Scompenso cardiaco
Aspetti di novità clinico - farmacologica
Attualità sulla terapia farmacologica
Alessandro Navazio
Reggio Emilia 16 Marzo 2007
Control volume
Diuretic
Reduce mortality
ACEI
ARBs
Betablocker
Aldosterone
antagonist
Digoxin
Treat residual symptoms
Control volume
Diuretic
Reduce mortality
ACEI
ARBs
Betablocker
Aldosterone
antagonist
Digoxin
Treat residual symptoms
Digossina
Digitalis Investigation Group. N Engl J Med. 1997; 336; 525
Digossina
Mortalità
Mortalit
à per peggioramento di IC
Mortalità
Mortalit
à per peggioramento di IC (%)
18
16
14
12
10
8
6
Placebo
4
p=0.06
2
Digossina
0
0
4
8
12
16
20
24
Mesi
Digitalis Investigation Group. N Engl J Med. 1997; 336; 525
28
32
36
40
44
48
52
Morte/ospedalizzazioni per peggioramento di IC (%)
Digossina
Morte / ospedalizzazioni per peggioramento di IC
50
40
30
Placebo
20
10
Digossina
P<0.001
0
0
4
8
12
16
20
24
Mesi
Digitalis Investigation Group. N Engl J Med. 1997; 336; 525
28
32
36
40
44
48
52
Relazione tra rischio relativo di morte e digossina
plasmatica
Hazard Ratio
(Dig contro Placebo)
1.5
donne
1.4
tutti
1.3
Uomini
1.2
1.1
1.04
1.0
0.9
0.8
0.7
0.6
0.5
Non dosabile
< 0.5
0.5
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Concentrazione sierica di digossina ( ng
ng/ml)
/ml)
Adams KF et al. In pubblicazione
Control volume
Diuretic
Reduce mortality
ACEI
ARBs
Betablocker
Aldosterone
antagonist
Digoxin
Treat residual symptoms
↓ RR 26 %
p < 0.0001
Lancet 2000; 355: 1575-1581
Mortalità CVS, IM, o Scompenso Cardiaco nei tre bracci di
Trattamento
0.4
Captopril
Probabilità di eventi
Valsartan
Valsartan + Captopril
0.3
0.2
0.1
Valsartan vs. Captopril: HR = 0.96; P = 0.198
Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369
0
Mesi
0
6
12
18
24
30
36
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Val -HeFT: ARBs Added to ACE Inhibitors
All-Cause Mortality
Death or CHF Hospitalization
% Event free survival
100
100
RRR 13.2%
Valsartan
90
90
Valsartan
80
Placebo
80
70
Placebo
P = 0.80
70
0
6
P = 0.009
60
12
18
Months
24
0
6
12
18
Months
24
Val-HeFT: Combined Morbidity Endpoint ACEI/BetaBlocker Subgroups
50
40
30
Placebo
Valsartan
47.0%
27.7%
36.3%
30.9%
34.8%
20.5% 22.0%
25.5%
20
10
0
ACEI (No) ACEI (Yes) ACEI (No) ACEI (Yes)
BB (No)
BB (No)
BB (Yes) BB (Yes)
(N = 227)
(N = 3038)
(N = 139)
(N = 1606)
CHARM Programme
3 component trials comparing
candesartan to placebo
Primary outcome: All-cause death
CHARM
Alternative
CHARM
Added
CHARM
Preserved
n=2028
n=2548
n=3025
LVEF ≤ 40%
ACE inhibitor
intolerant
LVEF ≤ 40%
ACE inhibitor
treated
LVEF >40%
ACE inhibitor
treated/not treated
Lancet. September 6, 2003
CHARM- Overall:
CV Death and non-CV Death
CV death
HR 0.88 (95% CI 0.790.79-0.97), p=0.012
Adjusted HR 0.87, p=0.006
30
25
Placebo
20
%
Candesartan
15
10
Non-CV death
Nonp=0.45
Candesartan
5
Placebo
0
0
Number at risk
Candesartan
Placebo
1
3803
3796
2
3
3.5
years
Lancet. September 6, 2003
CHARM- Overall:
CV Death or CHF Hospitalisation
50
%
40
Placebo
30
Candesartan
20
10
0
1310 (34.5%)
1150 (30.2%)
HR 0.84 (95% CI 0.770.77-0.91), p<0.0001
Adjusted HR 0.82, p<0.0001
0
1
2
3
3.5 years
Lancet. September 6, 2003
Control volume
Diuretic
Reduce mortality
ACEI
ARBs
Betablocker
Aldosterone
antagonist
Digoxin
Treat residual symptoms
US Carvedilol Study
Survival
Carvedilol
(n=696)
1.0
Survival
CIBIS--II
CIBIS
1.0
0.9
Bisoprolol
0.8
Placebo
(n=398)
0.8
0.7
Risk reduction = 65%
p<0.001
Placebo
Risk reduction = 34%
0.6
0.6
p<0.0001
0
0.5
0 50 100 150 200 250 300 350 400
Days
0
200
400
600
800
Lancet (1999)
Time after inclusion (da ys)
Packer et al (1996)
Mortality %
20
MERIT--HF
MERIT
Placebo
β blockers in
heart failure all-cause mortality
15
Metoprolol CR/XL
10
Risk reduction = 34%
5
p=0.0062
0
0
3
6
9
12 15
Months of follow-up
18
21
The MERIT-HF Study Gr oup (1999)
COPERNICUS
All-cause mortality
100
% Survival
90
80
Carvedilol
70
Placebo
p=0.00013
35% risk reduction
60
0
0
3
6
9
12
Months
15
18
21
Packer, AHA 2000
Control volume
Diuretic
Reduce mortality
ACEI
ARBs
Betablocker
Aldosterone
antagonist
Digoxin
Treat residual symptoms
RALES: All -Cause Mortality
1.00
P < 0.001
% Survival
0.90
0.80
Spironolactone
0.70
0.60
NYHA III
Placebo
IV:Mortalità 30%
0.50
0.40
0
Pitt B et al.
NEJM 1999 ;341 : 709-717
6
12
18
Months
24
30
36
Cumulative Incidence (%)
Ephesus Survival
40
35
P = 0.008
RR = 0.85 (95% CI 0.750.75-0.96
30
25
Placebo
20
Eplerenone
15
10
5
0
0
3
6
9
12
15
18
21
24
27
30
30
36
2
0
0
0
0
0
Months Since Randomisation
No. at Risk
Placebo
3313 3064 2983 2830 2148 1801 1213 709 323 99
Eplerenone 3319 3125 3044 2896 2463 1857 1260 728 336 110
Pitt et al. NEJM April 2003
Death or Hospitalisation from Cardiovascular Causes
Cumulative
Incidence (% )
40
P = 0.002
RR = 0.87 (95% CI 0.790.79-0.95)
30
Placebo
Eplerenone
20
10
0
0
3
6
9
12
15
18
Months
21
24
27
30
30
36
Sudden Death from Cardiac Causes
Cumulative
Incidence (% )
10
P = 0.03
RR = 0.79 (95% CI 0.640.64-0.97)
8
Placebo
Eplerenone
6
4
2
0
0
3
6
9
12
15
18
Months
21
24
27
30
30
36
Pitt et al. NEJM 2003
Mortalità per tutte le cause ad 1 anno per classe NYHA
(%) 50
40
30,0
30
18,2
20
11,2
8,5
10
3,8
0
Classe
NYHA
Adjusted
risk
I
1.00
II
III
IV
1.70
2.92
4.22
[1.26-2.29][2.15-3.96] [2.94-6.05]
Totale
INCHF
The disperate search for additional issues !
Mortality Trials in Systolic Heart Failure: 19861986-2004
ACE inhibitors
CONSENSUS-II
V-HeFT-II
SOLVD-T
SOLVD-P
SAVE
AIRE
TRACE
ATLAS
Vasodilators
V-HeFT
FIRST
PRAISE-I/-II
Aldosterone
antagonists
RALES
EPHESUS
Slide courtesy of G. Francis
β -Blockers
MDC
U.S. Carvedilol
ANZ Carvedilol
MERIT-HF
CIBIS-II
BEST
COPERNICUS
CAPRICORN
ARBs
ELITE-II
Val-HeFT
OPTIMAAL
CHARM
VALIANT
ACE/NEP Inhibitors
OVERTURE
Inotropic agents
PROMISE
VEST
DIG
OPTIME-II
Cytokine antagonists
RENAISSANCE
RECOVER
Endothelin antagonists
ENABLE-2
Sympatholytic agents
MOXCON
Positive
Borderline/Neutral
Negative
Diuretic Drugs Under Development
Natriuretics
– Adenosine type 1 antagonists
Aquaretics
– Vasopressin type 2 antagonists
NEJM ; 16 November 2006
SALT 1 e SALT 2 (US ed Europa) sono due trials randomizzati, in
doppio cieco, controllati con placebo con somministrazione di
Tolvaptan in pz con iponatriemia euvolemica o ipervolemica
(scompenso, cirrosi e SIADH)
End points primari: modifiche della “average daily area under the
curve for the serum sodium concentration” al 4° ed al 30 ° gg
rispetto al basale
Durante la settimana dopo
la sospensione del
Tolvaptan la sodiemia
ritornava ai livelli del
gruppo placebo. Non
variazioni sulla funzione
renale e sullo ionogramma
“It is a clean drug in the
sense that you can
improve hyponatriemia,
but you don’t change
renal function, heart rate
or blood pressure”
In attesa dei risultati dell’EVEREST, studio in pz ospedalizzati per peggioramento di
HF, randomizzati a Tolvaptan 30 mg/die o placebo per 60 gg con end points tempo per
mortalità totale e tempo per mortalità cardiovascolare o ospedalizzazione per HF
OVERTURE
Does inhibition of BNP degradation (when coupled to ACE inhibition) with omapatrilat improve survival?
5,770 patients with EF < 30% in NYHA class IIII- IV
Randomised to enalapril/omapatrilat
Death or CHF Hospitalisation
100
80
60
%
40
Enalapril
Omapatrilat
20
0
0
3
6
9
P = 0.187
12
Months
15
18
21
24
Packer M et al. Circulation 2002
Sympathetic activation
Moxonidine
β1
receptors
+
β2
receptors
+
Xamoterol Bucindolol
α1
receptors
MOXCON: Disegno dello Studio
Trial randomizzato in doppio cieco e placebo controllato
Obiettivo:
Obiettivo: reclutare 4540 pazienti con IC in Classe NYHA
II-- IV
II
End
End-- point primario
primario:: mortalit
mortalità
à per tutte le cause;
Lo studio ha comparato
comparato:: placebo con SR moxonidina
(agonista recettoriale selettivo (I1) per le imidazoline con
effetto centrale simpaticolitico
simpaticolitico))
Coats AJS. Int J Cardiol. 1999; 71: 109
MOXCON: Risultati
Nel gruppo che riceveva SR Moxonidina
Moxonidina,, veniva osservata
una pi
più
ù alta incidenza di mortalit
mortalità
à e ospedalizzazioni
ospedalizzazioni,,
dovuti a peggioramento dell
dell’’ IC e ad IMA
La noradrenalina plasmatica veniva significativamente
ridotta rispetto ai valori basali nel gruppo in trattamento
con SR Moxonidina
Moxonidina,, quando confrontata con placebo
La morte improvvisa era la causa di morte pi
più
ù frequente
frequente,,
questa occorreva pi
più
ù comunemente nel gruppo
randomizzato a SR Moxonidina
Coats AJS. Int J Cardiol. 1999; 71: 109
MOXCON Trial
Placebo
(n = 875)
Moxonidine
(n = 918)
Death
25 (2.8%)
46 (5.0%)
Worsening CHF
35 (4.0%)
47 (5.1%)
Myocardial infarction
4 (0.4%)
6 (0.6%)
Cardiovascular SAE
19 (2.2%)
41 (4.5%)
Combination
83 (9.5%)
140 (15.2%)
Endothelin
Angiotensin II
Norepinephrine
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis
Antagonisti delle Endoteline (ETA/B)
Il trial Enrasentan Cooperative Randomized Evaluation
(ENCOR) ha randomizzato 419 pazienti con IC in classe
NYHA IIII- III ad enrasentan
enrasentan,, enalapril e placebo
Nel gruppo che riceveva enrasentan
enrasentan,, era apprezzabile un
trend verso una maggiore mortalit
mortalità
à e una pi
più
ù alta incidenza
di risultati avversi
Abraham WT. Presentato all’ ACC Scientific Session, Orlando 2001
ENCORE: Effect of Enrasentan
Death or CHF Leading to Hospitalization or Withdrawal
100
Placebo
90
P = 0.007
80
Enrasentan
70
0
50
100
150
200
Days After Randomization
250
Antagonisti delle Endoteline (ETA/B)
Il trials Research on Endothelin Antagonism in
Chronic Heart Failure (REACH) trial ha studiato il
bosentan in pazienti con IC in classe NYHA III-IV
Lo studio è terminato precocemente a causa
dell’incremento delle transaminasi epatiche che
comunque regredivano dopo la sospensione del
trattamento
Packer M et al. Circulation. 1998; 98: I3
Packer M. Presentato all’ ACC Scientific Session, Atlanta 2002
Antagonisti delle Endoteline (ETA/B)
I trials Endothelin Antagonists Cooperative Randomized
Evaluation (ENABLE 1, 2) hanno comparato bosentan con
placebo (con dosi significativamente minori rispetto a
quelle usate nel REACH)
Il trattamento con bosentan
bosentan,, manifestava differenze
statisticamente significative nella frequenza di morti per
eventi cardiaci e nelle ospedalizzazioni per IC, oltre che
nella mortalit
mortalità
à per tutte le cause rispetto a placebo
Un aumento significativo sia della ritenzione di fluidi che di
enzimi epatici era apprezzabile nei pazienti sottoposti a
trattamento con bosentan
Packer M et al. Circulation. 1998; 98: I3
Packer M. Presentato all’ ACC Scientific Session, Atlanta 2002
ENABLE: Effect of Bosentan
Death or CHF Hospitalization
% Event free survival
100
P = 0.90
75
50
Placebo
Bosentan
25
0
0
6
12
18
Months
24
30
Cytokines
Angiotensin II
Norepinephrine
Hypertrophy, apoptosis, ischemia,
arrhythmias, remodeling, fibrosis
Trial sugli Antagonisti delle Citochine
Pazienti con IC in classe NYHA IIII-IV trattati con placebo o con
antagonisti del TNFTNF-α (etanercept e infliximab
infliximab):
):
Randomized Etanercept North American Strategy to Study
Antagonism of Cytokines –RENAISSANCE
RENAISSANCE- Research into Etanercept Antagonism in Ventricular Dysfunction RECOVER-RECOVER
Randomized Etanercept World
World--Wide Evaluation -RENEWAL
RENEWAL-(questo trial ha riunito i dati provenienti da entrambi i trial
precedenti))
precedenti
The Effects of AntiAnti-Tumor Necrosis Factor Therapy Against
Chronic Heart Failure -ATTACH
ATTACH--
Mann D. Presentato all’ Heart Failure Updata, Oslo 2002
Packer M. Presentato all’ Heart Failure Updata, Oslo 2002
Antagonisti delle Citochine: Risultati
RENEWAL ha manifestato un incremento del
rischio di morte nei pazienti che ricevevano
etanercept (OR 1,1), particolarmente in pazienti di
età < 65 anni e IC non ischemica
ATTACH ha mostrato un incremento della
mortalità e delle ospedalizzazioni per IC nel
gruppo randomizzato ad infliximab
Mann D. Presentatoal Heart Failure Updata, Oslo 2002
Packer M. Presentato al Heart Failure Updata, Oslo 2002
RENEWAL: Effect of Etanercept
Death or CHF Hospitalization
% Event free survival
100
80
60
40
Placebo
Etanercept
20
P = 0.33
0
0
12
24
36
48
Weeks
60
72
84
96
ATTACH: Effect of Infliximab
Death or CHF Hospitalization
% Event free survival
30
Infliximab
10 mg/kg
P < 0.05
20
Placebo
10
0
0
40
80
120
Days
160
200
Anemia and Heart Failure
Anemia is common in patients with heart failure
Little was known regarding the relationship of
anemia to heart failure symptoms and exercise
capacity in HF
Little was known regarding the relationship of
anemia to mortality in HF
Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786.
Relationship Between Anemia
and Heart Failure
Precipitating Cause
Anemia
Heart Failure
Precipitating Cause
Role in Progression?
Relationship Between Hemoglobin
and Mortality in Patients
with Advanced Heart Failure
Survival (% )
1
0.8
Hb>14.8
Hb 13.7-14.8
Hb 12.3-13.7
0.6
P=0.00001
Hb<12.3
0.4
0
2
4
6
Months
Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786.
8
10
12
Anemia and Heart Failure
Anemia is common in patients with heart failure,
especially those with advanced disease
Anemia is independently associated with increased
HF symptoms and worse exercise capacity
Anemia is independently associated with increased
mortality
Pilot studies have shown erythropoietin improves
functional capacity and reduces symptoms
Horwich and Fonarow. J Am Coll Cardiol. 2002;39:1780-1786.
(Circulation. 2006;113:2454-2461.)
Inotropic therapy in Advanced Heart
Failure Patients: Myth or Reality?
Natural History of Heart Failure
Pump Failure
Sudden
10
Annual Survival
____
100
75
Survival
Hospitalization
50
1
25
0
NYHA Class: I
.1
II
III
IV
Deceased
Adapted from Bristow MR, in Heart Disease: A Textbook of CV Medicine 7th edition, 2004
Hospitalizations / year
-----
Most common
Mode of death
Effects of Chronic Milrinone Administration
on Mortality in Heart Failure (PROMISE Trial)
Class IV patients (n = 557)
Survival probability
All patients (n = 1088)
1
1
0,9
0,9
0,8
0,8
0,7
Placebo
0,7
Placebo
0,6
0,6
Milrinone
0,5
0,5
0,4
0,4
0,3
0,3
Mortality 28% higher with
milrinone vs. placebo (p=0.038)
0,2
Milrinone
Mortality 53% higher with
milrinone vs. placebo (p=0.006)
0,2
0,1
0,1
0
3
6
9
12
15
18
21
0
3
6
9
12
15
18
21
Packer et al. NEJM 1991;325:1468
Vesnarinone is Associated with a Dose-dependent
Increase in Mortality and Improvement in Quality of
Life in Patients with Severe CHF
All-cause Mortality
% of patients
25
20
2
P=0.02
21
22.9
18.9
15
10
5
0
Change from baseline
30
Quality of Life Score
0
Placebo
30-mg Vesnarinone
60-mg Vesnarinone
-2
-4
-6
-8
-10
***
***
-12
Placebo 30-mg
60-mg
Vesnarinone
Base- 8 wk
line
16 wk 26 wk
Cohn et al, NEJM 1998;339:1810
Positive Inotropic Therapy:
2005 ESC Guidelines on CHF
Oral inotropic agents
– Repeated or prolonged treatment increases
mortality and is not recommended in CHF
Swedberg et al., Eur Heart J. 2005;26:1115-40
Long-term Treatment with Inotropic
Agents: Potential “new data”
Dose dependency
P.O. Enoximone
Enoximone:: Summary of Deaths and Withdrawals in PlaceboPlacebo-
Controlled Trials,
High vs Low Dose
Protocol
1° Endpoint Duration
Dose
(mg tid)
Deaths
Enox Placebo
Withdrawals
Enox Placebo
100-150
100
100
6/50
0/52
16/47
7/54
3/53
3/57
25/150 10/163
(17%) (6%)
18/50
4/47
22/53
44/150
(29%)
p = .004
13/52
3/54
11/57
27/163
(17%)
50
50
25/50
4/58
3/57
11/28
8/22
2/70
4/35
17/156 15/114
(11%) (13%)
p = NS
16/58
5/28
20/70
41/156
(26%)
p=
11/57
0/22
11/35
22/114
(19%)
NS
High Dose (≥ 3 mg/kg/d)
093-025 (US, multictr)
UK-29 (UK, multictr)
093-024 (US, multictr)
Subtotals
Exercise 16 wks
Survival 1-86 wks
Exercise 12 wks
p = .01
Low Dose (<3 mg/kg/d)
093-024 (US, multictr)
UK-29 (UK, multctr)
093-042 (US, multictr)
Subtotals
Exercise
Survival
Exercise
12 wks
1-86 wks
12 wks
Deaths: Test for interaction Low vs. High Dose, p = .013
Lowes BD, et al. J Card Fail. 2005;11:659-69.
Long-term Treatment with Inotropic
Agents: Potential “new data”
Dose dependency
Concomitant treatment
– AICD
– Beta
Beta--blockers
Overview of Enoximone
Phase III Program
Target Indication:
Inotropic Support for Advanced CHF
Patient population: Class III/IV patients; EF≤ 30%, progressive or persistent CHF course
off I.V. inotropes, > 1
hosp. or 2 ER visits in
last 12 mos.
+ beta-blockers unless
contraindicated
dependent
on I.V.
inotropes
EMOTE
My-022
(wean from I.V.
inotropes)
N=200
26 weeks
ESSENTIAL
My-021
My-026
N≈900
N≈900
N.& S. America
E. & W. Europe
(mortality + CV hospitalization,
submax ex, Sx; mortality (safety)
52+ weeks;
Survival
Analysis
N=1800
intolerant to
β -blockers
EMPOWER
My-023
( ↑ tolerability
of β -blockade)
N = 150
36 weeks
marked exercise
intolerance
on β -blockers
EXALT
My-030
(Exerci se
Tolerance)
N = 120
16 weeks
EMOTE: Time to Event Analyses
Primary outcome variable: Time to death or re-initiation of i.v. inotrope therapy
(from day of scheduled wean); all p values are nominal, HR = Hazard Ratio
1.00
Enoximone
0-60 days
HR 0.617
(0.429,0.887)
p=0.009
Survival
0.75
0.50
0-90 days
HR 0.691
(0.493,0.968)
p=0.031
Placebo
0-30 days
HR 0.699
(0.457,1.070)
p=0.098
0.25
0.00
0
Pts at risk Enox: 101
Pbo: 100
25
50
60
50
46
30
75
100
125
Time (Days)
34
24
150
175
200
21
17
Overview of Enoximone
Phase III Program
Target Indication:
Inotropic Support for Advanced CHF
Patient population: Class III/IV patients; EF≤ 30%, progressive or persistent CHF course
off I.V. inotropes, > 1
hosp. or 2 ER visits in
last 12 mos.
+ beta-blockers unless
contraindicated
dependent
on I.V.
inotropes
EMOTE
My-022
(wean from I.V.
inotropes)
N=200
26 weeks
ESSENTIAL
My-021
My-026
N≈900
N≈900
N.& S. America
E. & W. Europe
(mortality + CV hospitalization,
submax ex, Sx; mortality (safety)
52+ weeks;
Survival
Analysis
N=1800
intolerant to
β -blockers
EMPOWER
My-023
( ↑ tolerability
of β -blockade)
N = 150
36 weeks
marked exercise
intolerance
on β -blockers
EXALT
My-030
(Exerci se
Tolerance)
N = 120
16 weeks
ESSENTIAL Trials: Time to All-Cause Mortality
1.00
Survival
0.75
Hazard ratio = 0.97
(0.80, 1.17)
p = 0.73
0.50
0.25
Placebo: 210 deaths/928 subjects
Enoximone: 201 deaths/926 subjects
0.00
0
4
8
12
16
20
24
28
32
Time (Months)
Metra et al., presented at ESC 2005
Survival and Freedom from
CV Hospitalization
ESSENTIAL Trials: Time to All-Cause Mortality
or CV Hospitalization
1.00
Hazard ratio = 0.98
(0.86, 1.11)
p = 0.71
0.75
0.50
0.25
Placebo: 465 events/928 subjects
Enoximone: 458 events/926 subjects
0.00
0
4
8
12
16
20
24
28
32
Time (Months)
Metra et al., presented at ESC 2005
Positive Inotropic Therapy:
2005 ESC Guidelines on CHF
Oral inotropic agents
I.V. inotropic agents
Swedberg et al., Eur Heart J. 2005;26:1115-40
Increased Risk of Death Associated with Continuous (mean 14
days) Dobutamine Infusion in Patients with Advanced HF:
Insights from the FIRST
Adjusted survival curves
1,0
1,0
0,9
0,8
0,9
0,8
Fraction survived
Fraction survived
Unadjusted survival curves
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
controls
dobutamine
0,7
0,6
0,5
0,4
0,3
0,2
0,1
6-month mortality:
64%, dobutamine vs. 35%, controls
Risk ratio with dobutamine, 2.189
p=0.0001
0,0
0
0,25
0,5
0,75
1
1,25
Follow up in years
1,5
0
0,25
0,5
0,75
1
1,25
1,5
Follow up in years
Survival rates adjusted for age, sex, randomization to epoprostenol, LV EF, other drugs,
cause, NYHA class, 6-mins walk
O’Connor et al., Am Heart J 1999; 138:78
Effects of Dobutamine on Mortality
in Placebo-Controlled Trials
Thackray, Easthaugh, Freemantle, Cleland. Eur J Heart Fail 2002; 4:515
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.
LIDO: Primary Efficacy Endpoint
Proportion of patients showing a significant
haemodynamic improvement after 24 hours
infusion:
↑ CI ≥ 30% over baseline and
↓ PCWP ≥ 25% (and at least 4 mmHg) below
baseline and
– Not needing rescue therapy with other positive
inotropic agents or vasodilators
–
–
LIDO Trial: allall-cause mortality
Proportion of patients alive
1.00
levosimendan
0.90
0.80
0.70
dobutamine
0.60
Prospective 30 days: Hazard ratio 0.42 (95% CI 0.18-0.98; p=0.045)
Retrospective 180 days: Hazard ratio 0.57 (95% CI 0.34-0.95; p=0.029)
0.50
0
30
60
90
120
150
180
Days
Follath et al. 360:196 Lancet 2002
Levosimendan
36 pazienti in classeNYHA IV refrattari all’infusione continua per
24h di dobutamina (10µ
µg/Kg/min)
divisi in 2 gruppi
Gruppo I (n=18) trattati con dobutamina a 10 µg/kg/min per ≥
48h, seguiti da somministrazioni intermittenti settimanali di 8h.
Gruppo II (n=18) trattati con un bolo di levosimendan a 6 µg/kg,
seguito da infusione continua a 0,2 µg/kg/min per 24h, trattati
poi con infusione per 24h a 0,2 µg/kg/min ogni 2 settimane.
RISULTATI
L’aggiunta di levosimendan ha dimostrato di stabilizzare meglio i
pazienti, migliorare le condizioni cliniche ed emodinamiche ed
aumentare significativamente la sopravvivenza a 45 giorni
la sopravvivenza media nel gruppo I (dobutamina) è stata 19±3
giorni con 1 solo superstite a 45 giorni
la sopravvivenza media nel gruppo II
(dobutamina+levosimendan) è stata 36±3 giorni con 11 su 18
pazienti vivi per più di 45 giorni
61%
6%
Parissis JT et al, Heart 2006, in press
Natural History of Heart Failure:
Who Needs an Inotropic Support?
Sudden
Pump Failure
10
Annual Survival
100
75
Survival
Hospitalization
50
1
25
0
NYHA Class: I
CHF Stage:1
II
III
2
.1
Deceased
IV
3
Hospitalizations / year
Most common
Mode of death
4
Need of inotropic support
Adapted from Bristow MR, in Heart Disease: A Textbook of CV Medicine 7th edition, 2004
The Patient Who Needs an Inotropic Support:
How to identify?
Nohria, A. et al. JAMA 2002;287:628-640.
Copyright restrictions may apply.
Control volume
Diuretic
Reduce mortality
ACE I
ARBs
Betablocker
ICD
Aldosterone
antagonist
CRT
Digoxin
Treat residual symptoms
The Donkey Analogy
Ventricular dysfunction limits a patient's ability to perform the
the
routine activities of daily living…
living…
Digitalis Compounds
Like the carrot placed in front of the donkey
Diuretics, ACE I, ARBs
Reduce the number of sacks on the wagon
ß-Blockers
Limit the donkey’s speed, thus saving energy
Cardiac Resynchronization Therapy
Increase the donkey’s (heart) efficiency
Heart failure management will not
become easier in the future
• To test the hypothesis that nitric oxide enhancing
A
therapy
with a fixed-dose combination of isosorbide
dinitrate and hydralazine (ISDN/HYD) may provide
additional benefit to African-American patients with
advanced heart failure
Study Design
DoubleDouble-blind, placeboplacebo-controlled trial
1,050 African American patients with New York Heart
Association Class III or IV heart failure and dilated
ventricles
Randomized to receive the fixedfixed-dose ISDN/HYD (20
mg/37.5 mg) or placebo in addition to current standard
heart failure treatments
Designed for 18 months, but discontinued early due to
a significant survival benefit at median followfollow-up of 10
months
Commentary
Blood pressure effects (absolute difference up to
3.1-3.2 mmHg) in a largely preserved BP group.
Discrepancy between NYHA III-IV classification
and annualized mortality of 8.5% in placebo
group.
Mechanism of isosorbide dinitrate and nitric as
oxide donor in vivo – needs validation
Ethnicity differences
Anti -Aldosterone and ARBs:
Which One is the Third Pillar of Heart
Failure Therapy?
ACC/AHA
Heart failure
Guidelines,
August 2005
after RALES: RX
Juurlink et al. NEJM 2004;351:543
after RALES:Death
Juurlink et al. NEJM 2004;351:543
McMurray et al. Circulation 2004;110:3281
McMurray et al. Circulation 2004;110:3281
Carvedilol Reverses LV Remodelling to a
Greater Extent than Metoprolol
16
LV EDV
-5
14
***
12
10
8
LV ESV
0
P = 0.038
***
-10
ml/m 2
Absolute change from baseline
LVEF units (%)
LV Ejection Fraction
-15
-20
6
-25
4
-30
2
-35
0
**P < 0.01; ***P < 0.001
vs baseline
**
***
***
***
-40
Metoprolol
Carvedilol
Metra M et al. Circulation 2000
Percent Changes from Baseline in
Haemodynamic Variables After Long-term
Treatment with Metoprolol or Carvedilol
Peak exercise
% Change vs Baseline
Rest
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
Metoprolol
Carvedilol
*
***
* P < 0.05
** P < 0.01
*** P < 0.001
***
***
*
*
******
***
***
***
***
***
*
HR MAP CI SVI SVR PWP
**
***
**
HR MAP CI SVI SVR PWP
Metra M et al. Circulation 2000
Peak VO2
Six min walk
MLHF
NYHA class
Absolute Change from Baseline
(ml/kg/
ml/kg/min
min))
Absolute Changes in Exercise Tolerance and
Symptoms After Long-term Treatment with
Metoprolol or Carvedilol
100
0
0
2
**
-2
0.5
*
Meters
1
80
60
***
***
40
0
-0.5
-1
Metoprolol
-0.3
-4
20
Score
1.5
-6
-0.6
-8
-10
-12
***
***
-0.9
***
***
-1.2
-14
0
-16
-1.5
Carvedilol
MLHF = Minnesota Living with Heart Failure
Metra M et al. Circulation 2000
Meta-analysis of Direct Comparison Trials
with Metoprolol and Carvedilol in CHF
+12
P = 0.009
LV Ejection
Fraction (%)
+10
+8
+6
+4
+2
0
Metoprolol
(n = 123)
Carvedilol
(n = 125)
Packer M et al. Am Heart J 2001
LV EF Response Impacts on Mortality and
Hospitalisations
Freedom from cardiac death
Fraction of patients
0.80
∆ LV EF < 15
1.00
95%
77%
0.60
0.40
0.20
Fraction of patients
∆ LV EF > 15
1.00
Freedom from cardiac
death or hospitalisation
∆ LV EF > 15
0.80
79%
0.60
59%
∆ LV EF < 15
0.40
0.20
P < 0.001
P < 0.001
0
0.00
0
6
12
18
Time (months
( months))
24
0
6
12
18
Time (months
( months))
24
Metra M et al. Am Heart J 2003
Results of Direct Comparison Trials with
Metoprolol and Carvedilol in CHF
LV Ejection Fraction (%)
LV End-Diastolic Volume
+12
+12
P = 0.04
+10
+6
+8
0
ml/m 2
%
P = 0.009
+6
-6
+4
-12
+2
-18
0
-24
Metoprolol Carvedilol
Metoprolol Carvedilol
Am Heart J 2001
PRIME
PRIME 88 SETTIMANE:
SETTIMANE:
MORTALIT
À, OSPEDALIZZAZIONE
MORTALITÀ,
OSPEDALIZZAZIONE E
E
ABBANDONO
ABBANDONO DELLA
DELLA TERAPIA
TERAPIA
% pazienti con eventi
30
Placebo
20
10
Carvedilolo
.
0
0
2
4
6
8
Settimane dalla randomizzazione
(Pazienti a più elevato rischio)
Krum, 2002
.
(mortalità + ospedalizzazione + abbandoni)
% pazienti con eventi
II BENEFICI
BENEFICI DEL
DEL CARVEDILOLO
CARVEDILOLO SONO
SONO
PRECOCI
E
DOSE-DIPENDENTI
PRECOCI
E
DOSE-DIPENDENTI
30
Placebo
20
10
Carvedilolo
0
0
2
4
6
8
Settimane dalla randomizzazione
3,125 mg 6,25 mg 12,5 mg
BID
BID
BID
25 mg
BID
Drugs That Should Be Avoided
in Patients with CHF
Calcium channel blockers
Antiarrhythmic drugs
Nonsteroidal anti-inflammatory drugs
(including COX-2 inhibitors)
Centrally acting sympatholytics
TNF antagonists
Endothelin antagonists
Heart Failure Rages…..