© 2006 European Society of Cardiology
Levosimendan therapy in decompensated chronic heart failure: Favourable haemodynamic and neurohormonal effects but for how long?
Second Dept. of Cardiology, University of Athens Medical School, Attikon University Hospital Athens, Greece
* Corresponding author. Aftokratoros Irakliou 17 Str, Maroussi, Athens 15122, Greece. Tel.: +30 210 612 3720. E-mail address: jparissis{at}yahoo.com
Received August 21, 2005; Dear Editor,
Levosimendan, a novel positive inotropic agent that acts by enhancing calcium sensitivity of cardiac myofilaments, has been shown to have a favourable effect on central haemodynamics and neurohormonal and inflammatory activation [1,2]. More specifically, levosimendan has been shown to reduce serum levels of B-type natriuretic peptides (BNP or NT-proBNP), C-reactive protein (CRP) and the pro-inflammatory cytokine interleukin 6 (IL-6), but it increases interleukin 10. Interestingly, the reduction in BNP is correlated with the amelioration of haemodynamic parameters [1,2], and has been shown to have prognostic significance [1]. However, the duration of these effects had not yet been properly evaluated.
In their recent work, Moertl et al. administered levosimendan or prostaglandin E1 (PGE1) in patients with decompensated heart failure and assessed the effects on haemodynamic parameters and BNP [3]. Both drugs increased cardiac index and reduced pulmonary capillary wedge pressure and pulmonary artery pressure 24 and 48 h after administration. Moreover, BNP was also significantly reduced at 24 and 48 h. However, although this positive neurohormonal outcome was sustained at 1 week in the PGE1-treated group, it was not maintained in the levosimendan-treated patients.
Levosimendan has an elimination half-life of 1 h. However, the half-lives of its two circulating metabolites, OR-1855 and its acetylated form OR-1896, range between 70 and 80 h. These metabolites reach their maximum serum concentration 2 days after completion of a 24-h intravenous levosimendan infusion [4]. Since the OR-1896 metabolite is haemodynamically active, with properties similar to those of levosimendan, the haemodynamic effects of levosimendan should theoretically persist for at least 7 to 10 days following the intravenous infusion.
In our experience with serial levosimendan administrations in patients with advanced heart failure, the drug induced a favourable effect on left ventricular performance, BNP, CRP and IL-6, which appeared to be sustained for 2-3 weeks. This duration of response allowed us to schedule serial drug administrations every 20 days before decompensation occurred (unpublished data).
In view of these data, it seems that clinical trials to address the issue of repeat levosimendan administration are required to provide evidence to guide the timing of drug administration in patients with advanced heart failure.
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- Parissis J.T., Panou F., Farmakis D., et al. Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure. Am J Cardiol (2005) 96:423–426.[CrossRef][Web of Science][Medline]
- Kyrzopoulos S., Adamopoulos S., Parissis J.T., et al. Levosimendan reduces plasma brain natriuretic peptide and interleukin-6 and improves central hemodynamics in New York Heart Association class III/IV heart failure patients. Int J Cardiol (2005) 99:409–413.[CrossRef][Web of Science][Medline]
- Moertl D., Berger R., Huelsmann M., Bojic A., Pacher R. Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure. Eur J Heart Fail (2005) 7:1156–1163.
[Abstract/Free Full Text] - Poder P., Eha J., Sundberg S., et al. Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study. J Clin Pharmacol (2004) 44:1143–1150.
[Abstract/Free Full Text]
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