Delaney A, Bradford C, McCaffrey J, et al. Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials

Intensive Care Unit, Royal North Shore Hospital, Pacific Highway, St. Leonards, NSW, 2065, Australia.
International journal of cardiology (Impact Factor: 4.04). 10/2008; 138(3):281-9. DOI: 10.1016/j.ijcard.2008.08.020
Source: PubMed


The objective of this study was to critically review the literature to evaluate whether levosimendan compared to standard therapy, in patients with acute severe heart failure, is associated with improved clinical outcomes.
Medline, EMBASE, and the Cochrane central register of clinical trials were searched. We also searched clinical trials registries, bibliographies of included studies and review articles and contacted the manufacturers of levosimendan to identify unpublished studies. Randomised clinical trials comparing levosimendan to standard therapy or placebo, in adult patients with acute severe heart failure, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics, methodological quality and clinical outcomes, and combined using a fixed-effect meta-analysis.
We identified 19 RCTs enrolling 3650 patients, only two studies fulfilled all of the validity criteria. There was a non-significant reduction in mortality with levosimendan compared with placebo (OR 0.83, 95%CI, 0.62-1.10, p=0.20). Levosimendan was associated with reduced mortality compared to dobutamine (OR 0.75, 95%CI, 0.61-0.92, p=0.005). Levosimendan was associated with improvements in haemodynamic parameters when compared to either placebo or dobutamine.
Levosimendan improved haemodynamic parameters when compared with placebo, without showing evidence of survival benefit. Levosimendan improved both haemodynamics and survival when compared with dobutamine.

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Available from: Anthony Delaney, Oct 28, 2014
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    • "The most common adverse events of levosimendan are hypotension, headache, atrial fibrillation , hypokalemia and tachycardia [56] [57]. Several meta-analyses on the effects of levosimendan on mortality have been published recently [66] [67] [68] [69] [70], and among these, the investigations by Landoni et al. [67] [70] are the most comprehensive. These studies included 45–48 clinical trials with intravenous levosimendan for a total of nearly 6000 patients. "
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    ABSTRACT: The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on 'calcium sensitizers' instead of 'calcium mobilizers'. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the lat-est 30 years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field.
    Full-text · Article · Dec 2015 · International Journal of Cardiology
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    • "Its pharmacological effects include increased cardiac contractility, achieved without increased oxygen consumption, combined with vasodilation [5], which is often considered a suitable pharmacological strategy in acute heart failure when patients are 'wet and cold' [6]. In addition to these haemodynamic clinical improvements [7], levosimendan also enhances renal function [8] [9] and was shown to have positive effects on survival [10] [11] [12] [13] [14]. Furthermore, a greater proportion of days spent alive and outside hospital [11] and shorter hospital stay [14] [15] [16] is achieved for levosimendan-treated patients compared to those who receive dobutamine or placebo. "
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    ABSTRACT: Heart failure places a significant economic burden on health care. Acute heart failure requires hospitalization and often frequent re-hospitalization in expensive wards where vasoactive rescue therapy is often added on top of standard medications. In these lean times, there is a growing need for cost-effective therapeutic options that supply superior support and in addition shorten the length of stay in hospital and reduce re-hospitalization rates. The inodilator levosimendan represents the latest addition to the vasoactive treatments of acute heart failure patients, and it appears to meet these expectations. Our aim was to answer the question whether the treatment efficacy of levosimendan - when selected as therapy for patients hospitalized for acute heart failure - brings savings to hospitals in various European countries representing different economies. We took a conservative approach and selected some a fortiori arguments to simplify the calculations. We selected seven European countries to represent different economies: Italy, Spain, Greece, Germany, Sweden, Finland and Israel. Data on the costs of medications and on the cost per day were collected and fed in a simple algorithm to detect savings. These saving varied from country to country, from a minimum of €0.50 in Germany to a maximum of €354.64 in Sweden. The use of levosimendan as a therapy for patients hospitalized for acute heart failure provides a net saving to hospitals driven by a reduction in the length of hospital stay. This finding is true in each of the countries considered in this study. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Jul 2015 · International journal of cardiology
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    • "The clinical data for levosimendan, which combines positive inotropic, vasodilatory, and cardioprotective effects but does not evoke significant changes in oxygen requirements, were recently reviewed [19]. In the last five years, there have been ten meta-analyses on the clinical data of levosimendan from independent research groups [20] [21] [22] [23] [24] [25] [26] [27] [28] [29], all of which suggest a possible advantage of levosimendan in various clinical settings. "
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    ABSTRACT: Background The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. Methods and results A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. Conclusions The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.
    Full-text · Article · Jun 2014
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