marco metra cardiologia università e spedali civili di brescia, italia
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9 th 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. - PowerPoint PPT PresentationTRANSCRIPT
Marco MetraCardiologiaUniversità e Spedali Civili di Brescia, Italia
9th International Symposium Heart Failure & Co. Milano, Istituto Clinico Humanitas
Clinical Presentations of Acute Decompensated Heart Failure
The Burden of Acute HFThe Burden of Acute HF
• Most frequent cause of hospitalization for Most frequent cause of hospitalization for patients aged >65 yearspatients aged >65 years
• In-hospital stayIn-hospital stay– Duration, mean: 4 days (US) / 8 days
(Europe)– Mortality, 3% to 9%
• Follow-up (2-3 months)Follow-up (2-3 months)– Mortality, 9% to 13%– Rehospitalizations, 24% to 30%
Definition of Acute Heart FailureDefinition of Acute Heart Failure(ESC guidelines for the diagnosis and treatment (ESC guidelines for the diagnosis and treatment
of acute and chronic heart failure 2008)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 FailureDefinition of Acute Heart Failure(ESC guidelines for the diagnosis and treatment (ESC guidelines for the diagnosis and treatment
of acute and chronic heart failure 2008)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 Clinical classification of Acute Heart Failure (ESC guidelines 2008)(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 output syndrome)
Poor peripheral perfusion, SBP <90 mmhg or drop MBP >30 mmhg, anuria or oliguria (<0.5 ml/kg/h)
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 Factors influencing clinical presentations of AHFpresentations 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 syndromesAcute 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 cardiomyopathyNon-ischaemic cardiomyopathy– Ischaemia / necrosis precipitated by AHF ?
AHF & myocardial ischaemia
• Acute coronary syndromesAcute 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 cardiomyopathyNon-ischaemic cardiomyopathy– Ischaemia / necrosis precipitated by AHF ?
Precipitating factors in AHF: EHFS II
Nieminen et al., Eur Heart J 2006; 27:2725
AHF & myocardial ischaemia
• Acute coronary syndromesAcute 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 cardiomyopathyNon-ischaemic cardiomyopathy– Ischaemia / necrosis precipitated by AHF ?
Prevalence of Detectable (>0.01 pg/ml)Troponin T in patients with AHF with daily blood sampling
Coronary artery disease
26%
28%
46%
TnT (1 sample)
TnT (>1 sample)
No TnT
Idiopathic dilated cardiomyopathy
26%
14%60%
TnT (1 sample)
TnT (>1 sample)
No TnT
Metra et al., Eur J Heart Fail. 2007;9:776-86
Patients at risk Patients at risk:No cTnt 56 55 44 35 33 No cTnt 56 44 30 26 21cTnT 51 34 21 15 11 cTnt 51 23 11 9 4
No cTnT detectablecTnT detectable
P<0.0001
No cTnT detectablecTnT detectable
P<0.01
Cardiac mortality
0
0.2
0.4
0.6
0.8
1
0 90 180 270 360
Days
Fra
cti
on
of
pa
tie
nts
Cardiac mortality or CV hospitalizations
0
0.2
0.4
0.6
0.8
1
0 90 180 270 360
Days
Fra
cti
on
of
pa
tie
nts
Freedom from Death or CV Hospitalization and Freedom from Death or CV Hospitalization and cTnT plasma levels in Acute Heart FailurecTnT plasma levels in Acute Heart Failure
Metra et al., Eur J Heart Fail. 2007;9:776-86
107 patients discharged after AHF
NT-proBNP <6078pg/mLn= 76;
1-year survival, 91%
NT-proBNP >6078 pg/mLn= 31;
1-year survival, 34%
NYHA class I/IIn= 61;
1-year survival, 95%
cTnT undetectablen= 40;
1-year survival, 100%
cTnT detectablen= 21;
1-year survival, 78%
NYHA class III/IVn= 15;
1-year survival, 71%
P=0.018
P=0.021
P<0.0001
Prediction of Cardiac Death: CART analysis
Metra et al., Eur J Heart Fail. 2007;9:776-86
Acute HFAcute HFHemodynamic abnormalities + neurohorm./ Inflam. activation
Myocardial damage / Myocardial damage / necrosisnecrosis
↓↓Coronary Coronary perfusionperfusion
↑ myocardial VO2
Low CO / hypotension
↑ LVEDP /↑ wall stress
↑ Heartrate
Inotropicstimulation
CAD / hybernating myocardium / …..
Acute HF + VasodilatorsAcute HF + Vasodilators
Myocardial Myocardial damage / damage / necrosisnecrosis
↓↓Coronary Coronary perfusionperfusion
↑ myocardial VO2
Low CO / hypotension
↑ LVEDP /↑ wall stress
↑ Heartrate
Inotropicstimulation
CAD / hybernating myocardium / …..
?
Early: < 9 hrs.
Cohn JN, et al. N Engl J Med. 1982; 306:1129.
Nitroprusside and MortalityPatients Presenting With Presumed Acute MI and HF
All had a PA Catheter
Mullens, W. et al. J Am Coll Cardiol 2008;52:200-207
Sodium Nitroprusside for advanced low-output heart failure
(n=175, 50% ischemic, 30% prev CABG)
Acute HF + Inotropic agentsAcute HF + Inotropic agents
Myocardial Myocardial damage / damage / necrosisnecrosis
↓↓Coronary Coronary perfusionperfusion
↑ myocardial VO2
Low CO / hypotension
↑ LVEDP /↑ wall stress
↑ Heartrate
Inotropicstimulation
CAD / hybernating myocardium / …..
?
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
Inotropes
No Inotropes
CV mortality free survival. CAD (n=278)
0.0
0.2
0.4
0.6
0.8
1.0
0 60 120 180 240 300 360days
% P
atie
nts
CV mortality free survival NO CAD (n=220)
0.0
0.2
0.4
0.6
0.8
1.0
0 60 120 180 240 300 360days
% P
atie
nts
No Inotropes
Inotropes
P =0.007
P=0.203 after adjustment at multivariable analysis
P <0.0001
P=0.025 after adjustment at multivariable analysis
Survival in patients admitted for acute heart failure subdivided on the basis of treatment
with inotropic agents
Factors influencing clinical Factors influencing clinical presentations of AHFpresentations 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 Clinical significance of high blood pressure in AHFpressure in AHF
• Cause of AHFCause of AHF– Afterload mismatchAfterload mismatch
• Consequence of AHFConsequence of AHF– ↑↑neurohormonal activationneurohormonal activation– ↑↑cardiac functioncardiac function
SBP in AHF RegistriesSBP 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 2006Italian 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 Study48 612 patients FROM 259 us HOSPITALS
Hypertensive
1318
25
35
0
20
40
< 120 120-139
140-161
>161
SBP quartiles, mmhg
% o
f p
ati
en
ts
Gheorghiade et al., JAMA 2006; 296:2217
Ischemic
51 4944
39
0
20
40
60
< 120 120-139
140-161
>161
SBP quartiles, mmhg
% o
f p
ati
en
ts
Cause of AHF According to SBP: OPTIMIZE-HF Study48 612 patients FROM 259 us HOSPITALS
Gheorghiade et al., JAMA 2006; 296:2217
LV Systolic dysfunction
6352
4435
0
20
40
60
80
< 120 120-139
140-161
>161
SBP quartiles, mmhg
% o
f p
ati
en
ts
LV Ejection fraction
33.337.8 40.9 44.4
0
20
40
60
80
SBP quartiles, mmhg
LV
EF
un
its
< 120 120-139
140-161
>161
ADHERE: Risk Stratification for ADHERE: Risk Stratification for Inhospital Mortality in theInhospital Mortality in the
Validation CohortValidation Cohort32,229 hospitalizations
BUN < 43 mg/dLMortality, 2.8%
BUN ≥ 43 mg/dLMortality, 8.3%
24,702 hospitalizations 6,697 hospitalizations
SBP ≥ 115 mmHg
Low risk2.3% mortality
SBP< 115 mmHg
Intermediate risk5.7% mortality
SBP ≥ 115 mmHg
Intermediate risk5.6% mortality
SBP< 115 mmHg
15.3% mortality
1,862 hospitalizations
S-creatinine< 2.75 mg/dL
Intermediate risk13.2% mortality
S-creatinine≥ 2.75 mg/dL
High risk19.8% mortality
Fonarow GC, et al. Fonarow GC, et al. JAMAJAMA. 2005;293:572-580.. 2005;293:572-580.
Gheorghiade, M. et al. JAMA 2006;296:2217-2226.
In-Hospital Mortality Rates by Admission Systolic Blood Pressure Deciles (n = 48 567)
Indipendent Predictors of Outcomes
64%
SBP at discharge ≥ 110 mmHg (n=304) SBP at discharge < 110 mmHg (n=193)
P < 0.00140%
CV death, HF hospitalisation free survival
0.0
0.2
0.4
0.6
0.8
1.0
0 60 120 180 240 300 360Days
Fra
ctio
n o
f p
atie
nts
, %
Factors influencing clinical Factors influencing clinical presentations of AHFpresentations 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
RVP
ePAPD
HR
Adamson et al. JACC 2003; 41:565
RVP
ePAPD
Heart Rate
Patient # 1
Patient # 2
Chaudhry, … Krumholz. Circulation 2007;116:1549-1554
Patterns of Weight Change Preceding Hospitalization Patterns of Weight Change Preceding Hospitalization for Heart Failure: cases vs controls. n=268for Heart Failure: cases vs controls. n=268
En
roll
ed
Dis
ch
arg
es
7% 6%
13%
24%
33%
11%
3% 2%
0
5
10
15
20
25
30
(<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10)
Change in Weight (lbs)
All Enrolled Discharges from October 2001 to January 2004
Change in weight was assessed in 51,013 patient episodes
Lack of Weight Loss in Large Fraction of Patients Admitted for Acute Heart Failure. ADHERE Registry
Discharged Home (including home with additional and/or outpatient care)
16% no change 16% no change or gain in Body or gain in Body
WeightWeight
49% little or no 49% little or no Weight LossWeight Loss
Freedom from congestion predicts good survival also in patients with advanced HF
146 pts with NYHA IV
4-6 weeks after discharge re-evaluated for congestion
1. Orthopnoea2. JVP3. Oedema4. Weight gain5. baseline
diuretics
Criteria:
20
40
60
80
2-year survival
(%)
0 crit(n=80)
1-2 crit(n=40)
3 crit(n=26)
Orth+(n=33)
Lucas et al., Am Heart J 2000;140:840
High-risk group
48
Composite ComponentsComposite Components (Day 7 or Discharge)(Day 7 or Discharge)
Trial A Trial B
kg
-5
-4
-3
-2
-1
0
1
P<0.0001 P<0.0001
Change in Body Weight
Trial A Trial Bm
m0
5
10
15
20
P=0.52P=0.51
Change in Global Clinical Status
Additional weight loss0.6 kg 0.9 kg
No difference in GCS improvement
n=997 n=1007 n=1031 n=1008
n=903 n=910 n=931 n=900
Tolvaptan Placebo
50
Peto-Peto Wilcoxon Test: P=0.55
Months In Study
TLV
PLC
TLV 30 mgPLACEBOP
rop
ort
ion
Wit
ho
ut
Eve
nt
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
2072 1562 1146 834 607 396 271 149 58
2061 1532 1137 819 597 385 255 143 55
HR 1.04; 95%CI (.95-1.14)
CV Mortality or HF HospitalizationCV Mortality or HF Hospitalization
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 Lack of association of weight change with subsequent outcomes in patients hospitalised subsequent outcomes in patients hospitalised
with ADHF. Results from ESCAPEwith ADHF. Results from ESCAPE
Lowest tertile (n=128)
Middle tertile (n=128)
Highest tertile (n=127)
P Value
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 HFAcute HF
i.v. Furosemide
Low cardiac output
↑ venouspressure
KidneyKidneydysfunctiondysfunction
Neurohormonalactivation
Renal hypoperfusion
Tubuloglomerular feedback
Hypotension
ACEi/ARBs
Cardiac Cardiac damagedamage
Independent role of renal blood flow (RBF) and right atrial pressure (RAP) as determinants of
Glomerular Filtration Rate in heart failureMultivariable regression analysis for GFR
CI, cardiac index; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RBF, renal blood flow.
Variable Univariate correlation coefficient
Univariate β Multivariate correlation coefficient
Multivariate β Multivariate p-value
Age − 0.072 0.023
Sex − 0.218 − 0.028
RBFRBF 0.7970.797 0.7820.782 0.6640.664 0.6210.621 < 0.001< 0.001
RAPRAP − − 0.6160.616 − − 0.5790.579 − − 0.3670.367 − − 0.2760.276 0.0200.020CI 0.404 0.396
PVR − 0.298 − 0.297
Adjusted R2 0.609 < 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 ADHERE: Risk Stratification for Inhospital Mortality in theInhospital Mortality in the
Validation CohortValidation Cohort32,229 hospitalizations
BUN < 43 mg/dLMortality, 2.8%
BUN ≥ 43 mg/dLMortality, 8.3%
24,702 hospitalizations 6,697 hospitalizations
SBP ≥ 115 mmHg
Low risk2.3% mortality
SBP< 115 mmHg
Intermediate risk5.7% mortality
SBP ≥ 115 mmHg
Intermediate risk5.6% mortality
SBP< 115 mmHg
15.3% mortality
1,862 hospitalizations
S-creatinine< 2.75 mg/dL
Intermediate risk13.2% mortality
S-creatinine≥ 2.75 mg/dL
High risk19.8% mortality
Fonarow GC, et al. Fonarow GC, et al. JAMAJAMA. 2005;293:572-580.. 2005;293:572-580.
Patients at risk Patients at riskAbsolute and percent s-Cr change: Absolute s-Cr change:
< 0.3 or 25% 211 143 92 55 36 < 0.3 184 125 79 46 33 ≥ 0.3 & 25% 107 64 36 19 14 ≥ 0.3 134 82 49 27 21
HF hospitalizations andCV-mortality–free survival
55%
28%
0.0
0.2
0.4
0.6
0.8
1.0
0 90 180 270 360 450 540 630 720
Days
Pat
ien
ts (
%)
CV-mortality–free survival
P < 0.001
Δ creatinine < 25% and/or < 0.3 mg/dLΔ creatinine ≥ 25% and ≥ 0.3 mg/dL
86%
59%
0.0
0.2
0.4
0.6
0.8
1.0
0 90 180 270 360 450 540 630 720Days
Prognostic Significance of Worsening Prognostic Significance of Worsening Renal Function in Patients With ADHFRenal Function in Patients With ADHF
P < 0.001
Δ creatinine < 25% and/or < 0.3 mg/dLΔ creatinine ≥ 25% and ≥ 0.3 mg/dL
Pat
ien
ts (
%)
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.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
PredictorPredictor Odds ratio (95% CI)Odds ratio (95% CI) PP
History of chronic kidney diseaseHistory of chronic kidney disease 1.84 (1.04 – 3.27)1.84 (1.04 – 3.27) < 0.0001< 0.0001
IV furosemide dose > 100 mg/d IV furosemide dose > 100 mg/d 2.18 (1.27 – 3.73)2.18 (1.27 – 3.73) 0.0040.004
NYHA class (IV vs. III)NYHA class (IV vs. III) 2.07 (1.24 – 3.45)2.07 (1.24 – 3.45) 0.0050.005
LV ejection fraction < 30%LV ejection fraction < 30% 1.66 (1.01 – 2.75)1.66 (1.01 – 2.75) 0.0470.047
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
PROTECT Pilot Change in Serum Creatinine
−0.05
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Day 2 Day 3 Day 7 Day 14Mea
n c
han
ge
in s
eru
m c
reat
inin
e (m
g/d
L)
Placebo (n = 78)10 mg (n = 74)20 mg (n = 75)30 mg (n = 74)
*Nominal P < 0.05 for dose-related trend at Day 14
Cotter G, et al. J Card Fail. 2008;14:631-640.Cotter G, et al. J Card Fail. 2008;14:631-640.