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9th International Symposium
Heart Failure & Co.
Milano, Istituto Clinico Humanitas
Clinical Presentations of Acute
Decompensated Heart Failure
Marco Metra
Cardiologia
Università e Spedali Civili di Brescia, Italia
The Burden of Acute HF
• Most frequent cause of hospitalization for
patients aged >65 years
• In-hospital stay
– Duration, mean: 4 days (US) / 8 days
(Europe)
– Mortality, 3% to 9%
• Follow-up (2-3 months)
– Mortality, 9% to 13%
– Rehospitalizations, 24% to 30%
Definition of Acute Heart Failure
(ESC guidelines for the diagnosis and treatment
of acute and chronic heart failure 2008)
•
Rapid onset or change in the signs and
symptoms of HF, resulting in the need for
urgent therapy.
•
May be either
– New HF
– Worsening of pre-existing chronic HF
•
Patients may present as a medical
emergency (e.g. acute pulmonary edema)
Definition of Acute Heart Failure
(ESC guidelines for the diagnosis and treatment
of acute and chronic heart failure 2008)
•
Rapid onset or change in the signs and
symptoms of HF, resulting in the need for
urgent therapy.
•
May be either
– New HF
– Worsening of pre-existing chronic HF
•
Patients may present as a medical
emergency (e.g. acute pulmonary edema)
Clinical classification of Acute Heart Failure
(ESC guidelines 2008)
Dominant clinical
feature
Characteristics
Worsening or
decompensated
chronic HF (Peripheral
oedema/ congestion)
Hx of chronic HF. Systemic and pulmonary congestion (peripheral
oedema, raised JVP, pulmonary oedema, hepatomegaly, ascites,
congestion, cachexia). Low BP associated with poor prognosis
Pulmonary oedema
Severe respiratory distress, tachypnoea, orthopnoea, rales over
lungs, effusion, tachycardia, O2sat <90%
Hypertensive heart
failure (high blood
pressure)
High BP, usually LV hypertrophy, and preserved EF. Euvolaemic or
only mildly hypervolaemic, often with pulmonary congestion
without systemic congestion. Rapid response to appropriate
therapy, Low hospital mortality
Cardiogenic shock (low Poor peripheral perfusion, SBP <90 mmhg or drop MBP >30
mmhg, anuria or oliguria (<0.5 ml/kg/h)
output syndrome)
Right heart failure
Low output no pulm congestion, raised JVP, hepatomegaly, low LV
filling pressures
ACS and HF
Approx 15% of ACS have AHF, frequent arrhythmias
Factors influencing clinical
presentations of AHF
•
•
•
•
Myocardial ischemia
Blood pressure (peripheral perfusion)
Fluid overload
Kidney dysfunction
– Each may or may not be present, with
different relative importance, in each patient
AHF & myocardial ischaemia
• Acute coronary syndromes
– Myocardial infarction/unstable angina with large
extent of ischemia and ischemic dysfunction
– Mechanical complication of acute myocardial
infarction
– Right ventricular infarction
• Chronic coronary artery disease
– Ischaemia / necrosis precipitated by AHF
• Non-ischaemic cardiomyopathy
– Ischaemia / necrosis precipitated by AHF ?
AHF & myocardial ischaemia
• Acute coronary syndromes
– Myocardial infarction/unstable angina with large
extent of ischemia and ischemic dysfunction
– Mechanical complication of acute myocardial
infarction
– Right ventricular infarction
• Chronic coronary artery disease
– Ischaemia / necrosis precipitated by AHF
• Non-ischaemic cardiomyopathy
– Ischaemia / necrosis precipitated by AHF ?
% of patients
Precipitating factors in AHF: EHFS II
Nieminen et al., Eur Heart J 2006; 27:2725
AHF & myocardial ischaemia
• Acute coronary syndromes
– Myocardial infarction/unstable angina with large
extent of ischemia and ischemic dysfunction
– Mechanical complication of acute myocardial
infarction
– Right ventricular infarction
• Chronic coronary artery disease
– Ischaemia / necrosis precipitated by AHF
• Non-ischaemic cardiomyopathy
– Ischaemia / necrosis precipitated by AHF ?
Prevalence of Detectable (>0.01 pg/ml)Troponin T
in patients with AHF with daily blood sampling
Idiopathic dilated
cardiomyopathy
Coronary artery
disease
26%
26%
46%
60%
14%
28%
TnT (1 sample)
TnT (>1 sample)
No TnT
TnT (1 sample)
TnT (>1 sample)
No TnT
Metra et al., Eur J Heart Fail. 2007;9:776-86
Freedom from Death or CV Hospitalization and
cTnT plasma levels in Acute Heart Failure
Cardiac mortality or
CV hospitalizations
1
1
0.8
0.8
Fraction of patients
Fraction of patients
Cardiac mortality
0.6
0.4
P<0.0001
0.2
0.6
0.4
P<0.01
0.2
No cTnT detectable
cTnT detectable
No cTnT detectable
cTnT detectable
0
0
0
90
180
270
360
0
90
Days
Patients at risk
No cTnt
56
cTnT
51
55
34
44
21
180
270
360
Days
35
15
33
11
Patients at risk:
No cTnt
56
cTnt
51
44
23
30
11
26
9
21
4
Metra et al., Eur J Heart Fail. 2007;9:776-86
Prediction of Cardiac Death: CART analysis
107 patients discharged after AHF
P<0.0001
NT-proBNP <6078pg/mL
n= 76;
1-year survival, 91%
NT-proBNP >6078 pg/mL
n= 31;
1-year survival, 34%
P=0.021
NYHA class I/II
n= 61;
1-year survival, 95%
NYHA class III/IV
n= 15;
1-year survival, 71%
P=0.018
cTnT undetectable
n= 40;
1-year survival, 100%
cTnT detectable
n= 21;
1-year survival, 78%
Metra et al., Eur J Heart
Fail. 2007;9:776-86
Acute HF
Hemodynamic abnormalities + neurohorm./ Inflam. activation
Low CO /
hypotension
↑ LVEDP /
↑ wall stress
↓Coronary
perfusion
↑ Heart
rate
Inotropic
stimulation
↑ myocardial
VO2
CAD / hybernating myocardium / …..
Myocardial damage /
necrosis
Acute HF + Vasodilators
Low CO /
hypotension
?
↑ LVEDP /
↑ wall stress
↑ Heart
rate
↓Coronary
Inotropic
stimulation
↑ myocardial
VO2
perfusion
CAD / hybernating myocardium / …..
Myocardial
damage /
necrosis
Nitroprusside and Mortality
Patients Presenting With Presumed Acute MI and HF
All had a PA Catheter
Early: < 9 hrs.
Cohn JN, et al. N Engl J Med. 1982; 306:1129.
Sodium Nitroprusside for advanced low-output
heart failure
(n=175, 50% ischemic,
30% prev CABG)
Mullens, W. et al. J Am Coll Cardiol 2008;52:200-207
Acute HF + Inotropic agents
Low CO /
hypotension
?
↑ LVEDP /
↑ wall stress
↑ Heart
rate
↓Coronary
Inotropic
stimulation
↑ myocardial
VO2
perfusion
CAD / hybernating myocardium / …..
Myocardial
damage /
necrosis
Predictors of all-cause mortality on
multivariate analysis
Hazard
ratio
95% confidence
interval
p Value
Sodium nitroprusside
0.54
0.33-0.88
0.015
Beta-blocker
0.48
0.29-0.78
0.03
Inotropic agent
2
1.36-3.6
0.011
Serum creatinine
2.16
1.56-3.24
0.001
Diabetes
1.13
0.62-2.07
0.7
Mullens, W. et al. J Am Coll Cardiol 2008;52:200-207
Survival in patients admitted for acute heart
failure subdivided on the basis of treatment
with inotropic agents
CV mortality free survival.
CAD (n=278)
1.0
No Inotropes
1.0
Inotropes
0.8
% Patients
% Patients
0.8
CV mortality free survival
NO CAD (n=220)
0.6
0.4
No Inotropes
Inotropes
0.6
0.4
P <0.0001
P =0.007
P=0.025 after adjustment
at multivariable analysis
0.2
0.2
0.0
P=0.203 after adjustment at
multivariable analysis
0.0
0
60
120
180 240
days
300
360
0
60
120
180 240
days
300
360
Factors influencing clinical
presentations of AHF
•
•
•
•
Myocardial ischemia
Blood pressure (peripheral perfusion)
Fluid overload
Kidney dysfunction
– Each may or may not be present, with
different relative importance, in each patient
Clinical significance of high blood
pressure in AHF
• Cause of AHF
– Afterload mismatch
• Consequence of AHF
– ↑neurohormonal activation
– ↑cardiac function
SBP in AHF Registries
• ADHERE, AHJ 2005
– 107 362 patients from 282 hospitals
• Mean SBP, 144 mmhg
• SBP >140: 50% of pts
• OPTIMIZE-HF, JAMA 2006
– 48 612 patients from 259 hospitals
• Mean SBP, 143+33 mmhg
• SBP >140: 50% of pts
• Italian Survey, EHJ 2006
– 2807 patients from 206 cardiology centers
• Mean SBP, 141+37 mmhg, 138+36 WHF, 146+36 de novo
• SBP >140: 43%; 38% WHF, 49% de novo
• EFICA, EJHF 2006
– 599 patients from 60 centers
• Mean SBP, 126+39 mmhg; 139 without CS pts
Cause of AHF According to SBP: OPTIMIZE-HF Study
48 612 patients FROM 259 us HOSPITALS
Ischemic
35
40
25
20
13
18
0
% of patients
% of patients
Hypertensive
60
40
51
49
44
39
20
0
< 120 120- 140- >161
139 161
< 120 120- 140- >161
139 161
SBP quartiles, mmhg
SBP quartiles, mmhg
Gheorghiade et al., JAMA 2006; 296:2217
Cause of AHF According to SBP: OPTIMIZE-HF Study
48 612 patients FROM 259 us HOSPITALS
LV Systolic dysfunction
60
80
63
52
44
LVEF units
% of patients
80
LV Ejection fraction
35
40
20
60
40
33.3
37.8
40.9
44.4
20
0
< 120 120139
140- >161
161
SBP quartiles, mmhg
0
< 120 120- 140- >161
139 161
SBP quartiles, mmhg
Gheorghiade et al., JAMA 2006; 296:2217
ADHERE: Risk Stratification for
Inhospital Mortality in the
Validation Cohort
32,229 hospitalizations
BUN < 43 mg/dL
Mortality, 2.8%
BUN ≥ 43 mg/dL
Mortality, 8.3%
24,702 hospitalizations
6,697 hospitalizations
SBP
≥ 115 mmHg
Low risk
2.3% mortality
SBP
< 115 mmHg
Intermediate risk
5.7% mortality
SBP
≥ 115 mmHg
Intermediate risk
5.6% mortality
SBP
< 115 mmHg
15.3% mortality
1,862 hospitalizations
S-creatinine
< 2.75 mg/dL
Intermediate risk
13.2% mortality
S-creatinine
≥ 2.75 mg/dL
High risk
19.8% mortality
Fonarow GC, et al. JAMA. 2005;293:572-580.
In-Hospital Mortality Rates by Admission Systolic Blood
Pressure Deciles (n = 48 567)
Gheorghiade, M. et al. JAMA 2006;296:2217-2226.
Indipendent Predictors of Outcomes
Fraction of patients, %
CV death, HF hospitalisation free survival
1.0
0.8
64%
0.6
0.4
P < 0.001
40%
SBP at discharge ≥ 110 mmHg (n=304)
SBP at discharge < 110 mmHg (n=193)
0.2
0.0
0
60
120
180
Days
240
300
360
Factors influencing clinical
presentations of AHF
•
•
•
•
Myocardial ischemia
Blood pressure (peripheral perfusion)
Fluid overload
Kidney dysfunction
– Each may or may not be present, with
different relative importance, in each patient
Hemodynamic Changes Occur Before Clinical
Exacerbations in the Patients with CHF
Patient # 1
ePAPD
RVP
Heart Rate
Patient # 2
RVP
ePAPD
HR
Adamson et al. JACC 2003; 41:565
Patterns of Weight Change Preceding Hospitalization
for Heart Failure: cases vs controls. n=268
Chaudhry, … Krumholz. Circulation 2007;116:1549-1554
Lack of Weight Loss in Large Fraction of Patients
Admitted for Acute Heart Failure. ADHERE Registry
All Enrolled Discharges from October 2001 to January 2004
Change in weight was assessed in 51,013 patient episodes
Discharged Home (including home with additional and/or outpatient care)
33%
Enrolled Discharges
30
24%
49% little or no
Weight Loss
25
16% no change
11% or gain in Body
Weight
20
13%
15
10
7%
6%
3%
5
0
(<-20)
(-20 to -15) (-15 to -10) (-10 to -5)
(-5 to 0)
Change in Weight (lbs)
(0 to 5)
(5 to 10)
2%
(>10)
Freedom from congestion predicts good survival
also in patients with advanced HF
2-year survival
(%)
146 pts with NYHA IV
4-6 weeks after discharge reevaluated for congestion
80
High-risk
group
Criteria:
60
1.
2.
3.
4.
5.
Orthopnoea
 JVP
Oedema
Weight gain
 baseline
diuretics
40
20
0 crit 1-2 crit
(n=80) (n=40)
3 crit
(n=26)
Orth+
(n=33)
Lucas et al., Am Heart J 2000;140:840
Composite Components
(Day 7 or Discharge)
Change in Body Weight
Change in Global Clinical Status
Tolvaptan
Placebo
P=0.51
Additional weight loss
0.6 kg
0.9 kg
P=0.52
20
15
P<0.0001
P<0.0001
0
n=997 n=1007
mm
1
10
n=1031 n=1008
5
-1
kg
n=903
n=910
n=931
n=900
0
-2
Trial A
Trial B
-3
No difference in GCS
improvement
-4
-5
Trial A
48
Trial B
CV Mortality or HF Hospitalization
Proportion Without
Event
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
HR 1.04; 95%CI (.95-1.14)
TLV 30 mg
PLACEBO
Peto-Peto Wilcoxon Test: P=0.55
2072
1562
1146
834
607
396
271
149
58 TLV
2061
1532
1137
819
597
385
255
143
55 PLC
0
3
9
12
15
18
21
6
Months In Study
50
24
Weight changes in patients hospitalized with
ADHF. Results from ESCAPE (N=433)
Mehta et al. . Am J Cardiol 2009; 103:76
Lack of association of weight change with
subsequent outcomes in patients hospitalised
with ADHF. Results from ESCAPE
Lowest tertile
(n=128)
Middle tertile
(n=128)
Highest
P Value
tertile (n=127)
Days alive and
well
165 (120-174)
167 (119.175)
162 (68-172)
0.140
180-d mortality
19%
14%
21%
0.316
Death,
rehospitalization,
cardiac Tx
67%
62%
66%
0.623
Mehta, Rogers, Hasselblad, Tasissa, Binanay, Califf, O’Connor, on behalf of ESCAPE
Trial Investigators . Am J Cardiol 2009; 103:76
Comorbidities in AHF
•
Cardiac
– Ischaemia
– Valvular disease
– Arrhythmias (AF, etc)
•
Noncardiac
– CKD
– COPD
– Anaemia
– Cachexia
– Stroke
– Etc.
Potential impact of kidney dysfunction on
outcomes of patienst with AHF
• ↑ length of hospitalization
• Need of higher furosemide doses
• Intolerance to ACEi/ ARBs
• ↑ neurohormonal activation & inflammatory
activity
• Anemia
• …
Acute HF
Low cardiac output
Hypotension
Cardiac
damage
↑ venous
pressure
i.v. Furosemide
ACEi/
ARBs
Neurohormonal
activation
Tubuloglomerular
feedback
Renal
hypoperfusion
Kidney
dysfunction
Independent role of renal blood flow (RBF) and
right atrial pressure (RAP) as determinants of
Glomerular Filtration Rate in heart failure
Multivariable regression analysis for GFR
Variable
Univariate
correlation
coefficient
Univariate β
Age
− 0.072
0.023
Sex
− 0.218
− 0.028
Multivariate
correlation
coefficient
Multivariate β
RBF
0.797
0.782
0.664
0.621
RAP
− 0.616
− 0.579
− 0.367
− 0.276
CI
PVR
0.404
0.396
− 0.298
− 0.297
Adjusted R2
0.609
CI, cardiac index; PVR, pulmonary vascular resistance;
RAP, right atrial pressure; RBF, renal blood flow.
Multivariate
p-value
< 0.001
0.020
< 0.001
Damman et al. Eur J Heart Fail 2007;9:872-8.
Determinants of Glomerular filtration rate in
patients with heart failure
Variable
Univariate analysis
Partial R P value
Multivariate analysis
Partial R
P value
Age
-0.338
0.001
Gender
-0.312
0.003
Renal blood flow
0.888
<0.001
0.938
<0.001
Filtration fraction
0.573
<0.001
0.786
<0.001
Urinary albumin excretion
-0.306
0.005
Mean BP
0.306
0.005
Hemoglobin
0.312
0.004
-0.520
<0.001
NT-proBNP
-0.533
<0.001
Plasma renin activity
-0.501
<0.001
sVCAM-1
-0.279
0.010
Nox
-0.276
0.011
ADMA
-0.168
0.126
CRP
-0.016
0.88
Damman et al. Clin Res Cardiol 2009; 98:121
Urinary neutrophil gelatinase associated lipocalin
(NGAL), a marker of tubular damage, and urinary
Albumin Excretion (UAE) are increased in patients
with chronic heart failure
Damman et al., Eur J Heart Fail 10 (2008) 997–1000
ADHERE: Risk Stratification for
Inhospital Mortality in the
Validation Cohort
32,229 hospitalizations
BUN < 43 mg/dL
Mortality, 2.8%
BUN ≥ 43 mg/dL
Mortality, 8.3%
24,702 hospitalizations
6,697 hospitalizations
SBP
≥ 115 mmHg
Low risk
2.3% mortality
SBP
< 115 mmHg
Intermediate risk
5.7% mortality
SBP
≥ 115 mmHg
Intermediate risk
5.6% mortality
SBP
< 115 mmHg
15.3% mortality
1,862 hospitalizations
S-creatinine
< 2.75 mg/dL
Intermediate risk
13.2% mortality
S-creatinine
≥ 2.75 mg/dL
High risk
19.8% mortality
Fonarow GC, et al. JAMA. 2005;293:572-580.
Prognostic Significance of Worsening
Renal Function in Patients With ADHF
HF hospitalizations and
CV-mortality–free survival
CV-mortality–free survival
1.0
1.0
86%
0.8
55%
0.6
0.4
P < 0.001
Patients (%)
Patients (%)
0.8
28%
0.2
0.6
59%
0.4
P < 0.001
0.2
Δ creatinine < 25% and/or < 0.3 mg/dL
Δ creatinine ≥ 25% and ≥ 0.3 mg/dL
Δ creatinine < 25% and/or < 0.3 mg/dL
Δ creatinine ≥ 25% and ≥ 0.3 mg/dL
0.0
0.0
0
0
90 180 270 360 450 540 630 720
Days
Patients at risk
Absolute and percent s-Cr change:
< 0.3 or 25%
≥ 0.3 & 25%
211
107
143
64
92
36
90 180 270 360 450 540 630 720
Days
Patients at risk
Absolute s-Cr change:
55
19
36
14
< 0.3
≥ 0.3
184
134
125
82
79
49
46
27
33
21
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
Predictors of Worsening Renal Failure
Among 318 Patients Hospitalized for AHF
Results of Multivariable Analysis
Predictor
Odds ratio (95% CI)
P
History of chronic kidney disease
1.84 (1.04 – 3.27)
< 0.0001
IV furosemide dose > 100 mg/d
2.18 (1.27 – 3.73)
0.004
NYHA class (IV vs. III)
2.07 (1.24 – 3.45)
0.005
LV ejection fraction < 30%
1.66 (1.01 – 2.75)
0.047
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
PROTECT Pilot
Mean change in serum creatinine (mg/dL)
Change in Serum Creatinine
0.35
0.3
Placebo (n = 78)
10 mg (n = 74)
20 mg (n = 75)
30 mg (n = 74)
0.25
0.2
0.15
0.1
0.05
0
−0.05
Day 2
Day 3
Day 7
Day 14
*Nominal P < 0.05 for dose-related trend at Day 14
Cotter G, et al. J Card Fail. 2008;14:631-640.