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      Use of Levosimendan in Cardiac Surgery: An Update After the LEVO-CTS, CHEETAH, and LICORN Trials in the Light of Clinical Practice

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          Abstract:

          Levosimendan is a calcium sensitizer and adenosine triphosphate–dependent potassium channel opener, which exerts sustained hemodynamic, symptomatic, and organ-protective effects. It is registered for the treatment of acute heart failure, and when inotropic support is considered appropriate. In the past 15 years, levosimendan has been widely used in clinical practice and has also been tested in clinical trials to stabilize at-risk patients undergoing cardiac surgery. Recently, 3 randomized, placebo-controlled, multicenter studies (LICORN, CHEETAH, and LEVO-CTS) have been published reporting on the perioperative use of levosimendan in patients with compromised cardiac ventricular function. Taken together, many smaller trials conducted in the past suggested beneficial outcomes with levosimendan in perioperative settings. By contrast, the latest 3 studies were neutral or inconclusive. To understand the reasons for such dissimilarity, a group of experts from Austria, Belgium, Finland, France, Germany, Italy, Switzerland, and Russia, including investigators from the 3 most recent studies, met to discuss the study results in the light of both the previous literature and current clinical practice. Despite the fact that the null hypothesis could not be ruled out in the recent multicenter trials, we conclude that levosimendan can still be viewed as a safe and effective inodilator in cardiac surgery.

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          Most cited references46

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          Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan.

          The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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            Levosimendan for Hemodynamic Support after Cardiac Surgery.

            Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery.
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              Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery.

              Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery.
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                Author and article information

                Journal
                J Cardiovasc Pharmacol
                J. Cardiovasc. Pharmacol
                jcvp
                Journal of Cardiovascular Pharmacology
                Journal of Cardiovascular Pharmacology
                0160-2446
                1533-4023
                January 2018
                30 October 2017
                : 71
                : 1
                : 1-9
                Affiliations
                [* ]Dipartimento di Anestesia e Terapie Intensive, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy;
                []Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany;
                []Department of Anesthesiology and Critical Care Medicine, Hôpital Européen Georges Pompidou, Paris, France;
                [§ ]Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
                []Cardiac Anaesthesia, University Hospital, Zurich, Switzerland;
                []Department of Anesthesiology, University Hospital, Ghent, Belgium;
                [** ]Department of Anesthesiology, E. Meshalkin National Medical Research Center, Novosibirsk, Russia;
                [†† ]Klinische Abteilung für Herz-Thorax-Gefäßchirurgische Anästhesie und Intensivmedizin, Medical University of Vienna, Vienna, Austria;
                [‡‡ ]Critical Care Proprietary Products, Orion Pharma, Espoo, Finland; and
                [§§ ]Department of Cardiology S7, Jorvi Hospital, Espoo, Finland.
                Author notes
                Reprints: Piero Pollesello, PhD, Critical Care Proprietary Products, Orion Pharma, P.O. Box 65, 02101 Espoo, Finland (e-mail: piero.pollesello@ 123456orionpharma.com ).
                Article
                JCVP-17-437 00001
                10.1097/FJC.0000000000000551
                5768218
                29076887
                efccab9c-0c34-4e90-8f11-01ee16cff1bc
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 September 2017
                : 13 October 2017
                Categories
                Drugs in the Pipeline
                Custom metadata
                TRUE

                cardiac surgery,clinical trials,levosimendan,systematic review,opinion paper

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