Marco Metra Cardiologia Università e Spedali Civili di Brescia, Italia

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 ?







Precipitating factors in AHF: EHFS II

Nieminen et al., Eur Heart J 2006; 27:2725







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


107 patients discharged after AHF

NT-proBNP <6078pg/mLn= 76;

1-year survival, 91%

NT-proBNP >6078 pg/mLn= 31;


NYHA class I/IIn= 61;


cTnT undetectablen= 40;


cTnT detectablen= 21;


NYHA class III/IVn= 15;


P=0.018

P=0.021

P<0.0001

Prediction of Cardiac Death: CART analysis


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


↑ myocardial VO2



↑ Heartrate



?

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


↑ myocardial VO2



↑ Heartrate



?

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




• Fluid overload



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


SBP< 115 mmHg

15.3% mortality

1,862 hospitalizations

S-creatinine< 2.75 mg/dL


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

, %




• Fluid overload



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


SBP ≥ 115 mmHg


SBP< 115 mmHg

15.3% mortality

1,862 hospitalizations

S-creatinine< 2.75 mg/dL


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.

Documents

Marco Metra Cardiologia Università e Spedali Civili di Brescia, Italia