Erice May 2009
The pharmacologic management of
AHF: an alternative to
invasive approaches?
Emilio Vanoli
University of Pavia and
of Oklahoma
Cardiologia Riabilitativa
Policlinico di Monza
Why Focus on Acute Heart Failure?
Causes of hospital admissions
Medical DRG – Year 2003
Number
350.000
250.000
Vaginal delivery
324.975
300.000
HF - shock
Esofagitis,
gastroenterites
Chemiotherapy
113.959
101.547
0
123.310
50.000
134.501
100.000
125.081
150.000
190.340
200.000
Cerebrovascular
diseases
COPD
Psicosis
Temporal Trends in Hospitalizations in Italy
200.000
DRG 127
190.340
150.000
By cou rtesy:
rtesy :
Carlo Donati, Minister o de lla Salute
100.000
127.043
50000
1996
1997
1998
1999
2000
2001
+ 67%
2002
2003
Acute Heart Failure Syndromes (AHFS)
Epidemiology
•  1 million admissions per year with the primary
diagnosis of HF
•  3,000,000 admissions per year with primary or
secondary diagnosis of HF
•  Post discharge event rate (readmissions/ death): 35% at
60 days
Haldeman GA, et al. Am Heart J. 1999;137:352.
American Heart Association. Heart and Stroke Statistics. 2005 Update. 2005:26.
Cuffe SM, et al. JAMA. 2002;287:1541.
How many AHF?
ESC Guidelines. Eur Heart J 2008;29:2388–2442
AHF presentation
Prior heart failure (%)
New onset heart failure (%)
Cardiogenic shock (%)
LVEF < 40%
ADHERE
EURO HF
OPTIMIZE-HF
(>150,000 .)
(11,327 pts.)
(46,812 pts.) ¶
75
65
87
25
27
13
2
<1
<1
59
46
52
Adams KF, et al. Am Heart J. 2005;149: 209.
Cleland JGF et al. Eur Heart J. 2003; 24: 442;
Fonarow GC, et al. J Am Coll Cardiol. 2004; 844 – 4A.
Demographic and Clinical
Characteristics of AHFS Patients
Data on approximately 200,000 patients
Median age (years)
75
Hx of Atrial Fibrillation
30%
Women
>50%
Renal abnormalities
30%
Hx of CAD
60%
SBP >140 mm Hg
50%
Hx of Hypertension
70%
SBP 90-140 mm Hg
45%
Hx of Diabetes
40%
SBP <90 mm Hg
5%
Adams KF, et al. Am Heart J. 2005;149: 209.
Cleland JGF et al. Eur Heart J. 2003; 24: 442;
Fonarow GC, et al. J Am Coll Cardiol. 2004; 844 – 4A.
ESC Guidelines. Eur Heart J 2008;29:2388–2442
AHFS: Therapeutic Goals
¢ 
Early management (ED)
Improve symptoms
l  Heart rate control
l  Blood pressure control
l 
•  Hypertensive patients (~50%)
•  Hypotensive patients (<10%)
l 
Improve congestion (↓PCWP) and CO* without causing…
• 
• 
• 
• 
Decreased coronary perfusion (hypotension)
Myocyte damage (ischemia, necrosis, apoptosis)
Further renal dysfunction
Arrhythmias (including increased heart rate)
*The majority of patients do not have low CO at the time of admission
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
Available IV Therapies For Early
Management of AHFS
•  Decrease congestion
–  Diuretics
•  Decrease afterload / neurohormonal improvement
– 
– 
– 
– 
Nitroglycerin
Nitroprusside
Nesiritide
ACE Inhibitors
•  Improve cardiac function
– 
– 
– 
– 
– 
– 
Digoxin
Dobutamine
Dopamine
Milrinone
Enoximone (Available in Europe)
Levosimendan (Available in Europe)
Initial Treatment Algorithm in AHF
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Acute Heart Failure Strategy
According to Systolic Blood Pressure
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Acute Heart Failure Treatment Strategy
According to LV Filling Pressure
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Acute Exacerbations May Contribute to the
Acute Exacerbations
to
Progressionmay
of theContribute
Disease
Ventricular
Ventricularfunction
function
the Progression of the Disease
With
each
With
eachevent,
event,
hemodynamic
hemodynamic alterations
alterations
and
myocardialdamage
damage
andmyocardial
contribute
contributetotoprogressive
progressive
ventricular
ventricular dysfunction
dysfunction
Acute
Acuteevent
event
Time
Time
From
FromGheorghiade
Gheorghiade . .Am
AmJJCardiol
Cardiol2005
2005(modified)
(modified)
Myocardial Injury in AHFS: “The Perfect Storm”
• 
Decreases coronary perfusion due to:
–  High LV and RV diastolic pressure +/-decreased
systemic blood pressure
• 
Further activation of neurohormones/endothelial
dysfunction
• 
CAD/ischemia/hibernating myocardium
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
IV Enalapril and Mortality (CONSENSUS II)
Patients With Acute MI
Life-Table Mortality Rates
Early IV Enalapril
(<24 hours) (n=3044)
Placebo
(n=3046)
10-days
4.6
4.3
1 month
7.2
6.3
3 months
9.1
8.2
6 months
11
10.2
•  Relative Risk of Death in the Enalapril group: 1.10 (95% CI 0.93-1.29)
•  There were no benefits in patients with heart failure, or in patients with acute pulmonary
edema
Swedberg K, et al. N Engl J Med. 1992; 327: 678
The Effects of Diuretics on Mortality and
Nonrecovery of Renal Function
Time to Death or Dialysis From Day of Consultation in ICU
1.00
Day 1 Status
No Diuretics
Total Daily Furosemide Equivalent/
Total Urine Output < 1.0
Survival
0.75
Total Daily Furosemide Equivalent/
Total Urine Output > 1.0
0.50
0.25
0
0
10
20
30
40
50
60
Time From Consult to Dialysis/Death (d)
Mehta RL et al. JAMA. 2002;288:2547–2553.
ESCAPE: Use of Inotropic Agents Resulted in Higher
Mortality
Mortality
100%
Survival
80%
60%
Vasodilators
40%
Inotropes
Both
20%
0%
Neither
0
30
60
90
120
150
180
Days
Elkayam U et al.2004
ADHERE: Use of Inotropic Agents Resulted in Higher
Mortality
16
13,9
Hospital Mortality (%)
14
12,3
12
10
7,1
8
6
4,7
4
2
0
NTG
Nesiritide
Milrinone
Dobutamine
Abraham WT, et al. JACC 2005;46(1):57–64.
Milrinone in AHF
OPTIME-CHF: In Hospital AEs
20
P < 0.001
Events(%)
15
12.6
Milrinone
P < 0.001
Placebo
10.7
10
P = 0.004
P = 0.18
5
0
2.1
Uneffective therapy
because of AEs
4.6
3.8
3.2
1.5
Hypotension
AMI
1.5
0.4
FA
P = 0.19
2.3
Mortality
Cuffe MS et al. JAMA. 2002;287:1541–1547.
Survival
OPTIME-CHF: Etiology and Mortality
Felker GM et al. J Am Coll Cardiol. 2003; 287: 1541
Levosimendan - Dual Mechanism of Action
• Increases sensibility of troponin C to Ca
++
• Induces K+ ATP dependent channels
opening in the vascular muscolature
Figgitt et al. Drugs 2001;61:613-627.
Lilleberg et al. Eur Heart J 1998;19:660-668.
Hasenfuss et al. J Cardiovasc Pharmacol 1995;26 (suppl.1):S45-S51.
Hasenfuss et al. Circulation 1998;98:2141-2147.
Lancaster et al. Eur J Pharmacol 1997;339:97-100.
Lilleberg et al. Clin Pharmacol Ther 1994;56:554-563.
REVIVE II: Primary Endpoint (n=600)
60
Placebo
Levosimedan
% Patients
30
20
P=.015
10
0
Improved
Unchanged
Worse
Packer M, et al. Presented at AHA Scientific Sessions 2005.
Meta-analyses of Levosimedan vs. Placebo
on short term mortality
RUSSLAN
0.455 (0.254, 0.834)
CASINO*
0.734 (0.202, 2.524)
REVIVE-1
0.225 (0.004, 2.416)
REVIVE-II
1.726 (0.786, 3.948)
Fixed Effecta
0.721 (0.469, 1.113)
Random effects
0.718 (0.315, 1.637)
0.001
0.01
0.1 0.2
0.5 1
2
5
Eterogeneità = 9.579502 (df= 3) P= 0.0225
Cleland JGF et al. Eur J Heart Fail 2006, 8:105
Meta-analysis of Levosimedan vs. Dobutamine
on Long Term Mortality
LIDO
0.58 (0.30, 1.10)
CASINO*
0.26 (0.12, 0.55)
SURVIVE
0.91 (0.71, 1.17)
Effetti Fissi
0.75 (0.60, 0.93)
Effetti Random
0.55 (0.27, 1.11)
0.1
0.2
1
0.5
2
Eterogeneità = 12.570649 (df= 2) P= 0.0019
Cleland JGF et al, Eur J Heart Fail 2006;8:105
EVEREST – Vasopressin 2 antagonism:
Change in Patient-Assessed Dyspnea at Day 1 for
Patients Manifesting Dyspnea at Baseline
Percentage
40
30
Tolvaptan (n=1835)
Placebo (n=1829)
P<.001 for Overall Comparison
20
10
0
Markedly
Moderately
Better
Minimally
No Change
Worse
Self-assessed Dyspnea
Konstam MA, et al. JAMA 2007;297:1319-1331
Kaplan-Meier Analyses of All-cause mortality and
cardiovascular Mortality or Hospitalization for HF
Konstam MA, et al. JAMA 2007;297:1319-1331
VMAC: Primary End Point
Dyspnea at 3 Hours
100
P = 0.034
90
Improved (%)
80
P = 0.191
P values are based on
van Elteren test with
7-point ordinal scale
70
60
50
40
30
20
10
Worsened (%)
0
–10
Nesiritide
Nitroglycerin
Placebo
Added to standard therapy.
Scios Inc. NDA 20-920 Cardiovascular and Renal Drugs Advisory Committee Briefing Document:
Natrecor (nesiritide) for Injection. Sunnyvale, CA: Scios Inc; May 25, 2001.
VMAC: Kaplan-Meier Estimate of
Mortality Rate by Treatment Group
100
Nitroglycerin (n = 216)
Cumulative Mortality Rate (%)
90
Nesiritide, 0.01 µg/kg/min (n = 211)
80
All Nesiritide (n = 273)
70
60
50
40
30
20
10
0
0
30
60
90
120
150
180
Time Observed From the Start of Treatment (d)
Stratified log-rank test:
Nitroglycerin vs nesiritide, 0.01 µg/kg/min, P = 0.616
Nitroglycerin vs all nesiritide, P = 0.319
Added to standard therapy.
Scios Inc. NDA 20–920 Cardiovascular and Renal Drugs Advisory Committee Briefing Document:
Natrecor (nesiritide) for Injection. Sunnyvale, CA: Scios Inc; May 25, 2001.
Hemodynamic, Echocardiographic and
Neurohormonal Effects of Istaroxime, a
Novel Intravenous Inotropic and Lusitropic
Agent in Acute Heart Failure Syndromes
(HORIZON-HF)
Mihai Gheorghiade, MD; John E. A. Blair, MD; Cezar Macarie, MD; Witold
Ruzyllo, MD; Jerzy Korewicki, MD; Antonella Bacchieri, MS; Maurizio
Ceracchi, MS; Giovanni Valentini, MD; Hani N. Sabbah, PhD; Gerasimos S.
Filippatos, MD; for the HORIZON-HF investigators
Funding Source: Sigma-Tau
American College of Cardiology
Late Breaking Clinical Abstracts
Chicago, IL; April 1, 2008
HORIZON-HF PCWP
1
0
n=31
-1
-2
mmHg
n=30
n=29
-3
n=30
Placebo
Istar 0.5, p = 0.003
Istar 1.0, p = 0.014
Istar 1.5, p < 0.001
-4
-5
Infusion period
-6
0
1
2
3
Post-infusion
4
5
time (hours)
6
7
8
HORIZON-HF Cardiac Index
0,5
Placebo
Istar 0.5, p = 0.4
Istar 1.0, p = 0.8
Istar 1.5, p = 0.04
0,4
L/min/m2
0,3
n=30
0,2
n=31
n=30
0,1
0
n=29
-0,1
Infusion period
Post-infusion
-0,2
0
1
2
3
4
5
time (hours)
6
7
8
Early Management of AHFS
Lessons learned from recent trials
•  Current therapies may adversely affect short-term clinical
outcomes despite the observed hemodynamic and
symptomatic improvement
•  Troponin release (injury?) is common in AHFS and correlates with outcomes
•  Short-term therapy (hours or days) appears to affect post-discharge outcomes
Hypothesis
•  Adverse outcomes may be the result of myocardial damage induced by shortterm therapies
Current IV Therapies for Early
Management of AHFS
• When compared to placebo, available agents
have not shown improvement of in-hospital or
post-discharge outcomes
•  Inotropes (dobutamine and milrinone)
adversely affect in-hospital or post-discharge
outcomes, particularly in patients with CAD
• 
In spite of the negative data, inotropes
continue to be used in AHFS patients who do
not have a low BP
HF ACC/AHA 2009
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Trials Comparing Beta-Blocker vs Placebo or
Inactive Control in Which > 40 Deaths Occurred
MDC
CIBIS
1.08 (0.55, 2.13)
0.75 (0.49, 1.14)
COPERNICUS
0.63 (0.49, 0.80)
MERIT
0.65 (0.51, 0.81)
CIBIS II
0.64 (0.51, 0.80)
BEST
0.88 (0.74, 1.04)
SENIORS
0.85 (0.67, 1.08)
0.1
0.2
0.5
1
2
5
Cleland et al., Eur J Heart Fail 2004;6:787
The Gap in ICDs
Updated from S. Nisam
250
280
250
Annual ICD implants
per million inhabitants
200
208
180
150
132
105
100
84
50
24
0
154
USA
31
2,5 4
37
44
6
8
54
10
63
14
18
22
27
31
38
44
56
60
Europe
Risk-Treatment Mismatch in the
Heart Failure
Dispensed ACE Inhibitors or ARB Prescriptions
Dispensed β-Adrenoreceptor Antagonists
Low-Risk
Average-Risk
High-Risk
Lee DS et al JAMA. 2005;294:1240-1247
95% CI
p value
0.736, 0.931
0.0017 **
30
Relative
risk
Carvedilol vs 0.828
Metoprolol
20
17%
10
Metoprolol
Carvedilol
0
Percentage Mortality (%)
40
COMET: Primary endpoint of mortality
0
1
2
Time (years)
3
4
5
COMET: Death or all cause hospitalisation
Endpoint (%)
80
60
Metoprolol
Carvedilol
40
Hazard Ratio = 0.937
95% CI 0.863 – 1.017, p = 0.1219
20
0
0
Number at risk
Metoprolol 1518
1511
Carvedilol
1
918
931
2
3
Time (years)
689
519
693
554
4
5
386
431
115
143
BRING-UP 2 – 1518 Elderly HF Patients
Significant Benefit of β - blockers
• 50
On treatment
Not treated
Started treatment
Patients (%)
• 40
• 30
31.4
26
• 20
18.4
• 10
• 0
25.7
18.4
18
15
10.8
Worsening HF
Hospitalization
11.2
Total Death
HEART FAILURE
Myocardial
+
+
Myocardial
cell death
cell death
CARDIAC OUTPUT
Myocardial
energy
expenditure
Afterload
+
Myocardial
energy
expenditure
-
-
NEUROHUMORAL
Lusitropy
Inotropy
Renin-angiotensin
Cytosolic
Arrhythmias,
Sympathetic-adrenergic
Ca++
Sudden death
ACTIVATION
Vasoconstriction
Receptor density (fmol/mg protein)
Beta Receptors in HF
80
70
60
*P<.05
50
vs normal function
β1
β2
α1
*
40
30
20
10
0
Normal function (n=12)
Cardiomyopathy (n=54)
b1:b2 80%:20%
b1:b2 65%:35%
Mean + SD.
Adapted from Bristow. J Am Coll Cardiol. 1993.
Adrenergic Receptors Occupancy by NE
Fractional or % contribution
α1
ß1
ß2
Parameter
Fractional abundance in failing human LVs
0.50
0.25
0.25
Relative contribution @ 5 nM NE, %
89.7
4.8
5.6
Relative contribution @ 10 nM NE, %
88.0
5.6
6.4
Relative contribution @ 50 nM, %
81.4
7.2
11.4
Bristow et al., Journal of Cardiac Failure Vol. 9 No. 6, 2003
Autonomic Tone and Reflexes After
Myocardial Infarction
1,02
1
Proportion Surviving
0,98
0,96
0,94
BRS >3, LVEF <35 (120)
0,92
0,9
0,88
0,86
Log Rank = 47.97
(p<0.0001)
0,84
0,82
BRS <3, LVEF <35 ( 59)
0,8
0
0,5
1
1,5
Years
2
N° at Risk
BRS >3, LVEF >35
BRS <3, LVEF >35
BRS >3, LVEF <35
BRS <3, LVEF <35
879
124
120
59
851
116
110
53
761
104
94
46
598
81
71
35
373
47
52
19
Autonomic Profile
in Elderly Patients with LVEF 35%
STD
BRS
200
10
STD (msec)
msec/mmHg
15
5
0
no/no
no/yes
beta-blockers
yes/yes
100
0
no/no
no/yes
yes/yes
beta-blockers
Proportion surviving
Survival Curves according to dichotomized BRS
in patients not taking beta-blockers.
1.0
0.9
0.8
0.7
BRS ≥ 3 ms/mmHg
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
BRS < 3 ms/mmHg
Log-Rank=15.3
p<0.0001
10
20
Number at risk
30
40
Time (months)
50
60
BRS ≥ 3
52
50
37
28
21
10
7
BRS < 3
92
67
32
18
6
3
2
La Rovere M T, et al. J Am Coll Cardiol 2009;53:193-9
Proportion surviving
Survival Curves according to dichotomized BRS
in patients taking beta-blockers.
1.0
0.9
0.8
0.7
BRS ≥ 3 ms/mmHg
0.6
BRS < 3 ms/mmHg
0.5
0.4
0.3
0.2
0.1
0.0
0
Log-Rank=7.6
p<0.0001
10
20
Number at risk
30
40
Time (months)
50
60
BRS ≥ 3
71
69
63
55
42
31
24
BRS < 3
32
30
24
20
14
9
5
La Rovere M T, et al. J Am Coll Cardiol 2009;53:193-9
In Hospital Mortality according to
Beta-blocker strategy
All-cause in-hospital mortality (%)
20
7.12% total no. of deaths =112/1572
18
p<0.0001
16
14
12
No. of deaths=17
No. of deaths=82
10
8
6
10.1%
12.1%
4
No. of deaths=10
2
No. of deaths=3
0
2%
2.8%
Group A (no/no)
Group B (no/yes)
Group C (yes/no)
Group D (yes/yes)
n=811
n=258
n=141
n=362
Orso F, et al. Eur J Heart Fail 2009;11:77-84
Group D (yes/yes)
Group A vs. D: p=0.004
OR 3.28
95% CI 1.47-7.32
Group A
(no/no)
OR 0.34
95% CI 0.07-1.78
Group B
(no/yes)
Group C vs. D: p=0.004
OR 4.20
0
1
2
3
4
5
95% CI 1.59-11.10
6
7
8
9
Group A
(yes/no)
10
11
12
Orso F, et al. Eur J Heart Fail 2009;11:77-84
Effects of Diuretics on Neurohormones
•  Direct effects of diuretics
–  Natriuresis, diuresis
–  Electrolyte excretion: K+, Ca++, Mg++
•  Indirect effects of diuretics
–  Volume depletion, decreased circulating volume
–  Decreased renal perfusion and increased release of antidiuretic
hormone
–  Increased renin production, RAAS activation
–  Increased sympathetic activation
–  Reflex vasoconstriction, increased SVR, diminished CO
–  Increased water and sodium retention
–  Metabolic alkalosis
Kaplan NM. Treatment of hypertension: drug therapy in clinical hypertension. In: Kaplan NM,
Lieberman E, Neal WW, eds. Clinical Hypertension. 1994:199–211.
D. M.
• Female
• 60 years old
• Diabetes Mellitus Type 2
recently diagnosed
D. M.
•  14/2/2005: referred Policlinico San Matteo from another
hospital becouse of anterior AMI treated with TNK
•  Complicated by left ventricular dysfunction
•  Acutely treated with amines and nitroprussiate
•  ECG: sinus tachycardia, RBB, signs of anterolateral
necrosis
•  X-RAY: bilateral pleural effusion, suspected
pulmonary consolidation
•  Echocardiogram: LVEF=30%, akinesia of the apex and
distal segments, MR: +++-
•  8/3/05: on admission in our
centre
•  Physical examination:
•  Diagnosis: cardiogenic shock
•  HR 115 bpm
•  Patient pale, sweated
•  BP 90/60 mmHg
•  SAT O2: 97%
•  T3, systolic murmur, jugular venous
distention, pleurical effusion
Right heart catheterization:
Treated with IABP
(9/03/052/04/05)
•  HR: 112
•  CI: 1.58 l/min/m^2
9/03/05
2/04/05
•  PAPs: 45 mmHg
RBC (x10^6/l)
3.71
2.92
•  PAPd: 37 mmHg
HB (g/dl)
11
8.2
•  PAPm: 41 mmHg
WBC (x10^3/l)
6.67
7.72
GLUCOSE
(mg/dl)
175
104
CREATININE
(mg/dl)
1.14
1.65
AST (U/L)
15
39
GGT (U/L)
136
78
Na+ (mEq/l)
139
130
K+ (mEq/l)
4.7
3.9
•  RAP: 14 mmHg
•  WEDGE pressure: 37 mmHg
•  RVEF: 13%
The patient ENTERED
our waiting list for heart
transplantation
D. M.
2/4/05:
Cardiac transplantation
Overall 30-Day Survival in the Study
Hochman JS et al, N Engl J Med 1999;341:625-34
Algoritmo di Valutazione e Trattamento per AHFS
Asciutto e Caldo
Umido e Caldo
Initial Management
Continue oral heart
failure medications
Search for other
causes of symptoms
including PE, ACS,
depression, anemia,
hypothyroidism
Discharge
Initial Management
IV loop diuretics
IV nesiritide or
IV vasodilator
Oxygen, if indicated
Admit: Telemetry or
Observation Unit
Asciutto e Freddo
Initial Management
Consider RHC
Inotropes and/or
pressors
Consider decrease of
beta-blocker dose
Admit: ICU or
Telemetry
Umido e Freddo
Initial Management
IV loop diuretics
Consider RHC
If high SVR,
IV nesiritide or
IV vasodilator
If low SVR,
inotropes or pressor
Admit: ICU or
Telemetry
RHC = right heart catheterization; SVR = systemic vascular resistance;
ICU = intensive care unit; PE = pulmonary embolism; ACS = acute coronary syndrome.
The Effects of Diuretics on Mortality and
Nonrecovery of Renal Function
Odds Ratio (95% CI)
Variable
Unadjusted
Covariate and Propensity
Covariate Adjusted
Score Adjusted
In-hospital mortality
1.37 (0.97–1.92)
1.65 (1.05–2.58)
1.68 (1.06–2.64)
Nonrecovery of renal
function
1.53 (1.08–2.15)
1.70 (1.14–2.53)*
1.79 (1.19–2.68)‡
Death or nonrecovery
1.48 (1.02–2.12)
1.74 (1.12–2.68)†
1.77 (1.14–2.76)§
Covariate adjusted for age; sex; log urine output; serum creatinine level; blood urea nitrogen level;
respiratory, hepatic, and hematologic failure; and heart rate. The referent group was no diuretics; time
was first day of ICU consultation.
*Area under receiver operating characteristic (ROC) curve = 0.76; goodness-of-fit χ2 P = 0.89.
†Area under ROC curve = 0.82; goodness-of-fit χ2 P = 0.39.
‡Area under ROC curve = 0.85; goodness-of-fit χ2 P = 0.84.
§Area under ROC curve = 0.81; goodness-of-fit χ2 P = 0.58.
Mehta RL et al. JAMA. 2002;288:2547–2553.
Furosemide and Heart Failure:
Bolus Injection vs Continuous Infusion
Urinary Volume, Sodium, and Potassium (mean + SEM)
24 Hours After Furosemide Administration
Parameters
Urinary volume, mL
Urinary sodium, mmol
Urinary potassium, mmol
Bolus
Infusion
P Value
2260 ± 150
2860 ± 240
0.0005
150 ± 20
210 ± 40
0.0045
70 ± 5
80 ± 5
< 0.0001
Dormans TPJ et al. J Am Coll Cardiol. 1996;28:376–382.
Doses for Continuous Intravenous
Infusion of Loop Diuretics
Infusion Rate, mg/h*
Creatinine ClearanceCreatinine Clearance
Creatinine Clearance
IV Loading Dose,
mg
< 25 mL/min
25–75 mL/min
> 75 mL/min
Furosemide
40
20 then 40
10 then 20
10
Bumetanide
1
1 then 2
0.5 then 1
0.5
Torsemide
20
10 then 20
5 then 10
5
Diuretic
*Before the infusion rate is increased, the loading dose should be readministered.
Brater DC. N Engl J Med. 1998;339:387–395.
Inibitori della Fosfodiesterasi III - Meccanismo d’Azione
Phosphodiesterase
Inhibitors
•  amrinone
•  milrinone
Mechanism of Action
•  inhibition of type III phosphodiesterase
§  - ↑ intracellular cAMP
§  - activation of protein kinase A
o  ↑ Ca2+ entry through L type Ca channels
o  inhibition of Ca2+ sequestration by SR
•  - ↑ cardiac output
•  - ↓ peripheral vascular resistance
Sopravvivenza
Curve di Sopravvivenza di Kaplan-Meier per la
Sopravvivenza Intraospedaliera a 60 Giorni
Milirinone, ischemica
Milirinone, non ischemica
Placebo, ischemica
Placebo, non ischemica
Giorni
Felker GM et al, JACC 2003; 41:997-1003
Inotropi – Inibitori delle Fosfodiesterasi
Milrinone and enoximone
Milrinone and enoximone are the two type III phosphodiesterase inhibitors
(PDEIs) used in clinical practice. The agents inhibit the breakdown of
cyclic AMP and have inotropic and peripheral vasodilating effects, with an
increase in cardiac output and stroke volume, and a concomitant decline in
pulmonary artery pressure, pulmonary wedge pressure, and systemic and
pulmonary vascular resistance. As their cellular site of action is distal to
the β-adrenergic receptors, the effects of PDEIs are maintained during
concomitant β-blocker therapy. Milrinone and enoximone are
administered by a continuous infusion possibly preceded by a bolus dose
in patients with well-preserved BP. Caution should be used with the
administration of PDEIs in patients with CAD, as it may increase mediumterm mortality.
Class of recommendation IIb, level of evidence B
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Proprietà del Levosimendan
•  Il Levosimendan differisce dai farmaci inotropi
convenzionali.
•  Il farmaco ha proprietà vasodilatatrici ed ottiene un
effetto inotropo positivo aumentando la sensibilità
dei miociti al calcio che è già presente nelle cellule,
piuttosto che incrementando il calcio intracellulare.
Approximate Time-Dependent Rates of
“Moderate or Marked" Improvement in
Patient Global Assessment
Interval
Levosimendan,
n=299 (%)
Placebo,
n=301 (%)
p
24 h*
60
46
0.026
48 h
63
58
0.053
5d
76
65
0.001
*infusions halted at 24 h (data provided by Packer)
Meta-analisi di Levosimedan vs. Dobutamine
su Breve Periodo di Mortalità
LIDO
0.41 (0.15, 1.07)
CASINO*
0.43 (0.13, 1.27)
SURVIVE
0.81 (0.51, 1.26)
Effetti Fissi
0.66 (0.45, 0.96)
Effetti Random
0.62 (0.39, 0.99)
0.1
0.2
0.5
1
2
Eterogeneità = 2.669791 (df= 2) P= 0.2632
Cleland JGF et al, Eur J Heart Fail 2006;8:105
Meta-analisi di Levosimedan vs. Placebo
sulla Mortalità a Lungo Termine
RUSSLAN
0.54 (0.32, 0.90)
CASINO*
0.53 (0.24, 1.14)
REVIVE-1
0.75 (0.14, 3.74)
REVIVE-II
1.35 (0.82, 2.23)
Effetti Fissi
0.79 (0.58, 1.08)
Effetti Random
0.75 (0.43, 1.30)
0.1
0.2
0.5
2
1
5
Eterogeneità = 9.868768 (df= 3) P= 0.0197
Cleland JGF et al, Eur J Heart Fail 2006;8:105
SURVIVE
Mebazaa A et al, JAMA 2007;297:1883-1891
SURVIVE
Mebazaa A et al, JAMA 2007;297:1883-1891
SURVIVE – Effect of Dobutamine and
Levosimendan Treatment in All-Cause Mortality
Mebazaa A et al, JAMA 2007;297:1883-1891
SURVIVE – Primary, Secondary, and Post Hoc
All-Cause Mortality End Points
Mebazaa A et al, JAMA 2007;297:1883-1891
SURVIVE – Mean Change from Baseline in
B-Type Natriuretic Peptide Levels
Mebazaa A et al, JAMA 2007;297:1883-1891
SURVIVE – Mean Change from Baseline in
Systolic Blood Pressure, Diastolic Blood Pressure, and
Heart Rate Through 5 Days by Treatment Group
Mebazaa A et al, JAMA 2007;297:1883-1891
Inotropics- Levosimendan
Levosimendan may be effective in patients with
decompensated chronic HF. In that the inotropic
effect is independent of β-adrenergic stimulation, it
represents an alternative for patients on β-blocker
therapy.
Class of recommendation IIa, level of evidence B
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Terapia non Approvata in Italia o in
Fase di Sviluppo
• 
• 
• 
• 
• 
Neseritide
Antagonisti della vasopressina
Antagonisti dell’adenosina
Antagonisti dell’endotelina
Ularitide
Farmaci per pz con
PA alta/normale
•  Istaroxime
•  Attivatori della miosina cardiaca
•  Modulatori metabolici
Farmaci per pz con
PA bassa e bassa
portata cardiaca
Nesiritide (hBNP) Is Identical to the
Endogenous Hormone
D
M
R
I
S
S
S
S
K
G
R
L
G
F
C
S
P
K M
H
G
S
S
C
K
V
L
R
R
G
V
Q
G
S
Precise amino acid sequence
Identical pharmacologic profile
Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67–71.
Pharmacologic Actions of hBNP
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 P KMVQ GS
Cardiac3
  lusitropic
  antifibrotic
  antiremodeling
Hemodynamic1,2
(balanced vasodilation)
  veins
  arteries
  coronary arteries
Neurohumoral2
aldosterone4
endothelin2
norepinephrine4
Renal1,5
diuresis
natriuresis
1.  Marcus LS et al. Circulation. 1996;94:3184–3189.
2.  Zellner C et al. Am J Physiol. 1999;276(3 pt 2):H1049–H1057.
3.  Tamura N et al. Proc Natl Acad Sci U S A. 2000;97:4239–4244.
4.  Abraham WT et al. J Card Fail. 1998;4:37–44.
5.  Clemens LE et al. J Pharmacol Exp Ther. 1998;287:67–71.
Reasons for Decreased Responsiveness to
Natriuretic Peptides in CHF
•  Excessive stimulation of the RAAS
•  Natriuretic peptide receptor downregulation
•  Change in renal hemodynamics
•  Increased neutral endopeptidase activity
Nathisuwan S et al. Pharmacotherapy. 2002;22:27–42.
Nesiritide Efficacy Trial:
Study Design
• 
• 
• 
• 
Randomized
Double-blind
Placebo-controlled
Parallel arm
- Placebo → Standard therapy (after 6 hours)
- Nesiritide, 0.015 µg/kg/min
- Nesiritide, 0.030 µg/kg/min
•  N = 127
•  Baseline characteristics*:
N
CI
PCWP
BNP
*Values
PLC
42
2.0
29
1153
NES 0.015
43
1.8
28
1008
NES 0.030
42
1.9
28
1331
are group means: CI (L/min/m2); PCWP (mm Hg); BNP (pg/mL).
Colucci WS et al. N Engl J Med. 2000;343:246–253.
Nesiritide Efficacy Trial:
Clinical Outcomes
P < 0.001 vs placebo
P < 0.001 vs placebo
80
% Improved
70
60
50
Placebo
40
NES .015
30
NES .030
20
10
0
Global Clinical Status
(Physician)
Global Clinical Status
(Patient)
Added to standard therapy.
Colucci WS et al. N Engl J Med. 2000;343:246–253.
Nesiritide Efficacy Trial:
Effect of Nesiritide on PCWP
Change in PCWP (mm Hg)
4
6 Hours
2.0
2
0
Placebo
(n = 42)
-2
-4
-6
-8
-10
–6.0
Nesiritide,
0.015 µg/kg/min
(n = 43)
-12
–9.6
Nesiritide,
0.030 µg/kg/min
(n = 42)
P < 0.001
Added to standard therapy.
Colucci WS et al. N Engl J Med. 2000;343:246–253.
Nesiritide Efficacy Trial:
Effects of Nesiritide on Neurohormones
Plasma Aldosterone
Plasma Norepinephrine
P = NS
P = 0.03
–2.5 ng/dL
–1.6 ng/dL
+0.6 ng/dL
–75 pg/mL
+8 pg/mL
+36 pg/mL
Added to standard therapy.
Colucci WS et al. N Engl J Med. 2000;343:246–253.
Vasodilation in the Management of Acute
Congestive Heart Failure (VMAC) Trial
Design
•  Phase III randomized, double-blind, placebo-controlled
•  Multicenter (55) in the United States
•  Randomization strategy based on right-sided heart
catheterization
•  489 patients enrolled from October 1999 to July 2000
•  Acutely decompensated heart failure with dyspnea on
admission
•  Nesiritide vs IV nitroglycerin vs placebo
–  fixed-dose IV nesiritide
–  variable-dose IV nesiritide
–  IV nitroglycerin
–  placebo
Added to standard therapy.
VMAC Investigators. JAMA. 2002;187:1531–1540.
VMAC: PCWP Through 3 Hours
Mean PCWP (mm Hg)
30
Mean Change in PCWP (mm Hg)
–1
28
26
–4
†
*
*†
24
22
*
*
*†
*†
–7
P = NS
20
3h
2h
Time
Time
*P < 0.05 vs placebo.
†P < 0.05 vs nitroglycerin.
1h
30 min
3h
2h
1 min
30 min
15 min
BL
BL
15 min
–10
18
Placebo
Nitroglycerin
Nesiritide
Added to standard therapy.
VMAC Investigators. JAMA. 2002;187:1531–1540.
Nesiritide: Study Schema
Silver MA et al, JACC 2002;39:798-803
Nesiritide: Kaplan-Meier Estimate of Mortality
Silver MA et al, JACC 2002;39:798-803
Meta-analisi di Trial con Nesiritide
Mortalità entro 30 Giorni dal Trattamento
Sackner-Bernstein JD et al, JAMA 2005;293:1900-1905
Nesiritide: Kaplan-Meier Curva di Mortalità
30 Giorni
Sackner-Bernstein JD et al, JAMA 2005;293:1900-1905
Vasodilatatori – ESC 2008
ESC Guidelines Eur Heart J 2008;29:2388-2442
Vasopressin Antagonist for Heart Failure:
ACTIV in CHF Trial
Mean Body Weight Changes During Hospitalization
24 Hours
Discharge
0
-1
Kg
-2
*
*
*
-3
-4
*
-5
Placebo
Tolvaptan 30 mg
Gheorghiade M. JAMA. 2004;291:1963-1971.
Tolvaptan 60 mg
*
Tolvaptan 90 mg
* P<0.05 vs Placebo
Vasopressin Antagonist for Heart Failure:
ACTIV in CHF Trial
60-Day All-cause Mortality
P<0.05
Percent (%)
20
Placebo
Tolvaptan
20
18.7
P <0.05
17.8
13.2
9.1
8.7
10
5.5
5.4
0
N=
80
239
Overall
16
53
(20%) (22%)
30
110
(37%) (46%)
Hyponatremia
(Na+ <136 mEq/L)
BUN
(> 29 mg/dL)
Gheorghiade M. JAMA. 2004;291:1963-1971.
41
163
(51%) (68%)
Congestion*
* Edema, Dyspnea, and JVD at baseline
EVEREST - Flow of Participants Through the Trial
Konstam MA, et al. JAMA 2007;297:1319-1331
EVEREST – Baseline Participant Characteristics
Konstam MA, et al. JAMA 2007;297:1319-1331
EVEREST
Konstam MA, et al. JAMA 2007;297:1319-1331
Changes from Baseline in Body Weight and
Serum Sodium
Konstam MA, et al. JAMA 2007;297:1319-1331
Changes from Serum Urea Nitrogen and
Serum Creatinine Concentrations
Konstam MA, et al. JAMA 2007;297:1319-1331
A1-receptors in the Afferent Arteriole and
Proximal Tubule in Kidneys
De Luca L, et al. Eur J Heart Fail 2008;10:201-213
Schematic Illustration of Study Design
and Assessments
Greenberg B, et al. J Am Coll Cardiol 2007;50:600-606
Change from Baseline in Urine Volume for the 0 to
8 h After Drug Administration on Days 1, 6 and 10
Greenberg B, et al. J Am Coll Cardiol 2007;50:600-606
Cumulative Urinary Sodium Excretion
During Dosing
Greenberg B, et al. J Am Coll Cardiol 2007;50:600-606
Cumulative Urinary Potassium Excretion
During Dosing
Greenberg B, et al. J Am Coll Cardiol 2007;50:600-606
Change in Renal Function During Dosing
Greenberg B, et al. J Am Coll Cardiol 2007;50:600-606
Antagonisti dell’Endotelina – Effetti
del Tezosentan nel RITZ 4
Modificato da De Luca L, et al. Eur J Heart Fail 2008;10:201-213
Effects of a 10-hour Infusion of Urodilatin or Placebo on
Systolic Blood Pressure, Diastolic Blood Pressure,
Heart Rate and Central Venous Pressure
Elsner D, et al. Am Heart J 1995;129:766-773
Clinical Presentation: Normal vs. High BP
High (VASCULAR FAILURE)
Normal (CARDIAC FAILURE)
Rapid worsening
Gradual worsening (days)
Fluid redistribution
Fluid accumulation
PCWP acute +++
PCWP chronic +++
CXR pulm. congestion +++
CXR pulm. congestion +
Weight gain/ Edema +
Weight gain/ Edema +++
LVEF relatively preserved
LVEF usually low
Pathophysiology of AHFS
Hemodynamic deterioration
(eg, fluid overload)
↑↓
Myocardial injury (Tn release)
↑↓
Progression of heart failure
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
Effects of 10-hour
infusion of urodilatin
or placebo on urinary
sodium excretion and
urine flow in patients
with congestive heart
failure.
Elsner D, et al. Am Heart J 1995;129:766-773
Changes in LVEF with Increasing doses of
Normal Saline Solution and Istaroxime
LV Ejection Fraction
0.50
Control
Istaroxime
(ANOVA, p=0.57)
(ANOVA, p=0.0001)
0.40
*p<0.05 vs control
*
*
*
*
0.30
0.20
0.10
0. 0
Base
0.5
1.0
2.0
3.0
5.0
Istaroxime (µg/kg/min)
Sabbah HN, et al. Am J Cardiol 2007;99[suppl]:41A-46A
Changes in Deceleration Time of Early Mitral Valve
Inflow Velocity with Increasing doses of Normal Saline
Solution and Istaroxime
Deceleration Time (msec)
150
125
Control
Istaroxime
*p<0.05 vs control
(ANOVA, p=0.82)
(ANOVA, p=0.0001)
*
100
*
*
*
75
50
25
0
Base
0.5
1.0
2.0
3.0
5.0
Istaroxime (µg/kg/min)
Sabbah HN, et al. Am J Cardiol 2007;99[suppl]:41A-46A
Attivatori della Miosina Cardiaca
•  CK-0689705
•  116
CK-1122534
•  CK-1827452
Migliorano la contrattilità nel ratto e nel
cane scompensato senza aumentare il Ca
intracellulare.
In corso studi di Fase I
Modulatori Metabolici
Inibisce la carnitin
palmitol transferasi 1
(CPT-1)
De Luca L, et al. Eur J Heart Fail 2008;10:201-213
Effect of Perhexiline Treatment on VO2max and LVEF
in CHF Patients
22
p<0.001
p<0.001
40
18
30
16
14
12
10
8
LVEF (%)
VO2 max (ml/kg/min)
20
20
6
10
4
2
0
0
Pre Placebo Post Placebo Pre Perhexiline Post Perhexiline
Pre Placebo Post Placebo Pre Perhexiline Post Perhexiline
Lee L, et al. Circulation;112:3280-3288
CPAP/BiPAP
Razionale:
• Diminuzione afterload
• Diminuzione lavoro del muscolo respiratorio
• Reclutamento di polmone atelectasico
–  ↓ shunt e ↑ compliance
• Evitare intubazione e rischi connessi
Meccanismi della CPAP
•  Aumento della pressione
nelle vie aeree.
•  Vie aeree a rischio di
collasso per eccesso di
fluidi sono mantenute
distese ed aperte.
•  Gli scambi respiratori sono
mantenuti.
•  L’aumento del lavoro
respiratorio è minimizzato.
Controindicazioni Assolute
•  Età < 8
•  Arresto Respiratorio o Cardiaco
•  Respiro Agonico
•  PAS < 90 mm Hg
•  Pneumotorace
•  Trauma maggiore, in particolare trauma cranico con
aumento delle PIC, o grave trauma toracico
•  Patologia del viso (p.es. ustioni, fratture)
•  Vomito
Controindicazioni Relative
•  Storia di asma o BPCO
•  Storia di Fibrosi Polmonare
•  Claustrofobia o incapacità a tollerare
la maschera o il casco
CPAP/BiPAP
•  Meta-analisi di Pang et al. Chest 1998; 114: 1185-92
•  CPAP con maschera facciale a 10cm H20
–  ↓ necessità di intubazione e ventilazione meccanica nello
scompenso acuto
–  Trend verso una riduzione di mortalità
–  CPAP vs. BiPAP
–  Mehta et al. Crit Care Med 1997; 25: 620-28
–  Non differenze di mortalità o necessità di intubazione;
studio interrotto per tendenza ad aumento di IM nel gruppo
BiPAP
Ossigeno e Ventilazione
Oxygen
It is recommended to administer oxygen as early as possible in hypoxaemic
patients to achieve an arterial oxygen saturation ≥95% (>90% in COPD
patients). Care should be taken in patients with serious obstructive airways
disease to avoid hypercapnia.
Class of recommendation I, level of evidence C
Non-invasive ventilation
Indications
Non-invasive ventilation (NIV) refers to all modalities that assist ventilation
without the use of an endotracheal tube but rather with a sealed face-mask.
NIV with positive end-expiratory pressure (PEEP) should be considered as
early as possible in every patient with acute cardiogenic pulmonary oedema
and hypertensive AHF as it improves clinical parameters including respiratory
distress. NIV with PEEP improves LV function by reducing LV afterload. NIV
should be used with caution in cardiogenic shock and right ventricular failure.
Class of recommendation IIa, level of evidence B
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Ultrafiltration for Acute Heart Failure
•  Removal of excess volume mechanically
•  A simplified peripheral ultrafiltration system
including a miniaturized disposable circuit
developed for patients with volume-overload
states
•  Evaluated in observational studies; further
trials underway
•  Series of 25 AHF pts with 5 lb net weight
loss, improved NYHA status, reduction in
BNP levels, and stable renal function
Jaske B. J Card Fail. 2003;9:227-231.
Ultrafiltration for Decompensated Heart Failure
Pre- Versus Post- Ultrafiltration Weight
-2.6 kg
Effect of Ultrafiltration on Signs
and Symptoms of HF
P<0.0001
140
Weight (kg)
130
Baseline Post 24hr
120
110
100
90
91.9
89.3
80
Orthopnea
PND
JVD
Rales
S3
Peripheral Edema
21
13
23
15
8
24
12
5
12
10
2
18
-36%
-32%
-44%
-20%
-24%
-24%
70
60
Pre-treatment
Post-treatment
Jaske B. J Card Fail. 2003;9:227-231.
Studio RAPID-CHF
•  Studio Multi-centrico, randomizzato, controllato
•  Confronto degli effetti di trattamento tra ultrafiltrazione
vs cura abituali per pazienti ospedalizzati per scompenso
cardiaco acuto a 24 e 48 ore
•  Quaranta pazienti arruolati (20 nel braccio
ultrafiltrazione, 20 nel braccio cura abituali)
•  UF consistente in una sola sessione di 8 ore
Bart et. al. JACC 2005;46:2043-2046 (n=40)
Early Application of UF Resulted in
Significant Fluid Removal
Median cumulative fluid removal at 24 and 48 h in patients assigned to ultrafiltration (solid
line) and usual care (dashed line). *p = 0.001; **p = 0.012.
Bart et. al. JACC 2005;46:2043-2046 (n=40)
EUPHORIA Study
•  Single center, prospective study, 20 patients
•  Compared the feasibility and safety of reducing the length of
hospitalization by instituting ultrafiltration (UF) with the CHF
Solutions Aquadex FlexFlow as an initial primary therapy for
decompensated CHF patients demonstrating diuretic resistance
on admission
•  Initial UF within 12 hours of hospitalization and before any
significant administration of IV diuretics and/or vasoactive drugs
•  Follow-up one and three months after discharge
Costanzo et. al. JACC 2005;46:2047-2051 (n=20)
Average Weights
Weights decreased from 87 ± 23 kg to 81 ± 22 kg and remained lower than pretreatment weights at 30 (84 ± 21
kg) and 90 days (80±18 kg); p = 0.006
Costanzo et. al. JACC 2005;46:2047-2051 (n=20)
Average Calculated Creatinine Clearance
Pre-ultrafiltration sCr was 2.12 ± 0.60 mg/dl (range 1.0 to 3.6 mg/dl) and remained unchanged. Calculated CrCl
was 37.9 ± 13.4 ml/min and remained unchanged unchanged; p = 0.161
Costanzo et. al. JACC 2005;46:2047-2051 (n=20)
Average Serum Sodium
Average serum sodium (Na) for all 20 patients and for the seven patients presenting with Na <135 mg/dl. *Preultrafiltration (UF) to discharge; **pre-UF to 90 days
Costanzo et. al. JACC 2005;46:2047-2051 (n=20)
Average Minnesota Living With Heart
Failure Questionnaire Scores
Pretreatment MLWHFQ score of 70 ± 18 declined at discharge and 30 and 90 days to 65 ± 21,
60 ± 23.0, and 51 ± 27, respectively; p = 0.003
Costanzo et. al. JACC 2005;46:2047-2051 (n=20)
UNLOAD Trial
Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-683
Freedom from Heart Failure Rehospitalization
Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-683
Possibili complicanze
• Meccaniche
• Vascolari
–  Sanguinamento
–  Ischemia
–  Embolia
–  Amputazione
•  Infettive
–  Rottura pallone
–  Gonfiaggio inadeguato
–  Inadeguata
maggiorazione diastolica
•  Morte
–  Dissezione aortica
Prevalenza: 7%
Trost CJ, Hillis LD. Am J Cardiol 2006; 97: 1391-8
Indicazioni IABP
(scompenso cardiaco acuto)
Guidelines on the diagnosis and treatment of acute heart failure - ESC 2005
n= 43
n= 13; 10-86 giorni
Guidelines on the diagnosis and treatment of acute heart failure - ESC 2005
Guidelines on the diagnosis and treatment of acute heart failure - ESC 2005
Indice Cardiaco
+20%
2
1,9
p=0,06
1,8
l/min/m2 1,7
1,6
1,5
1,4
basale
IABP
Frequenza Cardiaca
100
p<0,01
95
bpm
-10%
90
85
80
basale
IABP
Gettata Sistolica
40
+30%
ml/m2
p<0,01
20
0
basale
IABP
Pressioni Polmonari
p<0,01
60
50
40
mmHg
30
20
Sistolica
10
Media
0
Diastolica
basale
IABP
Wedge e PVC
p<0,01
30
25
20
mmHg
15
p=0,06
10
5
Wedge
0
PVC
basale
IABP
FE del Ventricolo Destro
20
p=ns
15
%
+50%
10
5
0
basale
IABP
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Evaluation of Acutely Decompensated Chronic HF
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Evaluation of Patients with Suspected AHF
ESC Guidelines. Eur Heart J 2008;29:2388–2442
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
Jessup M, et al. 2009 Guideline Focused Update on Heart Failure. Circulation 2009;119:1977-2016
What is Acute Heart Failure?:
ESC 2008
ESC Guidelines Eur Heart J 2008;29:2388–2442
GRACE: Mortality Rates from Hospital Admission to 6-Month
Follow-up for Patients with HF at Admission vs no HF at Admission
Steg PG et al, Circulation 2004;109:494-9
GRACE: Incidence and Mortality Rates of HF According to
Type of ACS and Timing of Occurrence
HF at admission
No HF at any time
HF at
admission
HF during
hospitalization
HF any
time
No HF at
any time
Steg PG et al, Circulation 2004;109:494-9
AHFS: Clinical Presentation
•  HF with SBP > 150 mm Hg (≅ 35%)
•  HF with SBP 90 - 150 mm Hg (≅ 55%)
•  HF with SBP < 90 mm Hg (≅ 8%)
•  Cardiogenic shock (< 1%)
•  Pulmonary edema (< 3%) *
•  *CXR in 91%; Radiographic pulmonary
congestion in 74%.
•  Isolated right-sided HF (?)
•  ACS with HF
– 25% of ACS have HF; 10% of AHFS have ACS
HORIZON-HF Right Atrial Pressure
0
n=31
-0,5
n=30
-1
mmHg
n=29
-1,5
n=30
Placebo
-2
Istar 0.5, p = 0.009
Istar 1.0, p = 0.1
-2,5
Istar 1.5, p = 0.06
Infusion period
-3
0
1
2
3
Post-infusion
4
time (hours)
5
6
7
8
AHFS: Outcomes
ADHERE
EURO HF
OPTIMIZE-HF
(>150,000 pts.)
(11,327 pts.)
(46,812 pts.) ¶
> 2.5 kg weight loss (%)
50
N/A
50
HF Symptoms
Unchanged/worse
Better (symptomatic)
Better (asymptomatic)
Length of stay (days)
In-hospital mortality (%)
Mortality at 2-3 mos. (%)
<1
40
50
4.3 (3, 7)
4
N/A
11
7
6.5
<3
40
51
4 (3, 7)
4
9
N/A
24
31
Readmissions at 2-3 mos. (%)
Adams KF, et al. Am Heart J. 2005;149: 209.
Cleland JGF et al. Eur Heart J. 2003; 24: 442;
Fonarow GC, et al. J Am Coll Cardiol. 2004; 844 – 4A.
Pilot Randomized Study of Nesiritide vs. Dobutamine
in Heart Failure (PRESERVD-HF) Patients with CAD
•  At the time of admission for HF, elevations of TnT and
TnI are present in 43% and 74% of pts.
•  During hospitalizations, among those without elevated
Tn at baseline, 42% of pts. will release TnI and 8% of
pts. will release TnT.
•  TnT/I correlated with short term outcomes.
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
AHFS: Hospitalizations
•  Worsening chronic heart failure (HF)*
•  Acute de novo heart failure (diagnosed for the first
time)
•  Advanced/end-stage/refractory HF
*
The majority of admitted patients
Felker GM, et al. Am Heart J. 2003;145:S18-S25.
ADHERE: Impact of Use of
IV Agents in AHF
• Retrospective analysis of the first 65,180
patient episodes from the Acute
Decompensated Heart Failure National
Registry (ADHERE)
• Patients receiving nitroglycerin, nesiritide,
milrinone, or dobutamine were identified and
reviewed (n=15,230).
Abraham WT, et al. JACC 2005;46(1):57–64.