CLINICAL STUDY: LEFT VENTRICULAR ASSIST DEVICE
Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure
Markku S. Nieminen, MD, FACC, FESC*,
Juha Akkila, MSc ,
Gerd Hasenfuss, MD, FACC ,
Franz X. Kleber, MD, PhD ,
Lasse A. Lehtonen, MD, PhD,
Veselin Mitrovic, MD||,
Olof Nyquist, MD, PhD¶,
Willem J. Remme, MD, PhD, FACC# on behalf of the Study Group**
* Helsinki University, Helsinki, Finland
Orion Pharma Research, Espoo, Finland
University of Göttingen, Göttingen, Germany
Humboldt University, Berlin, Germany
|| Kerckhoff Clinic, Bad-Neuheim, Germany
¶ Huddinge Hospital, Stockholm, Sweden
# University Hospital, Utrecht, Netherlands
Manuscript received October 8, 1999;
revised manuscript received June 14, 2000,
accepted July 25, 2000.
Reprint requests and correspondence: Professor Markku S. Nieminen, Chief, Division of Cardiology, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.
markku.nieminen{at}hus.fi
OBJECTIVES
We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin.
BACKGROUND
Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure.
METHODS
A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 µg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 µg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 µg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a  15% increase in stroke volume (SV) at 23 h to 24 h; 2) a 25% decrease in pulmonary capillary wedge pressure (PCWP) (and 4 mm Hg) at 23 h to 24 h; 3) a 40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a 50% decrease in PCWP during two consecutive measurements.
RESULTS
The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p  0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages.
CONCLUSIONS
Dosing of levosimendan with a 10-min bolus of 6 to 24 µg/kg followed by an infusion of 0.05 to 0.2 µg/kg/min is well tolerated and leads to favorable hemodynamic effects.
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Abbreviations and Acronyms
| | CO | = cardiac output | | CHF | = congestive heart failure | | ECG | = electrocardiogram | | HR | = heart rate | | MBP | = mean blood pressure | | NYHA | = New York Heart Association | | PAP | = pulmonary artery pressure | | PCWP | = pulmonary capillary wedge pressures | | RAP | = right atrial pressure | | SV | = stroke volume |
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10(2):
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|
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32(4):
629 - 633.
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|
|
|
|
|
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|
A. Mebazaa, M. S. Nieminen, M. Packer, A. Cohen-Solal, F. X. Kleber, S. J. Pocock, R. Thakkar, R. J. Padley, P. Poder, M. Kivikko, et al.
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297(17):
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|
|
|
|
|
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|
|
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|
|
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|
|
|
|
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|
|
|
|
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|
|
|
|
|
|
|
J. A. Alhashemi
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November 1, 2005;
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|
|
|
|
|
|
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November 1, 2005;
39(11):
1888 - 1896.
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|
|
|
|
|
|
|
J. Dernellis and M. Panaretou
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
A. D. Michaels, B. McKeown, M. Kostal, K. T. Vakharia, M. V. Jordan, I. L. Gerber, E. Foster, and K. Chatterjee
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111(12):
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|
|
|
|
|
|
|
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26(4):
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[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Tachibana, H.-J. Cheng, T. Ukai, A. Igawa, Z.-S. Zhang, W. C. Little, and C.-P. Cheng
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Am J Physiol Heart Circ Physiol,
February 1, 2005;
288(2):
H914 - H922.
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[PDF]
|
|
|
|
|
|
|
P. Poder, J. Eha, S. Sundberg, S. Antila, M. Heinpalu, I. Loogna, U. Planken, S. Rantanen, and L. Lehtonen
Pharmacodynamics and Pharmacokinetics of Oral Levosimendan and Its Metabolites in Patients With Severe Congestive Heart Failure: A Dosing Interval Study
J. Clin. Pharmacol.,
October 1, 2004;
44(10):
1143 - 1150.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Sonntag, S. Sundberg, L. A. Lehtonen, and F. X. Kleber
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J. Am. Coll. Cardiol.,
June 16, 2004;
43(12):
2177 - 2182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. F. McBride and C. M. White
Levosimendan: Implications for Clinicians
J. Clin. Pharmacol.,
October 1, 2003;
43(10):
1071 - 1081.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Vroom
Epidemiology and Pharmacotherapy of Acute Heart Failure
Seminars in Cardiothoracic and Vascular Anesthesia,
March 1, 2003;
7(1):
3 - 12.
[PDF]
|
|
|
|
|
|
|
M. Kivikko, L. Lehtonen, W. S. Colucci, and on Behalf of the Study Investigators
Sustained Hemodynamic Effects of Intravenous Levosimendan
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January 7, 2003;
107(1):
81 - 86.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Greenberg, C. Borghi, and S. Perrone
Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan?
Eur J Heart Fail,
January 1, 2003;
5(1):
13 - 21.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.G.F. Cleland, A. Takala, M. Apajasalo, N. Zethraeus, and G. Kobelt
Intravenous levosimendan treatment is cost-effective compared with dobutamine in severe low-output heart failure: an analysis based on the international LIDO trial
Eur J Heart Fail,
January 1, 2003;
5(1):
101 - 108.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.J.S. Coats
Positive inotropy for acute heart failure complicating myocardial infarction
Eur. Heart J.,
September 2, 2002;
23(18):
1405 - 1406.
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. S. Moiseyev, P. Poder, N. Andrejevs, M. Y. Ruda, A. P. Golikov, L. B. Lazebnik, Z. D. Kobalava, L. A. Lehtonen, T. Laine, M. S. Nieminen, et al.
Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN)
Eur. Heart J.,
September 2, 2002;
23(18):
1422 - 1432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Poole-Wilson
Treatment of Acute Heart Failure: Out With the Old, In With the New
JAMA,
March 27, 2002;
287(12):
1578 - 1580.
[Full Text]
[PDF]
|
|
|
|
