Download Decompensated Heart Failure

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
Evolution to Cardiovascular Events;
What causes heart failure?
HTN
SNS
-R
S
A
R
SNS
MI
Metabolic
Syndrome
(Insulin resistance, diabetes)
HF
Adapted from HFSA. Pharmacotherapy. 2000;20:495.
AS
Cardiomyopathy
Heart Failure-How does it
happen?
Myocardial injury
Fall in LV performance
Activation of RAAS, SNS, ET,
and others
Myocardial toxicity
Morbidity and mortality
-
ANP
BNP
Peripheral vasoconstriction
Hemodynamic alterations
Remodeling and
progressive
worsening of
Heart failure symptoms
LV function
Example of Post-MI Remodeling
• Apical infarction from total occlusion LAD,
remainder of coronaries without obstruction
Acute MI
(hours)
Infarct expansion
(hours to days)
Global remodeling
(days to months)
Reversal of Remodeling With
Pharmacologic Treatment
Cardiac adrenergic,
RAS signaling
Myocyte
dysfunction
Improved myocyte
function
Relatively normal
chamber size &
geometry
Remodeled
ventricle
Antiadrenergic
therapy
Survival Benefit: ACEIs and
ß-Blockers-is mortality still an issue?
Death at 1 Year
%
16
14
SOLVD-T
MERIT-HF +
CIBIS II
15.6
12.4
12
*annual mortality
Rate in Val-HeFT:6%*
11.9
10
7.8
8
6
? Additional benefit
Of aldosterone antagonism
4
2
0
Placebo
Active treatment
Adapted from McMurray JJV. Heart. 1999;82(suppl IV):IV14–IV22.
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 Hospitalizations
The Number of Heart Failure Hospitalizations Is Increasing
in Both Men and Women
Annual Discharges
600,000
500,000
400,000
300,000
200,000
Women
Men
100,000
0
'79
'81
'83
'85
'87
'89
'91
'93
'95
'97
Year
CDC/NCHS: hospital discharges include patients both living and dead.
American Heart Association. 2002 Heart and Stroke Statistical Update. 2001.
'99
Patients Readmitted (%)
Rates of Hospital Re-admission
60
50%
50
40
30
20%
20
10
2%
0
Within 2
Days
Within 1
Month
Aghababian RV. Rev Cardiovasc Med. 2002;3(suppl 4):S3–S9.
Within 6
Months
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 ADHERE
Clinical 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 Registry
• Describe demographics and clinical characteristics of
patients hospitalized with acutely decompensated
heart 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
Cumulative Patient Enrollment
86,000
81,000
76,000
71,000
66,000
61,000
56,000
51,000
46,000
41,000
36,000
31,000
12/30/02
76,491
70,559
63,321
56,805
51,069
44,240
38,310
2/28/03
4/29/03
6/28/03
As of 10/03, >100,000 entries are in the ADHERE Database
Executive Summary
All Enrolled Discharges in the Last 12 Months (07.01.2002-06.30.2003)
Demographics/Patient Characteristics
Median Age (yrs)
Patients >75 Years (%)
Gender
Male (%)
Female (%)
Chronic Renal Dialysis (%)
LVEF Measured In-hospital (%)
LVEF <40% or Mod/Sev Impairment (%)
The Nation
n=58919
75.3
48
48
52
5
57 (n=33572)
46
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
Patients Treated (%)
History of HF and LVEF Documented and ≤ 0.40*
100
90
80
70
60
50
40
30
20
10
0
ACE Inhibitor
ARB
β -Blocker
Diuretic
Digoxin
80.8
57.4
50.8
41
12.8
Outpatient HF Medication
*Excludes patients with documented contraindications.
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 Hospitals
Presented at the Heart Failure Society of America Satellite Symposium, September 23, 2002.
Most Common IV Medications
% of Patients
All Enrolled Discharges (n=105388) from October 2001 to January 2004
100
90
80
70
60
50
40
30
20
10
0
88%
6%
IV Diuretic
Dobutamine
6%
Dopamine
3%
Milrinone
10%
Nesiritide
IV Vasoactive Meds
10%
1%
Nitroglycerin
Nitroprusside
Executive Summary (Continued)
All Enrolled Discharges in the Last 12 Months (07.01.2002-06.30.2003)
LOS
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
4.3
5.0 (n=46835)
4.1 (n=58919)
2.5 (n=11074)
Adverse Outcomes
In-hospital Mortality (%)
Mechanical Vent (%)
Renal Dialysis (%)
Defibrillation or CPR (%)
4.0
4.7
5.4
1.4
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 Process
Step 1
Step 2
Defining Covariate Adjusted
Odds Ratios of Death
Defining Covariate Adjusted
Probability of Treatment
“propensity score”
All Covariates
All Covariates
Risk Stratification Modeling
CART
•
•
•
•
•
•
Propensity Modeling Software
Predictors of Death (i.e.)
Predictors of Treatment (i.e.)
BUN
CREATININE
SPBP
SODIUM
AGE
SEX
•
•
•
•
•
•
Risk and
Propensity
Adjusted OR
of Death
BUN
CREATININE
SPBP
SODIUM
AGE
SEX
CART
ADHERE: Potential Predictors of
In-Hospital Mortality
Age
Qualitative LVEF / Pre-hosp/init eval
Length of stay-inpatient
Gender
Time in care
Race / ethnicity
Dyspnea category
HF: pre-hospital
Primary Insurance
Fatigue
First weight
Ischemic Etiology
Rales
First height
HF: Baseline NYHA class
Peripheral Edema
First systolic BP
CAD
NYHA Class IV / Pres
First diastolic BP
CAD: Prior MI
Congestion / 1st x-ray
heart rate
CAD: Prior revascularization
QRS duration >120 ms
Sodium
Atrial fibrillation
Cardiac enzymes
Creatinine
Diabetes
HBG < 12
BUN
Hypertension
Duration of symptoms
BUN / Creatinine ratio
Hyperlipidemia
Tachycardia >100
Hemoglobin
Stroke / TIA
Hypertensive-SBP >140
BNP
Ever smoked
Kirk Adams HF score
Dyspnea type
ADHERE: Potential Predictors of
In-Hospital Mortality
Age
Qualitative LVEF / Pre-hosp/init eval
Length of stay-inpatient
Gender
Time in care
Race / ethnicity
Dyspnea category
HF: pre-hospital
Primary Insurance
Fatigue
First weight
Ischemic Etiology
Rales
First height
HF: Baseline NYHA class
Peripheral Edema
First systolic BP
CAD
NYHA Class IV / Pres
First diastolic BP
CAD: Prior MI
Congestion / 1st x-ray
heart rate
CAD: Prior revascularization
QRS duration >120 ms
Sodium
Atrial fibrillation
Cardiac enzymes
Creatinine
Diabetes
HBG < 12
BUN
Hypertension
Duration of symptoms
BUN / Creatinine ratio
Hyperlipidemia
Tachycardia >100
Hemoglobin
Stroke / TIA
BNP
Ever smoked
Kirk Adams HF score
Dyspnea type
Hypertensive-SBP >140
3 Greatest Predictors of IHM
Variable Predictors of IHM
Non-Predictors of IHM
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
Less
than
BUN 43
N=32,324
Greater
than
2.68%
n=25,122
8.98%
n=7,202
SYS BP 115
SYS BP 115
n=24,933
n=7,147
5.49%
n=4,099
15.28%
n=2,048
2.14%
n=20,834
Cr 2.75
%’s = mortality rates
n=2,045
12.42%
n=1,425
Fonarow et al., Accepted HFSA 2003
6.41%
n=5,102
21.94%
n=620
ADHERE Mortality Analysis
Patients 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
Analysis
Nesiritide
Nesiritide Nesiritide
vs.
vs.
vs. NTG
milrinone dobutamine
Unadjusted
1.62*
0.53*
0.36*
Adjusted for covariates
sex, age, BUN, SBP,
DBP, CR
0.85§
0.58*
0.51*
Adjusted for covariates and
propensity score
0.83†
0.57*
0.41*
Nesiritide n=2,128; NTG n=3,457; milrinone n=1,205; dobutamine n=2,211
* p<0.0002, § p=0.24, †p=0.19
Abraham et al., Accepted HFSA 2003
ADHERE Mortality Analysis
Favors Nesiritide
Nitroglycerin
N = 3,457
Milrinone
N = 1,205
Dobutamine
N = 2,212
0
Nesiritide N = 2,128
Favors Other Agent
P = 0.186
P < 0.0002
P < 0.0002
1
Hazard Ratio
2
Utilization of inotropic agents
versus nesiritide
ADHERE National Benchmark Data
18%
16%
17%
16%
14%
15%
12%
12%
10%
8%
6%
15%
9%
10%
Inotrope Use*
Nesiritide Use
7%
4%
2%
0%
Q4 2002
Q1 2003
Q2 2003
Q3 2003
Based on cumulative national benchmark report data
* Inotropes: Dobutamine, Dopamine, and milrinone
ADHERE CM- LESSONS
LEARNED: RENAL
DYSFUNCTION
Prevalence of Renal Insufficiency
in Hospitalized Heart Failure
N = 52,047
20.0%
20.0%
15.0%
14.0%
10.0%
5.0%
5.0%
0.0%
Chronic Dialysis
SCr 1.5- 2.0mg/dL
SCr < 2.0mg/dL
Source: Scios ADHERE Registry April 2003. Note: P- values for categorical variables from Mantel-Haenszel Chisquare statistic.
Summary of Patient Characteristics Renal
Insufficiency vs. Without Renal Insufficiency
Outcomes - Mortality
6.0%
P-value = < 0.0001
5.7%
5.0%
4.0%
3.5%
3.0%
2.0%
1.0%
0.0%
Renal Insufficiency
n = 765
Without Renal Insufficiency
n = 1,151
Source: Scios ADHERE Registry April 2003. Note: P- values for categorical variables from Mantel-Haenszel Chisquare statistic.
Summary of Patient Characteristics Renal
Insufficiency vs. Without Renal Insufficiency
Outcomes - Total Hospital LOS (days) Mean
6.6
P-value = < 0.0001
6.6
6.4
6.2
6.0
5.8
5.6
5.6
5.4
5.2
5.0
Renal Insufficiency
n = 13,466
Without Renal Insufficiency
n = 33,125
Source: Scios ADHERE Registry April 2003. Note: P- values for categorical variables from Mantel-Haenszel Chisquare statistic.
Risk of Mortality in Relation to
Decreasing LVEF and GFRc
Hillege HL et al. Circulation 2000; 102: 203-10
Natriuretic peptides: ‘the opposition’
Baughman, et al. N Engl J Med 2002;347:158–159
Pharmacologic Actions of Human BNP
Hemodynamic
(balanced vasodilation)
• preload (veins)
• afterload (arteries)
• coronary arteries
R I SS
D
S
M
S
K
G
R
L
G
H
G
F
R
C S S CK V L R
G
S PKM V Q GS
Cardiac
lusitropic
anti-fibrotic
anti-remodeling
Neurohormoral
aldosterone, renin, AII
endothelin
norepinephrine
Renal
diuresis
natriuresis
GFR
Hemodynamic Effects of
Nesiritide in CHF Patients
A Randomized, Double-Blind, Placebo-Controlled Trial
Change From Baseline (%)
60
‡
Placebo (n = 4)
40
Nesiritide (n = 10)
20
0
–20
–40
‡
*
*
–60
HR
RAP
*P < 0.01 vs. baseline
†P < 0.05 vs. placebo
‡P < 0.05 vs. baseline
†
PCWP
SVR
CI
RAP = right arterial pressure.
Abraham WT et al. J Cardiac Fail. 1998;4:37–44.
SVI
Effects on Neurohormones at 6 Hours
Plasma Aldosterone
Plasma Norepinephrine
n
e in
i
e
d
d
i
m
ti g/m
i
rit kg/
r
i
si g/k
es µg/
e
o
N
µ
N
b
e
5
0
c
1
3
a
0
0
Pl
0.
0.
n
e in
i
e
d
d
i
m
ti g/m
i
rit kg/
r
i
si g/k
es µg/
e
o
N
µ
N
b
e
5
0
c
1
3
a
0
0
Pl
0.
0.
P = ns
P = 0.03
- 2.5 ng/dL - 1.6 ng/dL 0.6 ng/dL
- 75 pg/ml
8 pg/ml
Figure adapted from data published in Colucci WS et al. N Engl J Med 2000:343:246-53
36 pg/ml
Effects of nesiritide vs. dobutamine
on heart rate, premature ventricular beats (PVB),
and repetitive beats
PRECEDENT
PRECEDENT
P=0.001
80
Nesiritide 0.015 µg/kg/min
(n=84)
60
Mean change
from baseline in40
events/hour or
average HR 20
(bpm)
Dobutamine (n=83)
Nesiritide 0.030 µg/kg/min
(n=79)
P<0.001
P<0.001
0
-20
Heart rate
Burger AJ, et al. Am Heart J 2002;144:1102–1108
PVB
Repetitive beats
VMAC: Study Design
ActiveControlled Period
3-Hour PlaceboControlled Period
Nitroglycerin (n = 92)
Nitroglycerin (n = 60)
Placebo (n = 62)
Catheterized
(n = 246)
NES fixed dose (n = 62)
NES fixed dose (n = 92)
NES adjustable dose (n = 62) NES adjustable dose (n = 62)
Eligible Patients
(N = 489)
Nitroglycerin (n = 83)
Nitroglycerin (n = 124)
Noncatheterized Placebo (n = 80)
(n = 243)
NES fixed dose (n = 80)
Stratified
NES fixed dose (n = 119)
Randomized
Added to standard therapy
0
1
2
Treatment Duration (h)
End of Study Drug
3
6
Months
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 NTG
Publication Committee for the VMAC Investigators. JAMA 2002: 287(12); 1531-1540
Change from Baseline in PCWP
(mmHg)
Time on Study Drug (Hours)
0 0.25 0.5
1
2
3
6
9
12 24 36 48
0
PCWP - Placebo
-1
PCWP - IV NTG
-2
PCWP - Nesiritide
-3
-4
-5
-6
-7
-8
-9
†
†*
* †
* †
*
*
*
During 3-hour Placebo Period:
Placebo, n = 62
IV NTG, n = 60
Nesiritide, n = 124
†
* †
†
†
†
End of Placebo-Controlled Period
After 3-hour Period
IV NTG, n = 92
Nesiritide, n = 154
† P ≤ 0.05 vs. IV NTG
* P ≤ 0.05 vs. Placebo
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
Nesiritide
No Nes
P-value
Age
58±22
66 ±22
.07
EF
18±11
24 ±16
.023
SBP
115 ±21
126 ±25
.011
SCr
1.97±1.14
1.57 ±.85
.023
BUN
50±39
40 ±27
.067
Loma Linda Experience: Results
5
4.5
3.88
4
3.5
Days or mg/dl
3
2.81
2.5
2
1.97
1.86
1.57 1.56
1.5
1
0.5
0
Nesiritide No Nes
LOS (p<0.001)
Admit SCr
Discharge SCr
ADHERE: Loma Linda Experience
Loma
Linda
Hosp
All
Like
In
Hospitals
Hospital
Region
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
Nesiritide (n=29)
Milrinone (n=26)
P-value
Age
63 +/- 2.36
57 +/- 2.96
0.093
Weight (kg)
96 +/- 4.96
89 +/- 4.62
0.301
SCr (mg/dl)
1.87 +/- 0.14
1.42 +/- 0.17
0.048
Duration (hrs)
50.1 +/- 5.3
116.6 +/- 10.9
0.001
SBP
124 +/- 4.33
114 +/- 3.77
0.097
DBP
62 +/- 2.37
59 +/- 2.74
0.407
CI
2.4 +/- 0.22
2.2 +/- 0.16
0.523
RAP
15 +/- 1.69
14 +/- 1.52
0.652
SVR
1357 +/- 101
1271 +/- 106
0.564
PCWP
26 +/- 1.72
22 +/- 1.50
0.083
PAS
55 +/- 3.59
53 +/- 3.70
0.717
Effect of Nesiritide vs. Milrinone on Patient
Outcomes in the Treatment of acute HF
Parameters
Nes (N=29) Milrinone (N=25)
P-v alues
Baseline SrCr
1.87
1.42
0.048
Duration of Tx (hr)
50.1
116.6
0.001
7
8.2
0.328
ICU LOS
3.9
5.9
0.007
Floor LOS
3.1
2.3
0.463
30-day readm it
16%
28%
0.306
10.5 mmHg
4 mmHg
0.026
LOS (days)
Dec PCWP/ 48 hrs
Lewis DA, PharmD et al. ACCP Spring Forum April ,2003
Univ of KY Experience:
Secondary Outcomes
Diuresis
Milrinone
Nesiritide
P-value
24 hours
1067 ml
1823ml
0.10
48 hours
2205 ml
2985 ml
Hospital Cost
Drug Cost
Overall Cost
Costs
(LOS)
Milrinone
$4,273
$280
$4,553
Nesiritide
$3,409
$746
$4,155
Cleveland Clinic Experience
Hospital Floor
Observation Unit
• 159 admissions
• 48 admissions
• 22 Natrecor
• 18 Natrecor
– LOS 3.7 days
• 137 other therapy
– 16 (89%) DC Home
• 30 other therapy
– LOS 5.5 days
Peacock WF. Rev Cardiovasc Med 2002;3(suppl 4):S41-S48.
– 14 (47%) DC Home
PROACTION:
Emergency Medicine Pilot Trial
51% Discharged
(n = 61)
59 Patients Admitted
Nesiritide + SC
(n = 120)
Eligible CHF Patients
(n = 250)
53 Remain Stable After Discharge
6 Rehosp w/in 30 Days
4.6-Day LOS
(index + readmit)
≥12 hours
Standard Care (SC)
(n = 117)
64 Patients Admitted
45% Discharged
(n = 53)
15 Patients Rehosp w/in 30 Days
8.3-Day LOS
(index + readmit)
49 Remain Stable After Discharge
ED/OU
Outpatient Care
(APC Code)
Inpatient Care
(DRG Allowed)
Readmission w/in 30 Days
(No DRG Allowed)
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.
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
ED vs. Inpatient Initiation of
IV Vasoactive Therapy
Hospital Length of Stay
15
Length of Stay (d)
p = 0.04
12
9
9.4
6.3
6
3
0
ED Initiation
Inpatient Initiation
IV Vasoactive Therapy
ADHERE Registry: 14.7% of patients started IV therapy in the ED compared with 25.5% who started on admission;
CL et al. Ann Emerg Med. 2002;40(4 pt 2):162.
Emerman
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
D
Stages of
CHF
ACC/AHA
Guidelines
2001
Refractory
symptoms rest
+ hospitalizations
C
Structural heart disease,
prior or current symptoms
B
Structural heart disease, asymptomatic:
LVH, MI, low LVEF, dilatation, valvular disease
A
High-risk patients:
HTN, DM, CAD, + FH, LBBB, cardiotoxic drugs
Opposition of Neurohormonal
Forces in HF
Renin-Angiotensin-Aldosterone
Endothelin
Catecholamines
Vasodilation
Natriuresis/Diuresis
↓ Cardiac Stress
↓ Remodeling
Natriuretic
Peptides
Vasoconstriction
Sodium/Fluid Retention
Chronic Cardiac Stress → Tissue Remodeling/Fibrosis
FUSION Study Design
Weekly Outpatient Visits
Screening
n = 69
n = 210
Follow-up
Standard Care – Inotropes permitted
n = 72 Nesiritide 0.005 µg/kg/min, following bolus
– Inotropes not permitted
n = 69 Nesiritide 0.01 µg/kg/min, following bolus
– Inotropes not permitted
-30 to -5
days post
hospital
discharge
12 Weeks
4 Weeks
Standard Care vs. Nesiritide (0.005)
Standard Care vs. Nesiritide (0.01)
Standard Care vs. All Nesiritide
P=0.019
P=0.269
P=0.034
Standard Care
Nesiritide (0.005)
Nesiritide (0.01)
All Nesiritide
(n = 23)
(n = 24)
(n = 20)
(n = 44)
FUSION I
Improvement in Left Ventricular Systolic Function
Standard
Care
(n = 38)
Nesiritide
0.005 Dose
(n = 40)
Nesiritide
0.01 Dose
(n = 37)
All Patients
(n = 77)
EF at Baseline
29.6 +/- 18.6
28.8 +/- 15.8
37.7 +/- 13.8
28.25 +/- 14.8
Change at 12
Weeks
3.2 +/- 3.8
4.0 +/- 3.3
5.3 +/- 5.0
4.6 +/- 4.2
N/A
0.44
0.03
0.09
P-value*
*compared to standard care
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
Question From Live Broadcast
Clyde W. Yancy, M.D.
University of Texas Southwestern Medical Center
Dallas