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10 Jahre Levosimendan bei akuter und chronischer Herzinsuffizienz in Österreich: Was haben wir gelernt, wo stehen wir, was bringt die ZukunA
georg.delle-‐[email protected]
Akut dekompensiertes Herzversagen: Therapie
13,9
92,9
10,116,3
36,527,2
0
20
40
60
80
100
ASB-CPAPDiuretikaBeta-BlockerOpioideIV-NitrateIV Inotropika
Nieminen et. al: EuroHeart Failure Survey II; European Heart Journal, 2006Nov;27:2725-36
Perc
ent
9%
38%
34%
13%
6%
AdrenalinDobutaminDopaminLevosimendanNoradrenalin
Akut dekompensiertes Herzversagen: Inotrope Therapie
Nieminen et. al: EuroHeart Failure Survey II; European Heart Journal, 2006Nov;27:2725-36
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IV inotropes used in 31% of AHF paNents with iniNal SBP>=100mmHg compared to 72% use in paNents <100mmHg
86%91%
27%
47%
72%
31%
9% 6%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<100 mmHg (20% AHF) >100 mmHg (80% AHF)
IV Diuretics IV vasodilators IV inotropes SIMDAX
ALARM-HF : Sample =All AHF patients with specified initial SBP 5,009
Follath F et al. Intensive Care Med. 2011;37:619-26
6% 5% 6%
15% 14%16%
0%
10%
20%
All AHF AdCHF De Novo Patient died (SBP >=100) Patient died (SBP <100)
Mortality in paNents with iniNal SBP >= 100 vs <100mmHg: ADCHF vs De Novo AHF (cardiogenic shock excluded)
ALARM-HF: 951(19%) patients with initial SBP < 100mmHg (648 ADCHF, 303 De Novo AHF)
Follath F et al. Intensive Care Med. 2011;37:619-26
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OR-1896
OR-1855
0.05µg/kg/min
0.1 µg/kg/min
Levosimendan
J Clin Pharmacol 2002;42:43-51
Hämodynamische Effekte
Levosimendan acute hemodynamic effects in pts with CHF
CI
SV
SVR
PCWP
Slawsky et al. Circulation 2000;102:2222-27
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Inotropie – auch bei Stunning?
Intracoronary Levosimendan enhances Contractile Function of Stunned Myocardium
Anesth Analg 1997;85:23-9
• anästhesierte Hunde, n=9 • 5x5 min Perioden LAD Occlusion/ Reperfusion • 3 h Reperfusion • Levosimendan 1.5 - 12µg/min über 10min • Ultrasonic segment length transducers
Intracoronary Levosimendan enhances Contractile Function of Stunned Myocardium
Anesth Analg 1997;85:23-9
LAD Region
* p<0.05 vs 3h Reperfusion + p<0.05 vs 1.5µg/min Levo ++ p<0.05 vs 3µg/min Levo § p<0.05 vs drug vehicle
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Levosimendan Improves Stunned Myocardium
• 24 PaNenten mit PCI bei ACS (23 STEMI) • Alle PaNenten TIMI III Fluss • Doppelblind 24µg/kg Levosimendan gegen Placebo (2:1) • Ventrikulographie, PAC; Baseline -‐ 20‘
Sonntag et al; JACC 2004 43, 2177-2182
Levosimendan Improves Stunned Myocardium No of hypokineNc segments
012
34
56
78
9
Baseline 20'
LevoPlacebonu
mbe
rs
P = 0.015
Sonntag et al; JACC 2004 43, 2177-2182
• 10 Pat. mit KHK bei geplanter HK-‐Untersuchung • Links-‐, Rechts-‐ HK, TTE, BlutgasbesNmmung aus
Koronarsinus • Doppler Guidwire (FloWire) • Levosimendan 24-‐µg/kg IV • Messung: Baseline-‐15-‐30 Minuten
Levosimendan and Coronary Hemodynamics
Michaels et al. Circulation 2005;111:1504-1509
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Levosimendan and Coronary Hemodynamics
Michaels et al. Circulation 2005;111:1504-1509
P = 0.04
P = 0.04
Levosimendan und diastolische FunkNon
Effects of Levosimendan on leA ventricular relaxaNon and early filling at maintained preload and aAerload condiNons aAer
AorNc Valve Replacemet for AorNc stenosis
Jörgenensen et al. Circulation. 2008;117:1075-1081
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Unterschied zu anderen Inotropika
Kersten JR et al. Anesth Analg 2000;90:5–11.
Myo
card
ial I
nfar
ct S
ize,
%
of a
rea
at ri
sk
11 ± 2 * 24 ± 2 24 ± 4
Control (n = 8)
Levo (n = 9)
Levo + Glyburide
(n = 10)
Glyburide (n = 10)
60
50
40
30
20
10
0
28 ± 4
*P<0.05 compared with control and withLevo+Glyburide
Dogs with 60 min LAD Occlusion
Myocardial Infarct Size in Dogs
Tritapepe et al. Br J Anaesth 2009; 102: 198–204
Levosimendan pre-‐treatment improves outcomes in paNents undergoing coronary artery bypass graA surgery
24 µg kg-1
Bolus
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Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery
ICU LOS
Tritapepe et al. Br J Anaesth 2009; 102: 198–204
0
4
8
12
16
Placebo Levo
p < 0.0001
hour
s
Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery
p < 0.0001
Tritapepe et al. Br J Anaesth 2009; 102: 198–204
Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery
p < 0.007
Tritapepe et al. Br J Anaesth 2009; 102: 198–204
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Klinische Daten
REVIVE II: MulNcenter Placebo-‐Controlled Trial of Levosimendan on Clinical Status in Acutely Decompensated Heart Failure
Packer M et al. Am Coll Cardiol HF 2013;1:103–11
010203040506070
Improved
Unchanged
Worse
LevosimendanPlacebo
p-value = 0.015
REVIVE II: Multicenter Placebo-Controlled Trial of Levosimendan on Clinical Status in Acutely
Decompensated Heart Failure
Primary Endpoint (6h + 24h + 5d)
%
Packer M et al. Am Coll Cardiol HF 2013;1:103–11
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REVIVE II: Multicenter Placebo-Controlled Trial of Levosimendan on Clinical Status in Acutely
Decompensated Heart Failure
Packer M et al. Am Coll Cardiol HF 2013;1:103–11
BNP-‐levels
p < 0.001
REVIVE II: Multicenter Placebo-Controlled Trial of Levosimendan on Clinical Status in Acutely
Decompensated Heart Failure
Packer M et al. Am Coll Cardiol HF 2013;1:103–11
HR 1.26 (95% CI: 0.83 to 1.91) , p = 0.29
REVIVE II: Multicenter Placebo-Controlled Trial of Levosimendan on Clinical Status in Acutely
Decompensated Heart Failure
Packer M et al. Am Coll Cardiol HF 2013;1:103–11
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The SURVIVE Trial: Comparison of Dobutamine and Levosimendan on Survival in Acute Decompensated Heart
Failure
Mebazaa et al. JAMA. 2007;297:1883-1891
The SURVIVE Trial: Comparison of Dobutamine and Levosimendan on Survival in Acute Decompensated Heart
Failure
Mebazaa et al. JAMA. 2007;297:1883-1891
The SURVIVE Trial: Comparison of Dobutamine and Levosimendan on Survival in Acute Decompensated Heart
Failure BNP
Mebazaa et al. JAMA. 2007;297:1883-1891
P < 0.001
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Plasma B-‐type natriureNc pepNde reducNon predicts long-‐term response to levosimendan therapy in acutely decompensated
chronic heart failure
NYHA III-IV EF < 35% 0.1 µg/kg/min
Farmakis et al. Int J Cardiol 2010;139:75-9
87% sensitivity and 83% specificity.
0
20
40
60
afibhypotension
hypokalemia
headache
extrasystoles
The SURVIVE Trial: Comparison of Dobutamine and Levosimendan on Survival in Acute Decompensated Heart
Failure Adverse events
%
Mebazaa et al. JAMA. 2007;297:1883-1891
p= 0.05 p= 0.02 p= 0.01 p= 0.05
p= 0.48 Levo
Dobutamin
Levosimendan Infusion versus Dobutamine Trial
gleichzeitige ß Blockade
CO
1
1,3
0,8
0,5
0
0,2
0,4
0,6
0,8
1
1,2
1,4
med
ian
chan
ge in
CO
(L/m
in)
Levo Dobutamin
ohne ß Blocker
mit ß Blocker
p=0.01
Follath et al. Lancet 2002;360:196-202
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Levosimendan Infusion versus Dobutamine Trial
gleichzeitige ß Blockade
PCPW
-8-7-6-5-4-3-2-10
med
ian
chan
ge in
PCP
W
(mm
Hg)
Levo Dobutamin
ohne ß Blocker
mit ß Blocker
p=0.03
Follath et al. Lancet 2002;360:196-202
The SURVIVE Trial: Comparison of Dobutamine and Levosimendan on Survival in Acute Decompensated Heart
Failure Patients with ß-blockers
European Journal of Heart Failure Supplements 2007; 6: 95
The effect of levosimendan compared to placebo on mortality
Delaney A et al. Int J Cardiol (2008), doi:10.1016/j.ijcard.2008.08.020
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Delaney A et al. Int J Cardiol (2008), doi:10.1016/j.ijcard.2008.08.020
The effect of levosimendan compared to dobutamine on mortality
0.75 (0.61 to 0.92)
The effect of dobutamine compared to placebo on mortality
Delaney A et al. Int J Cardiol (2008), doi:10.1016/j.ijcard.2008.08.020
Landoni G et al. Crit Care Med 2012
Metaanalyse: Levosimendan
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„Add on“ Wirkung
Russ et al. Critical Care Medicine. 35; 2007:2732-2739
Dtsch Arztebl Int 2012;109:343-‐51.
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Levosimendan…
• Inotropika haben weiterhin Stellenwert bei der Behandlung der akut dekompensierten Herzinsuffizienz
• Levosimendan best-‐untersuchtes Inotropikum, in geeignetem Sesng Vorteile gegenüber Dobutamin
• Eine KombinaNon von Levosimendan mit Katecholaminen ist möglich und kann sinnvoll sein
• Keine Monotherapie bei hypotensiven PaNenten • Bolus?? • Stellenwert beim ACS?