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Controversial issues
in heart failure
Can we change the
outcome of patients
with acute heart
failure?
Marco Metra, MD, FESCAssociateprofessor of Cardiology.
University of Brescia
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%
Data from: Cleland et al. Eur Heart J. 2003;24:442; Gheorghiade et al. Circulation. 2005;112:3958. Rudiger A et
al. , Eur J Heart Fail 2005; 7:662; Adams et al. , Am Heart J. 2005;149:209; O'Connor et al. J Card Fail.
2005;11:200; Tavazzi L et al., Eur Heart J 2006; 27:1207; Zannad et al. , Eur J Heart Fail 2006; 8;697; Nieminen
M et al. Eur Heart J 2006; 27, 2725; Fonarow et al. J Am Coll Cardiol 2005;45:345A.
One-year survival in AHF patients discharged alive:
comparison between clinical classes.
Harjola V ... Tavazzi Eur J Heart Fail 2010;12:239-248
Renal dysfunction
↓ CO / ↑ LVEDP
End-organ hypoperfusion
↑ venous pressure
Neurohormonal activation
RAA – SNS - ADH
Inflammatory activation
Na-H2O retention
Congestion↑ LV preload
↑ LV wall stress
↑ LV afterload
Fluid redistribution
to the lungs
Lung congestion
↓ coronary perfusion
pressure
tachycardia
↑ MVO2
Myocardial ischemia
Diuretic use
Diuretic resistance
Cardiac dysfunction
diastolicsystolic
Metra et al.. ESC Intensive Acute Cardiac
Care textbook
Pathophysiologic
mechanisms in acute
heart failure
Renal dysfunction
↓ CO / ↑ LVEDP
End-organ hypoperfusion
↑ venous pressure
Neurohormonal activation
RAA – SNS - ADH
Inflammatory activation
Na-H2O retention
Congestion↑ LV preload
↑ LV wall stress
↑ LV afterload
Fluid redistribution
to the lungs
Lung congestion
↓ coronary perfusion
pressure
tachycardia
↑ MVO2
Myocardial ischemia
Diuretic use
Diuretic resistance
Cardiac dysfunction
diastolicsystolic
Metra et al.. ESC Intensive Acute Cardiac
Care textbook
Pathophysiologic
mechanisms in acute
heart failure
Change in dyspnoea from sitting to lying supine
Change in dyspnoea in the first 6 hours of treatment
Changes in symptoms (dyspnoea) in the
URGENT Trial
Mebazaa et al. Eur Heart J. 2010 Apr;31(7):832-41.
Hogg KJ, McMurray JJ. Eur Heart J. 2010 Apr;31(7):771-2.
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. Orthopnoea
2. JVP
3. Oedema
4. Weight gain
5. 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
Patients at risk Patients at risk
NT-ProBNP: NT-prBNP:
< 6078 76 69 69 42 32 <3275 57 46 28 24 19
> 6078 31 29 20 11 6 >3275 50 25 15 11 7
Discharge NT-ProBNP <3275
Discharge NT-ProBNP >3275
P<0.0001Discharge NT-ProBNP <6078
Discharge NT-ProBNP >6078
P<0.0001
Cardiac mortality
0
0.2
0.4
0.6
0.8
1
0 90 180 270 360
Days
Fra
cti
on
of
pati
en
ts
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
pati
en
ts
Prognostic value of NT-ProBNP at discharge in
patients hospitalised for AHF
Metra et al. Eur J Heart Fail. 2007;9:776-86.
NT-ProBNP
<3000 pg/mL
Dimissione
F-Up clinico
NT-ProBNp
ignotoNT-ProBNp
noto
F-Up clinico
Ospedalizzazione IC acuta / No SCA
Misurazione NT-ProBNP
48-72 ore pre-dimissione & alla dimissione
Rivalutazione terapia:↑dose diuretici / ACEi /
Dig/ARB/AA/IDN /Terapia i.v.
NT-ProBNP
>3000 pg/mL
Rivalutazione
NT- ProBNP
↓NT-ProBNP
>25% or <3000 pg/ml
Randomizzazione 1:1
NT-proBNP in
the Optimization
of Treatment in
Acute Heart
Failure (BOT-
AcuteHF) Trial
P = 0.035
0%
20%
40%
60%
80%
100%
0 60 120 180 240 300 360 420 480 540 600 660 720
Su
rviv
alp
rob
ab
ilit
y, %
Days of follow-up
Nt-pro-BNP guidedControl
All-cause mortality
Effects of Nt-proBNP guided therapy on survivavl after an AHF hospitalisation
Weight changes in patients hospitalized with
ADHF. Results from ESCAPE (N=433)
Mehta et al. . Am J Cardiol 2009; 103:76
40%
≈25%
Large RCTs in ADHF
Trial Agent Pts
No.
Effects on
symptoms
Effects on
outcomes
VMAC, 2002 Nesiritide 489Yes vs placebo
@ 3 hn.s.
OPTIME-CHF, 2002 Milrinone 951 No No, ↑ AEs
VERITAS, 2007 Tezosentan 1448 No No
EVEREST, 2007 Tolvaptan 4133 Mild No
REVIVE-II, 2009 Levosim. 600 Mild No, ↑ AEs
PROTECT* Rolofylline 2033 Mild No
VMAC PC JAMA 2002; 287:1531; Cuffe et al. JAMA 2002; 287:1541; McMurray et al., JAMA
2007;298:2009; Gheorghiade et al. JAMA 2007; 297:1332; de Lissovoy et al. Eur J Health Econ 2009;;
Massie et al. to be submitted
* All these changes corresponded to a 6 to 12% difference in the proportion of patients
with dyspnea improvement
Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema
Gray A et al. N Engl J Med 2008;359:142-151
Large RCTs in ADHF
Trial Agent Pts
No.
Effects on
symptoms
Effects on
outcomes
VMAC, 2002 Nesiritide 489Yes vs placebo
@ 3 hn.s.
OPTIME-CHF, 2002 Milrinone 951 No No, ↑ AEs
VERITAS, 2007 Tezosentan 1448 No No
EVEREST, 2007 Tolvaptan 4133 Mild No
REVIVE-II, 2009 Levosim. 600 Mild No, ↑ AEs
PROTECT* Rolofylline 2033 Mild No
VMAC PC JAMA 2002; 287:1531; Cuffe et al. JAMA 2002; 287:1541; McMurray et al., JAMA
2007;298:2009; Gheorghiade et al. JAMA 2007; 297:1332; de Lissovoy et al. Eur J Health Econ 2009;;
Massie et al. to be submitted
* All these changes corresponded to a 6 to 12% difference in the proportion of patients
with dyspnea improvement
Drug’s efficacy
Drug’s cardiovascular safety
Placebo IV
Rolofylline
30 mg IV
Treatment phase Follow-up
Randomisation
Rolofylline to
placebo, 2:1
All cause mortality
CV/Renal hosp All cause
mortality
PROTECT STUDY DESIGN
Kidney Function
Days 1 2 3 4 5 6 7 14 60 180
Screening
• AHF & fluid
overload, need of
iv loop diuretic
• CrCl, 20-80
ml/min
Symptoms relief and short-term outcomes in ADHF
Components of the primary end-point in PROTECT
2,1
0,6
9,7
11,1
1,7
0,4
9,1
12,7
0
2
4
6
8
10
12
14
Death day 7
HF Rehosp day 7
WHFday 7
WRF, day 7-14
PROTECT EC, PC & investigators. Presented at ESC 2009
44,5
51,2
0
10
20
30
40
50
60
Dyspnea relief
Fra
cti
on
of
pati
en
ts, %
Placebo (n=677)
Rolofylline (n=1356)
Time to Death or CV or Renal Rehospitalization - Day 60
0.4
0.3
0.2
0.1
0.0
0 5 10 15 20 25 30 35 40 45 50 55 60 65
Study Day
Cu
mu
lati
ve R
isk
Hazard Ratio (95% CI) = 0.98 (0.83, 1.17)
P-value = 0.861
Placebo
Rolofylline 30 mg
Study Day
No. of patients at risk
Placebo (N=677)
Rolofylline (N=1356)
7
657
1322
14
633
1263
30
566
1134
55
489
1001
65
74
158
Death: Placebo 9.5% vs rolofylline 8.9%
Re-hospitalization: Placebo 25.6% vs rolofylline 25.7%
Effects of rolofylline on short-term outcomes
Metra et al. Submitted to Eur Heart J
Effects of rolofylline on short-term outcomes
Short Term OutcomeBy Baseline Creatinine (Median)
Hazard Ratio (95% C.I.)
0.2 0.4 0.6 1.0 1.4 2.0
14 Days30 Days
In-hospital
14 Days30 Days
In-hospital
14 Days30 Days
In-hospital
14 Days30 Days
In-hospital
14 Days30 Days
In-hospital
14 Days30 Days
In-hospital
Favors Rolofylline Favors Placebo
Baseline Creatinine< 1.5 mg/dL
>= 1.5 mg/dL
All Cause Mortality
HF Mortality
CV Mortality
All Cause Mortality
HF Mortality
CV Mortality
Metra et al. Submitted to Eur Heart J
Renal dysfunction
↓ CO / ↑ LVEDP
End-organ hypoperfusion
↑ venous pressure
Neurohormonal activation
RAA – SNS - ADH
Inflammatory activation
Na-H2O retention
Congestion↑ LV preload
↑ LV wall stress
↑ LV afterload
Fluid redistribution
to the lungs
Lung congestion
↓ coronary perfusion
pressure
tachycardia
↑ MVO2
Myocardial ischemia
Diuretic use
Diuretic resistance
Cardiac dysfunction
diastolicsystolic
Metra et al. ESC Intensive Acute Cardiac
Care textbook
Acute HF treatment strategy according to SBP
Oxygen /NIV, loop diuretic + vasodilator
Clinical evaluation
SBP >100 mmhg SBP 90-100 mmhg SBP <90 mmhg
Vasodilator (NTG,
nitroprusside,
nesiritide),
levosimendan
Vasodilator
and/or inotrope (dobutamine, PDEI,
levosimendan)
Consider preload
correction with
fluids or inotrope (dopamine)
Good response
stabilize & initiate oral
diuretics, ACEI/ARB,
β-blocker
Poor response
inotrope, vasopressor,
mechanical support,
consider PAC
ESC 2008 guidelines
Significance of SBP in AHFS
• Index of cardiac function &
peripheral perfusion
• Indication for the choice of treatment
• Cause of end-organ damage
Increased symptom-improvement with the novel
vasodilator, relaxin, in AHF patients with
elevated BP. Results from Pre-Relax-AHF
Systolic blood pressure, mmhg
120 130 140 150 160 170 180
Placebo
Relaxin 30 mcg/kg/m
Pre
dic
ted
va
lue
of V
AS
AU
C c
ha
ng
e
Teerlink et al. Eur Heart J 2009 ; 30 ( Abstract Supplement ), 164
Sustained Dyspnea Improvement
through Day 14 (Visual Analog Scale)
Teerlink, Metra, Felker et al. Lancet 2009;373:1429.
RELAX-AHF: Cardiovascular Deaths
to Day 180
0.8
0.85
0.9
0.95
1
0 30 60 90 120 150 180
Kapla
n-M
eie
r E
vent-
free S
urv
ival (%
)
Days
Placebo
Relaxin 10 mcg/kg/d
Relaxin 100 mcg/kg/d
Relaxin 250 mcg/kg/d
Relaxin 30 mcg/kg/d(p<0.05)
Teerlink, Metra, Felker et al. Lancet 2009;373:1429.
Age per 10.52 years
Systolic BP per 19.17 mmhg
BUN per 11.34 mg/dl
Creatinine increase >0.3 mg/dl at day 5
BNP>500 or NTproBNP >2000 pg/mL
Sodium per 3.93 mEq/L
Relaxin 10 & 30 mcg vs Placebo
Relaxin 100 & 250 mcg vs Placebo
0.01 0.1 1 10 100
Hazard ratios and 95% CIs
Dyspnea AUC at 5 days per 2692.4 mm*h
WHF vs none
Prediction of CV death or HF/RF
rehospitalisations at 60 days: Multivariable
regression model
Metra et al. Presented at HFA 2009 LBCTs
Predictors of WRFin Pre-RELAX AHF:
Role of SBP
change in SBP (mmHg)
-100 -80 -60 -40 -20 0 20 40 60P
robabili
ty o
f pers
iste
nt W
RF
0,0
0,2
0,4
0,6
0,8
1,0
234 AHF patients (SBP≥125mmHg) from the Pre-RELAX-AHF study
Voors et al, Eur Heart J 2009 ; 30 ( Abstract Supplement ), 1020
• Persistent WRF was associated >5 times higher day 60 (p<0.001) mortality
• Adjusted for potential confounders, a higher baseline SBP (p<0.001) and a greater SBP drop
<48 hours of admission (p=0.008) were the strongest predictors of persistent WRF
Baseline SBP (mmHg)
100 120 140 160 180 200 220
Pro
babili
ty o
f pers
iste
nt W
RF
0,0
0,2
0,4
0,6
0,8
1,0
Renal dysfunction
↓ CO / ↑ LVEDP
End-organ hypoperfusion
↑ venous pressure
Neurohormonal activation
RAA – SNS - ADH
Inflammatory activation
Na-H2O retention
Congestion↑ LV preload
↑ LV wall stress
↑ LV afterload
Fluid redistribution
to the lungs
Lung congestion
↓ coronary perfusion
pressure
tachycardia
↑ MVO2
Myocardial ischemia
Diuretic use
Diuretic resistance
Cardiac dysfunction
diastolicsystolic
Metra et al. ESC Intensive Acute Cardiac
Care textbook
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 ?
Prevalence of Detectable (>0.01 pg/ml)Troponin T
in patients with AHF with daily blood sampling
26%
28%
46%
Coronary artery disease
TnT (1 sample)
TnT (>1 sample)
No TnT
26%
14%
60%
Idiopathic dilated cardiomyopathy
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 21
cTnT 51 34 21 15 11 cTnt 51 23 11 9 4
No cTnT detectable
cTnT detectable
P<0.0001
No cTnT detectable
cTnT 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
pati
en
ts
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
pati
en
ts
Freedom from Death or CV Hospitalization and
cTnT plasma levels in Acute Heart Failure
Metra et al., Eur J Heart Fail. 2007;9:776-86
Giorni
Rilascio TnT
(n=39)
Non Rilascio
TnT (n=141)
p=0.0372
Significato del rilascio di tropinina durnate l’ospedalizzazione per IC acuta:
Incidenza di morti o riospedalizzazioni
Renal dysfunction
↓ CO / ↑ LVEDP
End-organ hypoperfusion
↑ venous pressure
Neurohormonal activation
RAA – SNS - ADH
Inflammatory activation
Na-H2O retention
Congestion↑ LV preload
↑ LV wall stress
↑ LV afterload
Fluid redistribution
to the lungs
Lung congestion
↓ coronary perfusion
pressure
tachycardia
↑ MVO2
Myocardial ischemia
Diuretic use
Diuretic resistance
Cardiac dysfunction
diastolicsystolic
Metra et al. ESC Intensive Acute Cardiac
Care textbook
Worsening Renal Function and outcome
lower risk for WRF higher risk for WRF
.1 .2 .5 1 2 4 8
Study Odds ratio (95% CI)
Inhospital patientsKrumholz (2000), n=1681 1.41 ( 1.10, 1.82)Smith (2003), n=412 1.73 ( 1.00, 2.98)Akhter (2004), n=480 2.62 ( 1.66, 4.13)Cowie (2006), n=299
Jose (2006), n=1854Khan (2006), n=6535
Owan (2006), n=6052
Outhospital patients
Subtotal
De Silva (2005), n=1216
Subtotal
Overall
1.44 ( 0.98, 2.09)
1.61 ( 1.35, 1.93)
1.71 ( 0.96, 3.05)
1.46 ( 1.06, 2.02)
1.49 ( 1.30, 1.71)
1.69 ( 1.48, 1.94)1.79 ( 1.59, 2.02)
1.62 ( 1.45, 1.82)
Damman et al. J Card Fail 2007
Patients at risk Patients at risk
Absolute 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 and
CV-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
Pati
en
ts (
%)
CV-mortality–free survival
P < 0.001
Δ creatinine < 25% and/or < 0.3 mg/dL
Δ creatinine ≥ 25% and ≥ 0.3 mg/dL
86%
59%
0.0
0.2
0.4
0.6
0.8
1.0
0 90 180 270 360 450 540 630 720
Days
Prognostic Significance of Worsening Renal Function in Patients With ADHF
P < 0.001
Δ creatinine < 25% and/or < 0.3 mg/dL
Δ creatinine ≥ 25% and ≥ 0.3 mg/dL
Pati
en
ts (
%)
Metra M, … Dei Cas Eur J Heart Fail. 2008;10:188-195.
Adenosine type 1 receptor antagonists initial trials
Agent Author, year Model/ patients Effects
BG-9719 Lucas, JCP 2001 Pacing HF model ↓PWP, ↑CrCl, ↑uNa
BG-9719 Jackson, JPET
2001
CMP model ↑diuresis, ↑RBF, ↑GFR
BG-9719 Gottlieb,
Circulation 2002
63 CHF patients ↑diuresis, ↑uNa,
inhibition furosemide-
induced ↓GFR
BG-9928 Greenberg,
JACC 2007
50 CHF patients ↑uNa, ↓BW, =GFR
Rolofylline
(KW-3902)
Givertz, JACC
2007
146+35 CHF
patients
↑diuresis, ↑GFR,
↓s-Creat, ↓Fur dose,
sustained at 7 days
Rolofylline
(KW-3902)
Dittrich, JCF
2007
32 CHF patients 32%↑GFR, 45% ↑RBF
Rolofylline Cotter, JCF 2008 301 hospitalised
AHF patients
↑symptoms,↓BW,
↓s-Creat, …
Symptoms relief and short-term outcomes in ADHF
Components of the primary end-point in PROTECT
2,1
0,6
9,7
11,1
1,7
0,4
9,1
12,7
0
2
4
6
8
10
12
14
Death day 7
HF Rehosp day 7
WHFday 7
WRF, day 7-14
PROTECT EC, PC & investigators. Presented at ESC 2009
44,5
51,2
0
10
20
30
40
50
60
Dyspnea relief
Fra
cti
on
of
pati
en
ts, %
Placebo (n=677)
Rolofylline (n=1356)
Secondary Endpoint: Persistent Renal Impairment*P
erc
en
t o
f P
atie
nts
Odds ratio (95% CI) vs Pbo: 1.11 (0.85, 1.46); p = 0.441
0
2
4
6
8
10
12
14
1613.7
Ro 30 mg
15.0
Placebo
*Persistent renal impairment SCr ↑ >0.3 mg/dL at both Day 7 and Day 14 or
initiation of hemofiltration or dialysis through Day 7, or death by Day 7
Damman, K. et al. J Am Coll Cardiol 2009;53:582-588
Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values
Central venous pressure, mmHg
Cardiac index
>3.2 L/min/m2
2.5- 3.2 L/min/m2
<2.5 L/min/m2
50%
60%
70%
80%
90%
100%
0 60 120 180 240 300 360
Days
Su
rviv
al (
%)
No Congestion / No WRF (n=267)
No Congestion / WRF (n=178)
Congestion & WRF (n=183)
Congestion / No WRF (n= 101)
Survival in AHFS: Role of Congestion and
Worsening Renal Function
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 Study48 612 patients FROM 259 us HOSPITALS
1318
25
35
0
20
40
< 120 120-139
140-161
>161
% o
f p
ati
en
ts
SBP quartiles, mmhg
Hypertensive
Gheorghiade et al., JAMA 2006; 296:2217
51 4944
39
0
20
40
60
< 120 120-139
140-161
>161%
of
pati
en
ts
SBP quartiles, mmhg
Ischemic
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
63
5244
35
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
40.944.4
0
20
40
60
80
SBP quartiles, mmhg
LV
EF
un
its
< 120 120-
139
140-
161
>161
Cause of AHF According to SBP: OPTIMIZE-HF Study48 612 patients FROM 259 us HOSPITALS
7,2
3,62,5
1,7
0123456789
10
< 120 120-139
140-161
>161
% o
f p
ati
en
ts
SBP quartiles, mmhg
In-hospital mortality
Gheorghiade et al., JAMA 2006; 296:2217
14
8,4
6 5,4
0
4
8
12
16
< 120 120-139
140-161
>161%
of
pati
en
ts
SBP quartiles, mmhg
Postdischarge mortality
Cause of AHF According to SBP: OPTIMIZE-HF Study48 612 patients FROM 259 us HOSPITALS
30,6 29,9 30,327,6
05
101520253035404550
< 120 120-139
140-161
>161
% o
f p
ati
en
ts
SBP quartiles, mmhg
60-90 d rehospitalisations
Gheorghiade et al., JAMA 2006; 296:2217
Clinical signs & ECHO in the
management of AHFS
AHF with SBP < 100
mmHg
Assess volume status:
signs of dehydration
ECHO: Treatable cause
ECHO: LV systolic
dysfunction
ECHO: persistent
↑intracardiac pressure
IVC congestion
Fluid administration
Coronary angiography,
PCI, surgery, etc.
Inoropic agent
↑ diuretic dose / trial of
vasodilator
Yes
Yes
Yes
Yes
Risk of Worsening Renal Function With Nesiritide in Patients With ADHF
Nesiritide ≤ 0.03 μg/kg/min vs.non–inotrope-based controls
Nesiritide ≤ 0.03 μg/kg/min vs. all controls; nesiritide ≤ 0.015 μg/kg/min vs. non–inotrope-based controls
Nesiritide ≤ 0.015 μg/kg/min vs.non–inotrope-based controls
Nesiritide ≤ 0.015 μg/kg/min vs.all controls
Nesiritide ≤ 0.06 μg/kg/min vs.non–inotrope-based controls
Nesiritide ≤ 0.06 μg/kg/min vs.all controls
0 0.5 1 1.5 2 2.5
Risk ratio (95% CI)
Nesiritide better Nesiritide worse
Sackner-Bernstein JD, et al. Circulation. 2005;111:1487-1491.
Factors influencing clinical
presentations & prognosis of AHF
• Blood pressure (peripheral perfusion)
• Fluid overload
• Myocardial ischemia
• Kidney dysfunction
– Each may or may not be present, with
different relative importance, in each patient
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Seru
m c
rea
tin
ine c
han
ge (
mg
/dL
)
Ultrafiltration arm
Standard care arm
UF n = 72 90 69 47 86 71 75 66
SC n = 84 91 75 52 90 75 67 62
Ultrafiltration vs. IV Diuretics in
Patients Hospitalized for ADHF
Dys
pn
ea
sc
ore
7
6
5
4
3
2
1Ultrafiltration Standard care
m = 6.4, CI ± 0.11(n = 80)
m = 6.1, CI ± 0.15(n = 83)
P = 0.35
Ultrafiltration Standard care
We
igh
t lo
ss
(k
g)
6
5
4
3
2
1
0
m = 5.0, CI ± 0.68
kg(n = 83)
m = 3.1, CI ± 0.75 kg
(n = 84)
P = 0.001
1° efficacy endpoints 1° safety end points
P > 0.05 at all times
Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.
Freedom From Heart Failure Rehospitalization in UNLOAD
100
80
60
40
20
0
0 10 20 30 40 50 60 70 80 90
Ultrafiltration arm (16 events)
Standard care arm (28 events)
P = 0.037
Number of patients at risk
Ultrafiltration 88 85 80 77 75 72 70 66 64 45
Standard care 86 83 77 74 66 63 59 58 52 41
Pati
ents
fre
e fr
om
reh
osp
ita
liza
tio
n (
%)
Days
Costanzo MR, et al. J Am Coll Cardiol. 2007;49:675-683.
Gheorghiade, M. et al. Arch Intern Med 2007;167:1998-2005.
Predicted probability of freedom from death and death or heart failure (HF) rehospitalization across levels of sodium after adjusting for
important covariates
• Prognostic marker
– Peripheral hypoperfusion / Kidney dysfunction
– Neurohormonal activation (RAA, NE)
– Poor prognosis
• Treatment problem: loop diuretics
– Intolerance to neurohormonal antagonists
– Resistance to loop diuretics
– Exacerbation of hyponatremia
– ↑ free water clearance further ↓ s[Na]
• Cause of symptoms & poor prognosis (?)
Hyponatraemia in ADHF
Symptoms of Hyponatremia
Depend on– Severity
– Onset (acute vs chronic - < or >48 hours)
– Susceptibility• Age (young and old)
• CNS insult
• Respiratory reserve
• Female gender and hormonal milieu
– Volume status
140
110
120
130
s[Na+] mmol/L
•Normal
•…
•…
•Lethargy, Apathy
•Confusion
•Muscle Cramps
•Agitation
•Anorexia and nausea
•Hallucinations
•Seizures
•Coma
•Depressed reflexes
•Pseudobulbar palsy
•Hypothermia
•Death
135
Vasopressin antagonists
Antagonist Conivaptan Tolvaptan Lixivaptan Sitavaptan Mozavaptan
Receptors V1/V2 V2 V2 V2 V1/V2
V1/V2
selectivity
10:1 29:1 100:1 112:1 10:1
Route Iv, oral Oral Oral Oral Iv, oral
Half-life, hs 14-17 6-8 7-10 14-17 1-8
Indications HypoNa,
ADHF
HypoNa,
ADHF, PKD
HypoNa,
ADHF with
hypoNa
HypoNa,
ADHF,
cirrhosis
SIADH
Modified from Finley, Konstam, Udelson. Circulation 2008;118:410-421
Schrier RW et al. N Engl J Med 2006;355:2099-2112
EVEREST: Secondary Endpoints at Day 1
– 1.7
± 1.8
– 1.0
± 1.8
– 1.8
± 2.0
– 0.9
± 1.9
Both trials
P<0.001
Difference 0.7 kg 0.9 kg
Δ in
Dyspnea (% of pts with
baseline
dyspnea)
Trial A Trial B
Δ in BW (kg)
Tolvaptan Placebo Tolvaptan Placebo
Both trials
P<0.001
37 35 33 31
24 24 2523
1611 14
11
–2 –3 –2 –3
–20
0
20
40
60
80
Tolvaptan Placebo Tolvaptan Placebo(n=894) (n=915) (n=941) (n=914)
Improved
worsened
Markedly better
Moderately better
Minimally better
Worse
Gheorghiade et al. JAMA 2007;297:1332– 43