Levosimendan: The current situation and new prospects | Revista Portuguesa de Cardiologia (English edition)

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Lourenço, José Oliveira-Pinto, Tiago Henriques-Coelho, Adelino F. Leite-Moreira" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Nuno" "apellidos" => "Moreno" "email" => array:1 [ 0 => "numoreno@yahoo.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Marta" "apellidos" => "Tavares-Silva" ] 2 => array:2 [ "nombre" => "André P." "apellidos" => "Lourenço" ] 3 => array:2 [ "nombre" => "José" "apellidos" => "Oliveira-Pinto" ] 4 => array:2 [ "nombre" => "Tiago" "apellidos" => "Henriques-Coelho" ] 5 => array:2 [ "nombre" => "Adelino F." "apellidos" => "Leite-Moreira" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Departamento de Fisiologia e Cirurgia Cardiotorácica, Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Levosimendan: realidade atual e novas perspetivas" ] ] "textoCompleto" => "IntroductionLevosimendan is a novel inotrope that is effective in the treatment of acute heart failure (HF), with clear hemodynamic and clinical benefits. In spite of this, a lack of concrete data on prognosis has limited its application in clinical practice, and the most recent European Society of Cardiology (ESC) guidelines for the treatment of HF in fact downgraded the class of recommendation and level of evidence for its use.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Despite this, levosimendan is a drug with unique pharmacodynamic and pharmacokinetic characteristics that definitely warrants further trials and validation. This review aims to summarize current knowledge on the therapeutic actions of levosimendan in HF, as well as to explore potential off-label uses and future prospects.Mechanism of action and pharmacokineticsLevosimendan is a pyridazinone-dinitrile derivative class III Ca2+ sensitizer that increases the affinity of troponin C (TnC) for Ca2+. It binds to the N-terminal domain of cardiac TnC in a Ca2+ concentration-dependent manner, stabilizing the TnC-Ca2+ complex and inhibiting troponin I.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> It thereby accelerates the actin-myosin crossbridge formation rate and decelerates the dissociation rate. This positive inotropic effect is not due to Ca2+ overload, nor does it occur at the expense of an increase in myocardial O2 demand.<a class="elsevierStyleCrossRefs" href="#bib0020">4–7</a> Its actions depend on intracellular Ca2+ levels and as Ca2+ levels decrease during diastole, levosimendan does not impair ventricular relaxation.<a class="elsevierStyleCrossRefs" href="#bib0015">3,8</a> In fact, it has been shown that levosimendan improves diastolic function.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Beyond increasing the affinity of TnC for Ca2+, levosimendan activates ATP-sensitive K+ channels in the vascular smooth muscle sarcolemma, leading to cell hyperpolarization and vasodilation and reducing peripheral vascular resistance. Levosimendan relaxes both arterial and venous smooth muscle cells, leading to a decrease in both preload and afterload<a class="elsevierStyleCrossRefs" href="#bib0050">10,11</a> and increasing stroke volume and cardiac output (CO).<a class="elsevierStyleCrossRef" href="#bib0060">12</a> It may protect the myocardium from ischemia as it dilates the coronary arteries and improves O2 supply.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> It also opens myocardial mitochondrial ATP-sensitive K+ channels, thereby protecting cardiomyocytes against apoptosis, ischemia-reperfusion injury and oxidative stress.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Additionally, although levosimendan selectively inhibits phosphodiesterase type 3, thus increasing intracellular cyclic adenosine monophosphate (cAMP) and Ca2+, these effects are minor at usual doses.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>Although levosimendan's elimination half-life is only about one hour, its hemodynamic effects last for days. About 5% of the drug is metabolized in the intestine into OR-1855 and subsequently acetylated in the liver to form OR-1896.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> This second metabolite has a half-life of approximately 80 hours and shares most of levosimendan's hemodynamic actions,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> allowing for long-lasting effects after a 24-hour infusion. Acetylation of OR-1855 into OR-1896 shows individual variation; while most Caucasians are slow acetylators, Asians are typically fast acetylators.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> The hemodynamic effects, however, are similar in both groups.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Also, hepatic dysfunction does not warrant a dose adjustment even if the elimination half-life of metabolites is prolonged.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> Importantly, while some inotropes exhibit tolerance after an infusion of several hours, this was not shown for levosimendan. Lastly, withdrawal is not followed by a rebound effect.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Clinical evidenceLevosimendan has been very successful in the management of acute HF syndromes, leading to sustained improvement in hemodynamics and symptoms and reduced levels of B-type natriuretic peptide (BNP) and other neurohumoral markers of HF compared with standard inotropes (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0105">21–24</a> Nevertheless, its long-term effects on cardiac remodeling and cardiovascular mortality remain largely unknown.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The effect of levosimendan compared with beta-adrenergic agonists is still the subject of debate. In the Levosimendan Infusion versus DObutamine (LIDO) trial, levosimendan led to greater improvement in hemodynamics and in secondary and post-hoc analyses it was associated with a lower risk of death at 31 and 180 days,<a class="elsevierStyleCrossRef" href="#bib0125">25</a> whereas in the SURVIVE trial no difference between levosimendan and dobutamine groups was found for survival during long-term follow-up despite evidence for an early reduction in plasma BNP levels with levosimendan.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> However, in both studies, the subgroup of patients receiving concomitant beta-blockers showed lower mortality when treated with levosimendan compared to dobutamine. This was not shown in the BEAT-CHF trial, in which there was no superiority of levosimendan over dobutamine, with only a trend in favor of levosimendan at 24 hours after the start of drug infusion. However, this study had a major bias in patient recruitment.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> A recent meta-analysis demonstrated a long-term survival benefit of levosimendan over dobutamine and placebo in patients requiring inotropic support.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> This study also showed that levosimendan treatment is associated with a reduced hospital length of stay (LOS). Another meta-analysis suggested that in critically ill patients requiring inotropic support, levosimendan improves survival compared to dobutamine.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> This benefit was also shown in subgroups of patients such as those with ischemic HF, post-cardiac surgery and those under concomitant beta-blockade.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Therefore, levosimendan may be considered as an alternative to dobutamine in acutely decompensated HF patients chronically receiving beta-blockers.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> According to the 2012 ESC guidelines on HF, levosimendan is considered in acute HF without severe hypotension when beta-blockade is thought to contribute to hypoperfusion (class IIb, level of evidence C).<a class="elsevierStyleCrossRef" href="#bib0005">1</a>The results from other studies vary. A secondary analysis of the REVIVE trial showed that levosimendan improves symptoms in acutely decompensated HF, at the expense of an increase in adverse side-effects such as hypotension, tachycardia and arrhythmia.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> In the RUSSLAN trial levosimendan was well tolerated and effective in HF after acute myocardial infarction (MI). It was the first inotrope to decrease mortality after MI compared with placebo.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> The LEAF trial also showed that levosimendan is well tolerated and improves regional contractility in post-ischemic myocardium after percutaneous coronary intervention in ST-segment elevation MI complicated by HF.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>A concern regarding levosimendan is cost-effectiveness. A cost-effectiveness analysis of the REVIVE II trial on the use of levosimendan showed shorter hospital LOS and lower cost for the initial hospital admission compared to standard of care.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Side-effectsUnlike standard inotropes such as dobutamine or milrinone, levosimendan does not increase myocardial O2 consumption and is less pro-arrhythmic.<a class="elsevierStyleCrossRefs" href="#bib0025">5–7,35,36</a> Although some studies show increased ventricular tachycardia with levosimendan compared with placebo,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> others do not.<a class="elsevierStyleCrossRefs" href="#bib0130">26,33</a> This discrepancy may be due to different infusion rates. In the PORTLAND trial a 0.1 μg/kg/min infusion rate proved to be clinically effective and safe with no pro-arrhythmic effects.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Two major concerns with the use of levosimendan are hypokalemia and hypotension. The mechanism underlying hypokalemia is still unknown. Hypotension due to vasodilation and increased diuresis is more pronounced when a bolus is administered, and the new ESC guidelines on acute and chronic HF do not recommend bolus administration.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Renal blood flow and glomerular filtration rate are improved both acutely<a class="elsevierStyleCrossRef" href="#bib0190">38</a> and chronically<a class="elsevierStyleCrossRef" href="#bib0195">39</a> by levosimendan more than by dobutamine.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Levosimendan is reno-protective through activation of ATP-sensitive K+ and potent vasodilation, which leads to increased renal perfusion, and possibly through its anti-inflammatory effects.<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a>New prospectsOral and other forms of administrationAs chronic therapy for advanced HF, it has been demonstrated that intermittent levosimendan infusions are safe and improve ventricular function and quality of life.<a class="elsevierStyleCrossRefs" href="#bib0210">42,43</a>Levosimendan is most commonly administered intravenously, but its use via inhalation has also been shown to improve survival and to attenuate inflammation, particularly in acute lung injury.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>Additionally, levosimendan can also be given orally, which is useful for chronic therapy. Chronic oral levosimendan has shown promising results in both animal and human studies,<a class="elsevierStyleCrossRefs" href="#bib0225">45–47</a> preventing post-infarction HF, cardiomyocyte hypertrophy and apoptosis in spontaneously type 2 diabetic Goto-Kakizaki rats<a class="elsevierStyleCrossRef" href="#bib0225">45</a> and improved survival by preventing cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> In the PERSIST trial levosimendan decreased BNP levels and improved quality of life in patients with severe chronic HF, although no symptomatic improvement was shown compared to placebo.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> Oral levosimendan was also shown to reduce filling pressures as assessed by echocardiographic indices and systolic function in chronic HF patients.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Despite expectations it has been difficult to establish an optimal oral dosing regimen, and further research on safety and efficacy in HF patients is warranted. The ongoing LION-HEART (ClinicalTrials.gov Identifier: <a id="intr0005" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01536132">NCT01536132</a>) and LevoRep (ClinicalTrials.gov Identifier: <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01065194">NCT01065194</a>) trials aim to determine the safety and efficacy of intravenous administration of intermittent doses of levosimendan compared to placebo in ambulatory patients with severe chronic HF.Effects of levosimendan in cardiac surgeryPatients undergoing cardiac surgery frequently require inotropic support immediately after cardiopulmonary bypass. The commonly used inotropes enhance myocardial contractility by increasing cAMP concentration, which increases myocardial O2 consumption and further disrupts the supply-demand balance, especially in the failing myocardium.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> Levosimendan may have an advantage due to its distinct mechanism of action, enhancing myocardial performance, and offers a promising therapeutic option during off-pump coronary artery bypass grafting (CABG) in patients with normal or impaired myocardial function.<a class="elsevierStyleCrossRefs" href="#bib0250">50,51</a>Although the results are still controversial, most studies on levosimendan in cardiac surgery show a cardioprotective effect, with a decrease in the incidence of low CO syndromes and reduced cardiac troponin release in the postoperative setting that may reduce postoperative mortality.<a class="elsevierStyleCrossRefs" href="#bib0260">52–54</a>It has also been shown that pretreatment with levosimendan in patients undergoing CABG reduces myocardial injury, tracheal intubation time, requirement for inotropic support, and hospital LOS in the intensive care unit.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Right ventricular dysfunction and pulmonary hypertensionRight ventricular (RV) dysfunction is an indicator of poor prognosis in advanced HF. Several studies have shown that levosimendan improves echocardiographic and hemodynamic markers of RV function when administered to patients with advanced HF and compromised RV function, since it dilates pulmonary vessels and improves biventricular function.<a class="elsevierStyleCrossRefs" href="#bib0280">56,57</a> In experimental models of acute RV dysfunction due to RV MI in pigs, levosimendan improved global hemodynamics and optimized RV ventriculo-vascular coupling (VVC) by the double effect of increased contractility and reduced RV afterload.<a class="elsevierStyleCrossRefs" href="#bib0290">58,59</a> Further, in an experimental setting of acute pulmonary embolism and pulmonary hypertension (PH), levosimendan restored RV VVC due to the combination of pulmonary artery vasodilation and increased RV contractility.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>In case reports levosimendan shows a clear benefit during mitral valve surgery in patients with severe PH by reducing pulmonary artery pressure (PAP) and protecting RV contractility.<a class="elsevierStyleCrossRefs" href="#bib0305">61,62</a> However, in another case report of patients with idiopathic pulmonary arterial hypertension, levosimendan failed to reduce PAP.<a class="elsevierStyleCrossRef" href="#bib0315">63</a>Levosimendan has been shown to be superior to dobutamine in some patient groups: in children with PH undergoing cardiac surgery<a class="elsevierStyleCrossRef" href="#bib0320">64</a> and in patients with biventricular failure levosimendan improves ejection fraction and tricuspid annular plane systolic excursion, decreasing systolic PAP.<a class="elsevierStyleCrossRef" href="#bib0325">65</a>Nevertheless, the role that levosimendan may play in PH with preserved left ventricular function has been little investigated, particularly in chronic PH. It has been reported that levosimendan attenuates pulmonary vascular remodeling due to antiproliferative and anti-inflammatory effects in a rat model of monocrotaline-induced PH.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> Furthermore, in a pilot study enrolling patients with HF due to PH of various etiologies, repeated administration of levosimendan was effective in improving hemodynamics.<a class="elsevierStyleCrossRef" href="#bib0335">67</a> Its role in patients with chronic PH of other etiologies, particularly idiopathic, is unknown, but its positive inotropic effects and vasodilation of the pulmonary arteries suggest beneficial effects.<a class="elsevierStyleCrossRef" href="#bib0340">68</a>ConclusionsAlthough further studies are needed, current clinical evidence suggests that levosimendan is more effective than classical inotropes in improving cardiac mechanical efficiency and reducing congestion in acute HF patients without hypotension. Emerging new off-label uses in conditions such as PH and cardiac surgery may soon expand its clinical applicability. Further studies should be carried out in these patient groups.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres407250" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec383489" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres407249" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec383490" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Mechanism of action and pharmacokinetics" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Clinical evidence" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Side-effects" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "New prospects" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Oral and other forms of administration" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Effects of levosimendan in cardiac surgery" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Right ventricular dysfunction and pulmonary hypertension" ] ] ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 11 => array:2 [ "identificador" => "xack119461" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-08-27" "fechaAceptado" => "2014-05-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec383489" "palabras" => array:3 [ 0 => "Levosimendan" 1 => "Heart failure" 2 => "Inotropes" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec383490" "palabras" => array:3 [ 0 => "Levosimendan" 1 => "Insuficiência cardíaca" 2 => "Inotrópicos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance.In previous randomized studies levosimendan improved hemodynamics and clinical course, but its effect on prognosis is still unclear. This important issue has limited its use. Although primarily used in the management of acute heart failure syndromes, this new inotropic agent may play a role in other clinical conditions.This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "O levosimendan é um derivado da piridazinona-dinitrilo que induz um efeito inotrópico positivo e vasodilatador, exercendo efeitos benéficos sobre o desempenho do miocárdio.Em estudos aleatorizados prévios o levosimendan melhorou a hemodinâmica e a evolução clínica dos doentes, com um significado ainda pouco definido no prognóstico. Esta questão importante tem condicionado o seu uso. Embora seja utilizado principalmente no tratamento da insuficiência cardíaca aguda, este novo agente poderá desempenhar um papel importante em outras condições clínicas.Esta revisão pretende resumir o conhecimento atual sobre o levosimendan e mostrar perspetivas futuras no uso deste fármaco." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "LIDO, Levosimendan Infusion versus DObutamine; RUSSLAN, Randomised stUdy on Safety and effectivenesS of Levosimendan in patients with left ventricular failure due to an Acute myocardial iNfarct; SURVIVE, Survival of patients with acute heart failure in need of intravenous inotropic support; BEAT-CHF, Better Effectiveness After Transition – Heart Failure; LEAF, LEvosimendan in Acute heart Failure following myocardial infarction; REVIVE I and II, Randomized EValuation of Intravenous LeVosimendan Efficacy I and II; Plb, placebo; Dob, dobutamine; NT-proBNP, N-terminal pro-type B natriuretic peptide." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Authors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">NYHA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Dose (mg/kg/min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Duration (h) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Control group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">End point (primary) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Favourable outcome \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dose-ranging \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nieminen et al.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">151 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.05–0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Invasive hemodynamics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LIDO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Follath et al.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">203 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III/IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1–0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dob \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Invasive hemodynamics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemodynamics, survival \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RUSSLAN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moiseyev et al.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">504 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1–0.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Safety \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Survival, clinical evaluation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SURVIVE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mebazaa et al.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1327 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1–0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dob \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NT-proBNP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BEAT-CHF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bergh et al.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III/IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.05–0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dob \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Invasive hemodynamics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemodynamics, NT-proBNP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">LEAF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Husebye et al.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1–0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Echocardiography \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hemodynamics \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">REVIVE (I/II) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Packer et al.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100/600 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.1–0.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plb \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Composite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symptoms, clinical evaluation, 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Henriques-Coelho" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ijcard.2011.05.066" "Revista" => array:6 [ "tituloSerie" => "Int J Cardiol" "fecha" => "2012" "volumen" => "155" "paginaInicial" => "350" "paginaFinal" => "361" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21641060" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack119461" "titulo" => "Acknowledgments" "texto" => "This work was supported by the Portuguese Foundation for Science and Technology (Grants PEst-OE/SAU/UI0051/2014 and EXCL/BIM-MEC/0055/2012, partially funded by FEDER through COMPETE) through the Cardiovascular R&D Unit and by the European Commission (Grant FP7-Health-2010; MEDIA-261409)." 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Review article

Levosimendan: The current situation and new prospects

Levosimendan: realidade atual e novas perspetivas

Nuno Moreno

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numoreno@yahoo.com

Corresponding author.

, Marta Tavares-Silva, André P. Lourenço, José Oliveira-Pinto, Tiago Henriques-Coelho, Adelino F. Leite-Moreira

Departamento de Fisiologia e Cirurgia Cardiotorácica, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Levosimendan is a novel inotrope that is effective in the treatment of acute heart failure &#40;HF&#41;&#44; with clear hemodynamic and clinical benefits&#46; In spite of this&#44; a lack of concrete data on prognosis has limited its application in clinical practice&#44; and the most recent European Society of Cardiology &#40;ESC&#41; guidelines for the treatment of HF in fact downgraded the class of recommendation and level of evidence for its use&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Despite this&#44; levosimendan is a drug with unique pharmacodynamic and pharmacokinetic characteristics that definitely warrants further trials and validation&#46; This review aims to summarize current knowledge on the therapeutic actions of levosimendan in HF&#44; as well as to explore potential off-label uses and future prospects&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Mechanism of action and pharmacokinetics</span><p id="par0015" class="elsevierStylePara elsevierViewall">Levosimendan is a pyridazinone-dinitrile derivative class III Ca<span class="elsevierStyleSup">2&#43;</span> sensitizer that increases the affinity of troponin C &#40;TnC&#41; for Ca<span class="elsevierStyleSup">2&#43;</span>&#46; It binds to the N-terminal domain of cardiac TnC in a Ca<span class="elsevierStyleSup">2&#43;</span> concentration-dependent manner&#44; stabilizing the TnC-Ca<span class="elsevierStyleSup">2&#43;</span> complex and inhibiting troponin I&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> It thereby accelerates the actin-myosin crossbridge formation rate and decelerates the dissociation rate&#46; This positive inotropic effect is not due to Ca<span class="elsevierStyleSup">2&#43;</span> overload&#44; nor does it occur at the expense of an increase in myocardial O<span class="elsevierStyleInf">2</span> demand&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;7</span></a> Its actions depend on intracellular Ca<span class="elsevierStyleSup">2&#43;</span> levels and as Ca<span class="elsevierStyleSup">2&#43;</span> levels decrease during diastole&#44; levosimendan does not impair ventricular relaxation&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;8</span></a> In fact&#44; it has been shown that levosimendan improves diastolic function&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Beyond increasing the affinity of TnC for Ca<span class="elsevierStyleSup">2&#43;</span>&#44; levosimendan activates ATP-sensitive K<span class="elsevierStyleSup">&#43;</span> channels in the vascular smooth muscle sarcolemma&#44; leading to cell hyperpolarization and vasodilation and reducing peripheral vascular resistance&#46; Levosimendan relaxes both arterial and venous smooth muscle cells&#44; leading to a decrease in both preload and afterload<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> and increasing stroke volume and cardiac output &#40;CO&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> It may protect the myocardium from ischemia as it dilates the coronary arteries and improves O<span class="elsevierStyleInf">2</span> supply&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> It also opens myocardial mitochondrial ATP-sensitive K<span class="elsevierStyleSup">&#43;</span> channels&#44; thereby protecting cardiomyocytes against apoptosis&#44; ischemia-reperfusion injury and oxidative stress&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Additionally&#44; although levosimendan selectively inhibits phosphodiesterase type 3&#44; thus increasing intracellular cyclic adenosine monophosphate &#40;cAMP&#41; and Ca<span class="elsevierStyleSup">2&#43;</span>&#44; these effects are minor at usual doses&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Although levosimendan&#39;s elimination half-life is only about one hour&#44; its hemodynamic effects last for days&#46; About 5&#37; of the drug is metabolized in the intestine into OR-1855 and subsequently acetylated in the liver to form OR-1896&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> This second metabolite has a half-life of approximately 80 hours and shares most of levosimendan&#39;s hemodynamic actions&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> allowing for long-lasting effects after a 24-hour infusion&#46; Acetylation of OR-1855 into OR-1896 shows individual variation&#59; while most Caucasians are slow acetylators&#44; Asians are typically fast acetylators&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The hemodynamic effects&#44; however&#44; are similar in both groups&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Also&#44; hepatic dysfunction does not warrant a dose adjustment even if the elimination half-life of metabolites is prolonged&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> Importantly&#44; while some inotropes exhibit tolerance after an infusion of several hours&#44; this was not shown for levosimendan&#46; Lastly&#44; withdrawal is not followed by a rebound effect&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Clinical evidence</span><p id="par0035" class="elsevierStylePara elsevierViewall">Levosimendan has been very successful in the management of acute HF syndromes&#44; leading to sustained improvement in hemodynamics and symptoms and reduced levels of B-type natriuretic peptide &#40;BNP&#41; and other neurohumoral markers of HF compared with standard inotropes &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;24</span></a> Nevertheless&#44; its long-term effects on cardiac remodeling and cardiovascular mortality remain largely unknown&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The effect of levosimendan compared with beta-adrenergic agonists is still the subject of debate&#46; In the Levosimendan Infusion versus DObutamine &#40;LIDO&#41; trial&#44; levosimendan led to greater improvement in hemodynamics and in secondary and post-hoc analyses it was associated with a lower risk of death at 31 and 180 days&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> whereas in the SURVIVE trial no difference between levosimendan and dobutamine groups was found for survival during long-term follow-up despite evidence for an early reduction in plasma BNP levels with levosimendan&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> However&#44; in both studies&#44; the subgroup of patients receiving concomitant beta-blockers showed lower mortality when treated with levosimendan compared to dobutamine&#46; This was not shown in the BEAT-CHF trial&#44; in which there was no superiority of levosimendan over dobutamine&#44; with only a trend in favor of levosimendan at 24 hours after the start of drug infusion&#46; However&#44; this study had a major bias in patient recruitment&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> A recent meta-analysis demonstrated a long-term survival benefit of levosimendan over dobutamine and placebo in patients requiring inotropic support&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> This study also showed that levosimendan treatment is associated with a reduced hospital length of stay &#40;LOS&#41;&#46; Another meta-analysis suggested that in critically ill patients requiring inotropic support&#44; levosimendan improves survival compared to dobutamine&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> This benefit was also shown in subgroups of patients such as those with ischemic HF&#44; post-cardiac surgery and those under concomitant beta-blockade&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Therefore&#44; levosimendan may be considered as an alternative to dobutamine in acutely decompensated HF patients chronically receiving beta-blockers&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> According to the 2012 ESC guidelines on HF&#44; levosimendan is considered in acute HF without severe hypotension when beta-blockade is thought to contribute to hypoperfusion &#40;class IIb&#44; level of evidence C&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The results from other studies vary&#46; A secondary analysis of the REVIVE trial showed that levosimendan improves symptoms in acutely decompensated HF&#44; at the expense of an increase in adverse side-effects such as hypotension&#44; tachycardia and arrhythmia&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In the RUSSLAN trial levosimendan was well tolerated and effective in HF after acute myocardial infarction &#40;MI&#41;&#46; It was the first inotrope to decrease mortality after MI compared with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The LEAF trial also showed that levosimendan is well tolerated and improves regional contractility in post-ischemic myocardium after percutaneous coronary intervention in ST-segment elevation MI complicated by HF&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">A concern regarding levosimendan is cost-effectiveness&#46; A cost-effectiveness analysis of the REVIVE II trial on the use of levosimendan showed shorter hospital LOS and lower cost for the initial hospital admission compared to standard of care&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Side-effects</span><p id="par0055" class="elsevierStylePara elsevierViewall">Unlike standard inotropes such as dobutamine or milrinone&#44; levosimendan does not increase myocardial O<span class="elsevierStyleInf">2</span> consumption and is less pro-arrhythmic&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;7&#44;35&#44;36</span></a> Although some studies show increased ventricular tachycardia with levosimendan compared with placebo&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> others do not&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;33</span></a> This discrepancy may be due to different infusion rates&#46; In the PORTLAND trial a 0&#46;1 &#956;g&#47;kg&#47;min infusion rate proved to be clinically effective and safe with no pro-arrhythmic effects&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Two major concerns with the use of levosimendan are hypokalemia and hypotension&#46; The mechanism underlying hypokalemia is still unknown&#46; Hypotension due to vasodilation and increased diuresis is more pronounced when a bolus is administered&#44; and the new ESC guidelines on acute and chronic HF do not recommend bolus administration&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Renal blood flow and glomerular filtration rate are improved both acutely<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> and chronically<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> by levosimendan more than by dobutamine&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Levosimendan is reno-protective through activation of ATP-sensitive K<span class="elsevierStyleSup">&#43;</span> and potent vasodilation&#44; which leads to increased renal perfusion&#44; and possibly through its anti-inflammatory effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">New prospects</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Oral and other forms of administration</span><p id="par0070" class="elsevierStylePara elsevierViewall">As chronic therapy for advanced HF&#44; it has been demonstrated that intermittent levosimendan infusions are safe and improve ventricular function and quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Levosimendan is most commonly administered intravenously&#44; but its use via inhalation has also been shown to improve survival and to attenuate inflammation&#44; particularly in acute lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Additionally&#44; levosimendan can also be given orally&#44; which is useful for chronic therapy&#46; Chronic oral levosimendan has shown promising results in both animal and human studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#8211;47</span></a> preventing post-infarction HF&#44; cardiomyocyte hypertrophy and apoptosis in spontaneously type 2 diabetic Goto-Kakizaki rats<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> and improved survival by preventing cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl&#47;Rapp rats&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> In the PERSIST trial levosimendan decreased BNP levels and improved quality of life in patients with severe chronic HF&#44; although no symptomatic improvement was shown compared to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Oral levosimendan was also shown to reduce filling pressures as assessed by echocardiographic indices and systolic function in chronic HF patients&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Despite expectations it has been difficult to establish an optimal oral dosing regimen&#44; and further research on safety and efficacy in HF patients is warranted&#46; The ongoing LION-HEART &#40;ClinicalTrials&#46;gov Identifier&#58; <a id="intr0005" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01536132">NCT01536132</a>&#41; and LevoRep &#40;ClinicalTrials&#46;gov Identifier&#58; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01065194">NCT01065194</a>&#41; trials aim to determine the safety and efficacy of intravenous administration of intermittent doses of levosimendan compared to placebo in ambulatory patients with severe chronic HF&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Effects of levosimendan in cardiac surgery</span><p id="par0090" class="elsevierStylePara elsevierViewall">Patients undergoing cardiac surgery frequently require inotropic support immediately after cardiopulmonary bypass&#46; The commonly used inotropes enhance myocardial contractility by increasing cAMP concentration&#44; which increases myocardial O<span class="elsevierStyleInf">2</span> consumption and further disrupts the supply-demand balance&#44; especially in the failing myocardium&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Levosimendan may have an advantage due to its distinct mechanism of action&#44; enhancing myocardial performance&#44; and offers a promising therapeutic option during off-pump coronary artery bypass grafting &#40;CABG&#41; in patients with normal or impaired myocardial function&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Although the results are still controversial&#44; most studies on levosimendan in cardiac surgery show a cardioprotective effect&#44; with a decrease in the incidence of low CO syndromes and reduced cardiac troponin release in the postoperative setting that may reduce postoperative mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#8211;54</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">It has also been shown that pretreatment with levosimendan in patients undergoing CABG reduces myocardial injury&#44; tracheal intubation time&#44; requirement for inotropic support&#44; and hospital LOS in the intensive care unit&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Right ventricular dysfunction and pulmonary hypertension</span><p id="par0105" class="elsevierStylePara elsevierViewall">Right ventricular &#40;RV&#41; dysfunction is an indicator of poor prognosis in advanced HF&#46; Several studies have shown that levosimendan improves echocardiographic and hemodynamic markers of RV function when administered to patients with advanced HF and compromised RV function&#44; since it dilates pulmonary vessels and improves biventricular function&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;57</span></a> In experimental models of acute RV dysfunction due to RV MI in pigs&#44; levosimendan improved global hemodynamics and optimized RV ventriculo-vascular coupling &#40;VVC&#41; by the double effect of increased contractility and reduced RV afterload&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a> Further&#44; in an experimental setting of acute pulmonary embolism and pulmonary hypertension &#40;PH&#41;&#44; levosimendan restored RV VVC due to the combination of pulmonary artery vasodilation and increased RV contractility&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In case reports levosimendan shows a clear benefit during mitral valve surgery in patients with severe PH by reducing pulmonary artery pressure &#40;PAP&#41; and protecting RV contractility&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> However&#44; in another case report of patients with idiopathic pulmonary arterial hypertension&#44; levosimendan failed to reduce PAP&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Levosimendan has been shown to be superior to dobutamine in some patient groups&#58; in children with PH undergoing cardiac surgery<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> and in patients with biventricular failure levosimendan improves ejection fraction and tricuspid annular plane systolic excursion&#44; decreasing systolic PAP&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Nevertheless&#44; the role that levosimendan may play in PH with preserved left ventricular function has been little investigated&#44; particularly in chronic PH&#46; It has been reported that levosimendan attenuates pulmonary vascular remodeling due to antiproliferative and anti-inflammatory effects in a rat model of monocrotaline-induced PH&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> Furthermore&#44; in a pilot study enrolling patients with HF due to PH of various etiologies&#44; repeated administration of levosimendan was effective in improving hemodynamics&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> Its role in patients with chronic PH of other etiologies&#44; particularly idiopathic&#44; is unknown&#44; but its positive inotropic effects and vasodilation of the pulmonary arteries suggest beneficial effects&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">Although further studies are needed&#44; current clinical evidence suggests that levosimendan is more effective than classical inotropes in improving cardiac mechanical efficiency and reducing congestion in acute HF patients without hypotension&#46; Emerging new off-label uses in conditions such as PH and cardiac surgery may soon expand its clinical applicability&#46; Further studies should be carried out in these patient groups&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "New prospects"
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              "identificador" => "sec0030"
              "titulo" => "Oral and other forms of administration"
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              "titulo" => "Effects of levosimendan in cardiac surgery"
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              "titulo" => "Right ventricular dysfunction and pulmonary hypertension"
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          "titulo" => "Conclusions"
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          "titulo" => "Acknowledgments"
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          "titulo" => "References"
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    "fechaRecibido" => "2013-08-27"
    "fechaAceptado" => "2014-05-04"
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            0 => "Levosimendan"
            1 => "Heart failure"
            2 => "Inotropes"
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          "palabras" => array:3 [
            0 => "Levosimendan"
            1 => "Insufici&#234;ncia card&#237;aca"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">In previous randomized studies levosimendan improved hemodynamics and clinical course&#44; but its effect on prognosis is still unclear&#46; This important issue has limited its use&#46; Although primarily used in the management of acute heart failure syndromes&#44; this new inotropic agent may play a role in other clinical conditions&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug&#46;</p>"
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      "pt" => array:2 [
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        "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">O levosimendan &#233; um derivado da piridazinona-dinitrilo que induz um efeito inotr&#243;pico positivo e vasodilatador&#44; exercendo efeitos ben&#233;ficos sobre o desempenho do mioc&#225;rdio&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Em estudos aleatorizados pr&#233;vios o levosimendan melhorou a hemodin&#226;mica e a evolu&#231;&#227;o cl&#237;nica dos doentes&#44; com um significado ainda pouco definido no progn&#243;stico&#46; Esta quest&#227;o importante tem condicionado o seu uso&#46; Embora seja utilizado principalmente no tratamento da insufici&#234;ncia card&#237;aca aguda&#44; este novo agente poder&#225; desempenhar um papel importante em outras condi&#231;&#245;es cl&#237;nicas&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Esta revis&#227;o pretende resumir o conhecimento atual sobre o levosimendan e mostrar perspetivas futuras no uso deste f&#225;rmaco&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">LIDO&#44; Levosimendan Infusion versus DObutamine&#59; RUSSLAN&#44; Randomised stUdy on Safety and effectivenesS of Levosimendan in patients with left ventricular failure due to an Acute myocardial iNfarct&#59; SURVIVE&#44; Survival of patients with acute heart failure in need of intravenous inotropic support&#59; BEAT-CHF&#44; Better Effectiveness After Transition &#8211; Heart Failure&#59; LEAF&#44; LEvosimendan in Acute heart Failure following myocardial infarction&#59; REVIVE I and II&#44; Randomized EValuation of Intravenous LeVosimendan Efficacy I and II&#59; Plb&#44; placebo&#59; Dob&#44; dobutamine&#59; NT-proBNP&#44; N-terminal pro-type B natriuretic peptide&#46;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black">Authors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">NYHA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Dose &#40;mg&#47;kg&#47;min&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Duration &#40;h&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Control group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">End point &#40;primary&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Favourable outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dose-ranging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nieminen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">151&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;05&#8211;0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Invasive hemodynamics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LIDO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Follath et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">203&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&#47;IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dob&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Invasive hemodynamics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemodynamics&#44; survival&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RUSSLAN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moiseyev et al&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">504&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Survival&#44; clinical evaluation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SURVIVE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mebazaa et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2007&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1327&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dob&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NT-proBNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BEAT-CHF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bergh et al&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&#47;IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;05&#8211;0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dob&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Invasive hemodynamics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemodynamics&#44; NT-proBNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LEAF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Husebye et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Echocardiography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hemodynamics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">REVIVE &#40;I&#47;II&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Packer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Plb&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Symptoms&#44; clinical evaluation&#44; NT-proBNP&nbsp;\t\t\t\t\t\t\n
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        "texto" => "<p id="par0135" class="elsevierStylePara elsevierViewall">This work was supported by the <span class="elsevierStyleGrantSponsor" id="gs1">Portuguese Foundation for Science and Technology</span> &#40;Grants <span class="elsevierStyleGrantNumber" refid="gs1">PEst-OE&#47;SAU&#47;UI0051&#47;2014 and EXCL&#47;BIM-MEC&#47;0055&#47;2012</span>&#44; partially funded by <span class="elsevierStyleGrantSponsor" id="gs2">FEDER</span> through COMPETE&#41; through the Cardiovascular R&#38;D Unit and by the <span class="elsevierStyleGrantSponsor" id="gs3">European Commission</span> &#40;Grant <span class="elsevierStyleGrantNumber" refid="gs3">FP7-Health-2010&#59; MEDIA-261409</span>&#41;&#46;</p>"
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2014.05.010

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Year/Month	Html	Pdf	Total

2024 November	6	5	11
2024 October	38	18	56
2024 September	42	24	66
2024 August	50	32	82
2024 July	30	27	57
2024 June	25	23	48
2024 May	31	21	52
2024 April	30	25	55
2024 March	29	19	48
2024 February	30	22	52
2024 January	29	24	53
2023 December	28	23	51
2023 November	29	26	55
2023 October	33	20	53
2023 September	30	14	44
2023 August	57	16	73
2023 July	47	9	56
2023 June	25	12	37
2023 May	40	25	65
2023 April	14	6	20
2023 March	20	22	42
2023 February	23	19	42
2023 January	18	10	28
2022 December	20	14	34
2022 November	30	19	49
2022 October	16	19	35
2022 September	26	20	46
2022 August	24	25	49
2022 July	27	31	58
2022 June	12	15	27
2022 May	21	45	66
2022 April	31	21	52
2022 March	27	22	49
2022 February	22	24	46
2022 January	29	17	46
2021 December	17	28	45
2021 November	25	29	54
2021 October	25	32	57
2021 September	11	28	39
2021 August	32	18	50
2021 July	14	29	43
2021 June	13	24	37
2021 May	28	23	51
2021 April	59	81	140
2021 March	71	12	83
2021 February	82	18	100
2021 January	58	15	73
2020 December	75	9	84
2020 November	33	15	48
2020 October	27	16	43
2020 September	41	5	46
2020 August	31	8	39
2020 July	54	5	59
2020 June	43	5	48
2020 May	58	13	71
2020 April	57	8	65
2020 March	56	8	64
2020 February	93	18	111
2020 January	53	16	69
2019 December	55	7	62
2019 November	53	10	63
2019 October	59	8	67
2019 September	45	10	55
2019 August	33	7	40
2019 July	37	12	49
2019 June	26	10	36
2019 May	35	3	38
2019 April	39	15	54
2019 March	79	11	90
2019 February	66	8	74
2019 January	26	9	35
2018 December	112	17	129
2018 November	356	25	381
2018 October	586	13	599
2018 September	43	13	56
2018 August	79	6	85
2018 July	62	6	68
2018 June	87	12	99
2018 May	168	10	178
2018 April	144	9	153
2018 March	296	15	311
2018 February	145	8	153
2018 January	94	13	107
2017 December	150	13	163
2017 November	93	15	108
2017 October	36	11	47
2017 September	36	11	47
2017 August	42	18	60
2017 July	24	8	32
2017 June	45	25	70
2017 May	48	13	61
2017 April	25	27	52
2017 March	40	16	56
2017 February	54	7	61
2017 January	66	15	81
2016 December	59	7	66
2016 November	54	13	67
2016 October	63	19	82
2016 September	31	28	59
2016 August	21	21	42
2016 July	29	9	38
2016 June	34	17	51
2016 May	41	19	60
2016 April	90	1	91
2016 March	117	27	144
2016 February	54	18	72
2016 January	37	21	58
2015 December	35	30	65
2015 November	38	20	58
2015 October	42	36	78
2015 September	46	19	65
2015 August	54	22	76
2015 July	63	9	72
2015 June	48	11	59
2015 May	58	24	82
2015 April	65	15	80
2015 March	45	17	62
2015 February	72	39	111
2015 January	61	8	69

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