days standard therapy, 4.6 days nesiritide

Cost Analysis:• Improved outcomes neutralize cost

Hospital Length of Stay

ADHERE Registry: 14.7% of patients started IV therapy in the ED compared with 25.5% who started on admission; EmermanCL et al. Ann Emerg Med. 2002;40(4 pt 2):162.

ED vs. Inpatient Initiation of IV Vasoactive Therapy

0

3

6

9

12

15

Leng

th o

f Sta

y (d

)

ED Initiation Inpatient Initiation

IV Vasoactive Therapy

6.3

9.4p = 0.04

Conclusions• Several pharmacoeconomic analyses have shown

nesiritide use in ADHF patients to be cost-effective by:

– Reducing index admissions, or LOS (ICU and overall) for those requiring hospitalization

– Achieving rapid hemodynamic improvement and diuresis while maintaining renal function

– Reducing the need for prolonged hospitalization due to electrolyte imbalances or renal dysfunction

– Reducing the likelihood of readmission, especially within 30 days (non-reimburseable)

ADDRESSING AN UNMET CLINICAL NEED:

Natriuretic Peptides in Chronic Decompensated

Heart Failure

Stages ofCHF

ACC/AHAGuidelines

2001

AHigh-risk patients:

HTN, DM, CAD, + FH, LBBB, cardiotoxic drugs

BStructural heart disease, asymptomatic:

LVH, MI, low LVEF, dilatation, valvular disease

CStructural heart disease,

prior or current symptoms

DRefractory

symptoms rest + hospitalizations

Renin-Angiotensin-AldosteroneEndothelin

Catecholamines

Natriuretic Peptides

VasoconstrictionSodium/Fluid Retention

Chronic Cardiac Stress → Tissue Remodeling/Fibrosis

VasodilationNatriuresis/Diuresis↓ Cardiac Stress↓ Remodeling

Opposition of Neurohormonal Forces in HF

FUSION Study Design

n = 69n = 69

n = 72n = 72

n = 69n = 69 Nesiritide 0.01 Nesiritide 0.01 µµg/kg/ming/kg/min, following bolus, following bolus–– Inotropes not permittedInotropes not permitted

Nesiritide 0.005 Nesiritide 0.005 µµg/kg/ming/kg/min, following bolus, following bolus–– Inotropes not permittedInotropes not permitted

Standard CareStandard Care –– Inotropes permittedInotropes permitted

--3030 to to --5 5 days post days post hospital hospital dischargedischarge

Weekly Outpatient VisitsWeekly Outpatient Visits

n = 210n = 210

4 Weeks4 Weeks

ScreeningScreening

12 Weeks12 Weeks

FollowFollow--upup

Standard Care vs. Nesiritide (0.005) P=0.019Standard Care vs. Nesiritide (0.01) P=0.269Standard Care vs. All Nesiritide P=0.034

Standard Care (n = 23)Nesiritide (0.005) (n = 24)Nesiritide (0.01) (n = 20)All Nesiritide (n = 44)

FUSION I Improvement in Left Ventricular Systolic Function

*compared to standard care

0.090.030.44N/AP-value*

4.6 +/- 4.25.3 +/- 5.04.0 +/- 3.33.2 +/- 3.8Change at 12 Weeks

28.25 +/- 14.837.7 +/- 13.828.8 +/- 15.829.6 +/- 18.6EF at Baseline

All Patients(n = 77)

Nesiritide 0.01 Dose

(n = 37)

Nesiritide 0.005 Dose

(n = 40)

Standard Care

(n = 38)

Summary

• Outpatient nesiritide can be safely administered and is well tolerated as adjunctive therapy for chronic decompensated HF

• Subjects on nesiritide were alive and out of hospital longer vs. standard care

• Mortality/hospitalization was better in the high-risk group treated with nesiritide, P<0.05

• Neurohormonal and echo data suggest a favorable influence on remodeling as a potential mechanism of benefit

• A theoretical biological hypothesis suggests that BNP exerts a negative influence on growth and fibrosis

• FUSION pilot supports further clinical trials

Decompensated Heart Failure:

Focusing on Early and Aggressive Treatment to

Improve Patient and Economic Outcomes

Clyde W. Yancy, M.D.University of Texas Southwestern Medical Center

Dallas

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