Heart Fail Rev (2009) 14:265–275 DOI 10.1007/s10741-008-9128-4
Levosimendan: from basic science to clinical practice John T. Parissis Æ Pinelopi Rafouli-Stergiou Æ Ioannis Paraskevaidis Æ Alexandre Mebazaa
Published online: 20 December 2008 Ó Springer Science+Business Media, LLC 2008
Abstract Levosimendan is a new cardiac enhancer that exerts positive inotropic effects on the failing heart mediated by calcium sensitization of contractile proteins as well as peripheral vasodilatory effects mediated by opening of ATP-sensitive potassium channels in vascular smoothmuscle cells. Levosimendan is the most well-studied calcium sensitizer in the real clinical practice, producing greater hemodynamic and symptomatic improvement in patients with acute heart failure syndromes (AHFS) than those with traditional inotropes. Immunomodulatory and anti-apoptotic properties of levosimendan may be an additional biologic mechanism that prevents further cytotoxic and hemodynamic consequences of abnormal immune and neurohormonal responses in AHFS. Recent mortality trials showed that levosimendan does not improve short- and long-term prognosis in AHFS in comparison to dobutamine or placebo. However, in patients with a previous history of CHF and on beta-blocker on admission, levosimendan seems to have a beneficial effect on short-term mortality. According to the recent guidelines of the European Society of Cardiology, levosimendan is indicated in patients with symptomatic low cardiac output HF secondary to cardiac systolic dysfunction without severe hypotension (Class IIa, Level of Evidence B).
J. T. Parissis (&) P. Rafouli-Stergiou I. Paraskevaidis Heart Failure Clinic and Second Cardiology Department, Attikon University Hospital, Navarinou 13, Maroussi, Athens 15122, Greece e-mail:
[email protected] A. Mebazaa Hospital Lariboisiere APHP, University Paris, 7 Diderot, Paris, France
Keywords Inotropes Prognosis Pathophysiologic mechanisms Calcium sensitizing agents
Introduction The two most frequent scenarios of acute heat failure syndromes (AHFS) admitted in emergency department and/or intensive care unit are acutely decompensated chronic heart failure (ADHF) and pulmonary edema with elevated systemic blood pressure [1]. AHFS have 10% 60-day mortality, exhibiting also high rates of hospital re-admissions, and impaired quality of life [2]. The treatment of AHFS is guided by the systolic blood pressure (SBP), which is also a major determinant of survival [1, 3, 4]. According to this parameter, patients with SBP [ 100 mmHg and congestive symptoms are mainly treated with intravenous vasodilators and diuretics, if signs of systemic overload exist, while patients with SBP \ 100 mmHg, peripheral hypoperfusion, and low diuresis need inotropic support with classical agents (beta-agonists and phosphodiesterase inhibitors) or the new cardiac enhancer levosimendan [3]. Levosimendan has a different mechanism of action from classical inotropes. The classical inotropes increase myocardial contractility via augmenting the intracellular Ca2? levels through various pathways, such as adrenergic nervous system activation or inhibition of phosphodiesterase (PDE). Those inotropic agents have been used in the presence of signs of hypoperfusion or shock, and as a bridge to other treatments, such as revascularization or cardiac transplantation (short-term management) [5–7]. Moreover, prolonged and/or repeated infusions as well as continuous outpatient inotropic support with these drugs have been used as a palliation of symptoms in end-stage heart failure (long-term management) [5–7].
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However, the use of these agents should be limited, as much as possible, as the enhancement of myocardial oxygen consumption and the incidence of major arrhythmias can be deleterious. Levosimendan belongs to class III calcium sensitizing agents and seems to promote cardioprotection [3, 8, 9]. It increases contractility of working myocardium without increasing oxygen demand and, in addition, acts on ATPsensitive potassium channels (KATP) causing peripheral vasodilation and anti-ischemic effects (‘‘preconditioning’’ mechanism) [8, 10]. This dual mechanism of action results in increased cardiac output by the synergistic effects of positive inotropism and afterload reduction. A new mechanism of action, recently identified, is the activation of mitochondrial ATP-sensitive potassium (mitoKATP) channels with consequent reduction of the ischemiareperfusion damage into the heart via limiting myocyte apoptosis [11–13]. It has also been shown that levosimendan inhibits PDE at higher doses. Since levosimendan acts directly on cardiac myofilament, there are no antagonistic effects when it is administered with b-adrenergic receptor blockers [1]. This review summarizes current knowledge about the beneficial pathophysiologic mechanisms of levosimendan on the failing heart as well as existing evidence (benefits and drawbacks) of the drug use in real clinical practice.
Fig. 1 a Levosimendan as a cardiac enhancer. Levosimendan binds to troponin C during systole, increasing the sensitivity of myofilaments to Ca2? levels. This process increases the contractility of myocardium during systole, without affecting diastolic function. b Levosimendan leads to an opening of the active sites of troponin C, increasing in this way its sensitivity to intracellular calcium (modified from reference [8])
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Mechanism of action and pharmacokinetics of levosimendan Inotropic effects The molecular mechanism of action is better understood, reminding the basic contractile apparatus of myocardial cell. Myocardial cells are composed of filaments that slide upon each other to cause shortening. Shortening of myofilaments is facilitated by calcium (Ca?2) binding to troponin C, hydrolysis of ATP to ADP, and free energy from heavy myosin head leading to actin–myosin interaction. Ca?2 binding to the NH2 terminal of troponin C changes its configuration to facilitate myosin head sliding. Troponin C molecule has four Ca?2 binding sites, namely, NH2 terminal (sites I and II) and C-terminal (sites III and IV). NH2 terminal Ca?2 binding determines the shortening process, while sites III and IV are Mg?2-binding sites [8]. The inotropic effect of levosimendan is described in Fig. 1. Levosimendan is a pyridazinone-dinitrile derivative molecule that increases troponin C affinity for Ca?2 and stabilizes the conformation of troponin C. By improving the sensitivity of the contractile apparatus to intracellular calcium, levosimendan leads to positive inotropic properties without impairing ventricular relaxation or inducing cytosolic Ca?2 overload [3, 8, 9, 14, 15].
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Vasodilatory and anti-ischemic effects Levosimendan induces peripheral arterial and venous dilation by opening of ATP-sensitive potassium (KATP) channels in vascular smooth-muscle. It reduces peripheral vascular resistance and afterload leading, besides positive inotropism, to increased stroke volume and cardiac output. Moreover, levosimendan-induced vasodilation of the coronary vessels increases coronary blood flow and improves oxygen supply to the myocardium which might result in anti-ischemic effects. An additional mechanism is the reduction of sensitivity of contractile system to calcium in vascular smooth-muscle cells [1, 3, 8, 14, 15].
Further evaluation is required in order to define the relationship between the levosimendan infusion and the increased risk for atrial fibrillation [14]. In clinical trials, it has also been reported that patients treated with levosimendan had a slightly higher incidence of ventricular tachycardias versus placebo (REVIVE-II, randomized multicenter evaluation of intravenous levosimendan efficacy versus placebo in the short-term treatment of decompensated heart failure [17]), and similar incidence of ventricular tachycardias versus dobutamine (SURVIVE, survival of patients with acute heart failure in need of intravenous inotropic support [18]). The drug bolus dosing and the concomitant therapies led to more hypotensive episodes in levosimendan arm, which were associated with the increased risk of arrythmogenesis [3].
PDE inhibitory effects Cardioprotective effects Several studies showed that levosimendan may induce a moderate increase in intracellular calcium via PDE inhibition. Both levosimendan and its active metabolite OR-1896 are selective inhibitors of PDE type III, the most abundant in the human heart, and may provoke moderate elevation of intracellular cAMP. This remains, however, minor especially at high doses [8, 14]. Arrhythmogenic effects Evidence suggests that PDE inhibitors and dobutamine induce serious arrhythmias, such as non-sustained ventricular tachycardias, which result in an increase of overall mortality. Despite the inhibition of PDE III, levosimendan seems neither to provoke significant ventricular arrhythmias nor to increase the QT interval [16]. However, it has been observed to augment heart rate (9 beats/min on average) and to increase the incidence of atrial fibrillation mostly when high bolus dose or prolonged dose ([48 h) of levosimendan is given. Although the mechanism of levosimendan-induced tachycardia is still obscure, one possible mechanism is the activation of baroreceptor reflexes due to vasodilation [8].
There is evidence that levosimendan may protect cardiomyocytes from apoptosis via activation of KATP mitochondrial channels. Particularly, the drug-induced increase in potassium influx prevents mitochondrial calcium overload, stabilizes the mitochondrial membrane potential, and preserves high energy phosphates, as well as mitochondrial function via regulation of mitochondrial matrix volume. This cardioprotective mechanism is associated with preconditioning in response to situations of distress, such as oxidative stress, ischemia, and/or reperfusion [1, 8, 11]. The molecular targets, the mechanisms of action, and the pharmacological effects of levosimendan are listed in Table 1.
Pharmacokinetics Levosimendan has a unique pharmacokinetic profile, being active not only during administration of the parent drug but also many days later, due to long half-life of one active metabolite. This explains the prolonged clinical and
Table 1 Molecular targets, biologic mechanisms and pharmacological effects of levosimendan (modified from references [11, 14]) Molecular targets
Mechanisms of action
Pharmacological effects
Therapeutic effects
Selective binding to the calciumsaturated form of cardiac troponin C
Calcium sensitization
Positive inotropic
Increased ejection fraction
Positive lusitropic
Decreased left ventricular filling pressures
Opening of sarcolemma KATP channels on smooth-muscle cells in vasculature
Hyperpolarization
Vasodilation in all vascular beds (also coronary and peripheral circulation)
Lowered pre- and after-load
Opening of mitochondrial KATP channels in cardiomyocytes
Protection of mitochondria in ischemia-reperfusion
Anti-ischemic Better tissue perfusion Normalization of neurohormones
Preconditioning, anti-stunning anti-apoptotic
Cardioprotection Anti-ischemic
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hemodynamic improvement after 24 h infusion. Following intravenous administration, the parent drug reaches desirable blood levels in approximately 1 h (0.94 h terminal half-life) and is conjugated with serum proteins ([90% is bound to albumin). Dosage regimen starts mostly with a loading dose of 6–12 lg/kg delivered in 10 min, followed by a continuous 24 h administration of 0.05–0.2 lg/kg/ min. Some clinical studies report that the loading dose is omissible, especially in the case of hypotension (SBP \ 100 mmHg). In patients with severe renal insufficiency, a dose reduction (50%) is critical due to the 1.5 prolonged half-life of the metabolites. On the other hand, alterations of dosage may not be required in patients with impaired hepatic function, although the elimination of metabolites is prolonged. Levosimendan is metabolized to a reduced metabolite, the OR-1855, and an acetylated one, OR-1896, whose hemodynamic properties are similar to those of parent drug with the exception of a longer half-life. Acetylation of OR-1896 is facilitated by the enzyme N-acetyltransferase. According to the capacity of acetylation of metabolite OR-1896, patients may be classified as rapid and slow acetylators; OR-1896 serum concentrations of rapid acetylators are 3.5 times higher than those of slow acetylators. In the vast majority, Asian patients are fast acetylators (70–80%), while Caucasian patients are slow acetylators (40–70%). OR-1896 half-life is 80–90 h, owing to its long acting effects of the parent drug. Finally, neither tolerance to the levosimendan effects nor rebound decline in hemodynamic variables have been reported after withdrawal of the drug [1–3, 8, 15, 19].
Clinical use Acute heart failure-clinical and hemodynamic effects In patients with AHFS, levosimendan is recommended as a second-line therapy, according to guidelines of the European Society of Cardiology [2]. The drug has been only approved in some countries of Europe, South America, Asia, and Australia. Several studies have already been performed to verify the short-term hemodynamic and clinical effects of levosimendan in patients with AHFS, and the comparison with other inotropic agents, such as dobutamine [1, 3, 5, 8, 15]. The LIDO [20] trial (levosimendan vs. dobutamine in AHFS) was a double-blind parallel group trial that randomized 203 patients with AHFS defined as left ventricle ejection fraction (LVEF) \ 35%, cardiac index (CI) \ 2.5 l/min/m2 and pulmonary capillary wedge pressure (PCWP) [ 15 mmHg. The Levosimendan group received an initially loading dose of 24 lg/kg/min and
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continuous infusion of 0.1 lg/kg/min for 24 h, while the dobutamine group received continuous infusion of 5 lg/kg/ min without loading dose. Primary end-point of the study was the improvement of the hemodynamic profile of the levosimendan group (defined as [30% increase in cardiac output and [25% decline in PCWP), which was observed in 28% of patients on levosimendan versus 15% of those on dobutamine. The beneficial hemodynamic effects of levosimendan were increased and conversely those of dobutamine reduced by the concomitant treatment with beta-blockers. The RUSSLAN [21] study (randomized study on safety and effectiveness of levosimendan in patients with left ventricular failure after myocardial infarction) included 504 patients with postmyocardial infarction left ventricular dysfunction who were treated with four 6-h dosing regimens of either levosimendan at doses of 0.1–0.2 lg/kg/min or placebo. The primary end-point was to identify the safety of the drug and the result was that levosimendan did not increase the risk of ischemia or hypotension. Moreover, it was also observed that the incidence of worsening heart failure was smaller with levosimendan at 6 and 24 h. The REVIVE study was a double blind placebo-controlled trial that included patients with AHFS, LVEF \ 35% and dyspnea at rest. The levosimendan group received a loading dose of 12/lg/kg/min over 10 min followed by an infusion of 0.1 lg/kg/min for 50 min which if tolerated was titrated up to 0.2 lg/kg/min for 23 h. This study was divided into a pilot study (REVIVE-1) and a full-scale pivotal trial (REVIVE-2) [17]. Both REVIVE-1 and REVIVE-2 studies showed improved clinical status and hemodynamic profile of the patients, while REVIVE-2 study reported decline in the duration of hospitalization and reduced levels of B-type natriuretic peptide (BNP). The dose-ranging study [22] showed that all doses used, induced PCWP decline and enhancement of cardiac output and stroke volume more than dobutamine or placebo. At higher doses, an increase in the heart rate and a small reduction of SBP, as well as favorable effects on pulmonary hemodynamics were observed. The dose escalation study [23] was enrolled 146 patients with heart failure NYHA classes III–IV. Improvement of symptoms, including fatigue, was observed in the levosimendan group, while the cardiac index, stroke volume, and heart rate were elevated. The hemodynamic effects seemed to be sustained for the subsequent 48 h approximately after 24 h of levosimendan infusion. Finally, the 7-day study [24, 25], which included 24 patients with heart failure NYHA classes III–IV, reported augmentation in the heart rate that persists 14 days after cessation of therapy, and reduction in blood pressure which reached the baseline levels after 3 days from cessation of infusion. The hemodynamic effects after
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24 h of infusion include elevation in cardiac output (40%) and decline in PCWP [26]. Finally, levosimendan favorably affects endothelial function by improving the flowmediated vasodilatation and reducing serum levels of soluble cellular adhesion molecules (ICAM-1, VCAM-1), which have detrimental effects in patients with advanced chronic heart failure [27]. Small clinical trials have shown that repeated levosimendan infusions may be a useful approach for the treatment of resistant advanced heart failure and an alternative choice instead of continuous dobutamine infusions, since they are well tolerated and improve clinical and neurohormonal status [28, 29]. In specific cases, it can be administered in the community to diminish the hospitalization and its cost. Further evidence is necessary to explore the efficacy and safety of this approach. Consequently, levosimendan is a novel agent that seems to be effective in the treatment of ADHF, since clinical studies report not only the short-term but also the longer beneficial effects on clinical symptoms and central hemodynamics [8, 14]. Effects on markers of neurohormonal activation The levels of B-type natriuretic peptide (BNP) have been associated with the severity of symptoms and adverse clinical outcomes in patients with AHFS [30]. Levosimendan seems to have beneficial effects in the vicious cycle of neuroendocrine modulation, as it induces a significant decline in BNP levels when administered in patients with heart failure, which accompanies the improvement in NYHA class, left ventricular ejection fraction, E deceleration time, and E/e ratio [31]. Furthermore, the SURVIVE trial [18] described marked changes of BNP levels within 5 days of levosimendan or dobutamine administration. Specifically, BNP reduction that often exceeds 50% reduction has been observed in 46% of patients of the levosimendan group, versus 13% of those of dobutamine one. Similar results have been observed in REVIVE-2 trial [17]. In addition, recent trials have shown that the percentage reduction of BNP after levosimendan infusion is more important than absolute BNP values in predicting long-term event-free survival [31–33]. Levosimendan also intervenes in the vicious cycle of neurohormonal dysfunction in patients with ADHF via preventing the stimuli for cytokine production of myocardium and propagation into circulation [34]. A potential mechanism is the elevation of intracellular calcium sensitivity. Another mechanism is the improvement of systolic function and the induction of peripheral vasorelaxation that diminish peripheral tissue hypoperfusion with subsequent down-regulation of extra-cardiac production of cytokines via transcriptional factors (e.g. NF-jB) [35]. Specifically,
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levosimendan has anti-inflammatory and anti-apoptotic effects that result in improvement of symptoms (dyspnea and fatigue) of decompensated heart failure, increase LV ejection fraction, and reduction of NT-proBNP levels and end-systolic wall stress [36]. A reason for this improvement is the property of cytokines to transit asymptomatic heart failure to symptomatic via depressing myocardial contractility, inducing cardiomyocyte apoptosis, and succedent remodeling of myocardium [8, 37]. It has also been reported that the anti-inflammatory effects and the absence of intracellular calcium overloading may lead to decline of apoptotic markers soluble Fas and Fas ligand, besides the modification of proinflammatory cytokines interleukin-6, interleukin-10, and tumor necrosis factor-a [31]. Further studies are necessary to assess whether the anti-inflammatory and anti-apoptotic effects of levosimendan are sustained in the long-term and whether these mechanisms contribute to a potential superiority of levosimendan against other inotropic agents [8, 37]. Finally, neurohormonal activation is associated with oxidative stress that contributes to worsening of chronic heart failure and is correlated with cardiac remodeling and vascular dysfunction [38]. Levosimendan seems to prevent the detrimental effects of oxidative and nitrosative stress mediators (malondialdehyde (MDA), protein carbonyls, nitrotyrosine) by maintaining their serum levels stable in patients with advanced heart failure, in contrast to placebo treatment that leads to their elevation. This observation suggests another cardioprotective mechanism of levosimendan in patients with advanced heart failure [39, 40]. Effects on renal function In ADHF, the renal blood flow and the glomerular filtration rate (GFR) are reduced not only due to pump failure that is accompanied by redistribution of blood flow to vital organs, but also because of the intra-renal vasoconstriction which results from increased production of catecholamines, vasopressin and endothelin, augmentation of renal sympathetic tone, and finally from the activation of reninangiotensin pathway. The reduction of renal blood flow and GFR induces moderate increment in blood urea nitrogen and creatinine levels. In a recent study [41] levosimendan administration up to 72 h induced a significant improvement in calculated GFR after 24 h, while dobutamine had a neutral effect. However, both inotropic agents improved 24 h urinary outputs. This improvement, in dobutamine group, is not attributed to renal enhancement effect [42], but to the transit of congested fluid due to enhancing cardiac contractility. On the other hand, the improvement of calculated GFR induced by levosimendan is attributed to its reno-protective effects. Specifically, the main mechanism for these effects
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is the activation of ATP-sensitive potassium channels that leads to potent vasodilation and subsequent increment in renal perfusion. In addition, the hemodynamic improvement is associated with increase of renal blood flow, while the possible anti-inflammatory properties may also be involved [43, 44]. Another study [41] has reported that the improvement in renal function persisted for up to 3 months after 24-h administration of levosimendan in patients with advanced chronic heart failure awaiting cardiac transplantation, while LIDO trial also showed amelioration of serum creatinine levels after levosimendan infusion, in contrast to dobutamine [20, 41, 44]. Effects on diastolic function It has been shown that levosimendan ameliorates diastolic function via increasing relaxation rate, reducing relaxation time, and subsequently improving diastolic filling [45, 46]. In a molecular status, this agent binds in a calciumdependent way to the N-terminal region of troponin-C. Thus, this binding is significantly weaker during diastole, when there are low levels of intra-cellular calcium, resulting in the dual beneficial effect that combines increase in myocardial contractility and improvement in LV diastolic function [47, 48]. It has been showed that 24 h levosimendan administration in patients with depressed LV systolic function improves echocardiographic indexes of LV diastolic dysfunction, such as mitral annulus and transmitral flow velocities, according to findings from tissue Doppler imaging and transthoracic pulse-wave Doppler, respectively. It also provoked augmentation of LVEF, reduction of LV endsystolic diameter, mitral E/A, E/e, and E/flow propagation rates, whereas it increased isovolumic relaxation time and deceleration time (DT), in contrast to placebo treatment which increased only E/e and E/flow propagation rates [31]. Moreover, in severe heart failure patients with a restrictive pattern of LV filling, levosimendan ameliorated both systolic and diastolic function via augmenting LV filling, stroke volume, cardiac output, deceleration time, and A wave, while it diminished pulmonary capillary wedge pressure (PCWP), E wave and atrial reversal. It was also found that the decrease in the early/late transmitral diastolic peak flow velocity (E/A) ratio and the increase in the isovolumetric relaxation time (IVRT) predict independently the increment of cardiac output, while independent predictors of the PCWP reduction are the increase in systolic/diastolic (S/D) ratio and the decrease in E/A ratio [15, 49]. Similar findings were observed in patients with LV hypertrophy after aortic valve replacement for aortic stenosis, as long as levosimendan induced a direct positive lusitropic effect via reducing IVRT and improvement of LV filling [50].
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Effects on right ventricular function Right ventricular (RV) systolic dysfunction is considered to be a significant indicator of poor prognosis in the case of advanced heart failure, since RV function has a crucial role in global cardiac function. Several studies have shown that levosimendan ameliorates echocardiographic and hemodynamic markers of RV systolic and diastolic function when administered to patients with advanced heart failure [51, 52]. Specifically, the combination of dilation in pulmonary vascular bed, LV function improvement, and RV contractile efficiency amelioration leads to subsequent reduction of systolic pulmonary arterial pressure (marker of RV afterload) and vascular resistance. Moreover, the tissue Doppler imaging S wave (maximal systolic tricuspid annular velocity), the respective E wave (RV early diastolic velocity) and the early/late diastolic peak flow velocity (E/A) ratio are remarkably increased after levosimendan infusion. An explanation for the improvement of these echocardiographic indexes is the increment of LV function and filling pressures, which may result from the stronger binding of the agent to troponin-C when the systolic cytosolic calcium concentration is high and the opposite action during diastole that is accompanied by decreased intracellular calcium levels [3, 51]. Similar finding was observed in patients with idiopathic dilated cardiomyopathy, in whom levosimendan administration increased peak myocardial velocity of RV free wall [52]. Effects on coronary artery flow and acute coronary syndromes Levosimendan induces peripheral vasodilation by opening of ATP-sensitive potassium (KATP) channels in vascular smooth-muscle, as it is mentioned above. Thus, vasodilation of the coronary vessels induces reduction in coronary vascular resistance and therefore, increases coronary blood flow and improves oxygen supply to the myocardium which may result in anti-ischemic effects [1, 3, 8], that are observed as amelioration in ischemic myocardium performance [48, 53–55]. A recent study [56] has shown that 24 h levosimendan infusion induces improvement in echocardiographic indexes of coronary flow in patients with ADHF. In particular, it increased the maximal velocity and the deceleration time of diastolic coronary flow wave in left anterior descending coronary artery, whereas it reduced BNP levels, pulmonary artery systolic pressure and E/E0 at greater extent than the placebo treatment. This increases coronary flow and microcirculation, accompanied by improvement in cardiac performance and neurohormonal activation. Another clinical study [57] on patients with coronary artery disease showed that although the coronary
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angiography revealed a reduction in coronary perfusion pressure, the coronary blood flow was augmented after infusion due to primary coronary vasodilation. Moreover, levosimendan seems to augment cardiac output and stroke volume without increasing myocardial oxygen demand in patients with coronary artery bypass grafting [48]. Finally, it represents a useful tool for the estimation of contractile reserve in patients with chronic ischemic LV dysfunction [58]. Effects on quality of life It has been reported that patients with advanced heart failure treated with levosimendan have better scores at questionnaires addressing quality of life (Kansas city cardiomyopathy questionnaire, Duke activity status index) and emotional stress (Zung Self-rating Deprtession Scale, Beck Depression Inventory) than the placebo group [59]. This improvement may be attributed to drug-induced symptomatic amelioration that is accompanied by improvement in functional capacity and physical ability, to anti-inflammatory and hemodynamic effects, and to the decrease of hospitalization length. It has been recently reported that 6-min walking distance, NYHA class, and plasma BNP levels were improved after levosimendan treatment. It is obvious that symptoms of depression are associated with increased mortality and readmission risk in ADHF patients; these adverse clinical outcomes are also associated with the poor compliance of depressive ADHF patients to chronic medical therapy and diet instructions [60, 61]. Thus, the drug-induced improvement of emotional stress scales may have important prognostic implications.
Mortality trials Four major trials have investigated the mortality rate in patients with ADHF treated with levosimendan. The LIDO trial’s secondary end-points included number of days alive and all cause mortality at 31 days. All targets of the study were successfully reached including clinical and hemodynamic improvement, as well as reduction in all cause mortality at 31 days in comparison to the dobutamine group. Moreover, the mortality rate at 180 days was 26% in the levosimendan group when compared to 38% in dobutamine one [20]. The RUSSLAN study examined primarily the safety of the agent and showed that the levosimendan group compared to placebo group had significantly lower short-term and long-term mortality rates at 14 and 180 days (11.7% and 22.6% vs. 19.6% and 31.4%, respectively) [21]. Recently, the REVIVE study did not show significant survival difference at 31 or 90 days in comparison to placebo treatment. The mortality rate was 15.1% versus 11.6%
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of the placebo group. Nevertheless, the study was not designed as a mortality trial and the study population included relatively young patients, parameters that may affect the results mentioned earlier [17]. Finally, the SURVIVE study was the first that had as a primary endpoint mortality rates at 180 days between levosimendan and dobutamine groups. Also this study did not show significant differences in mortality rates among the groups (26% vs. 28%, respectively), despite an improvement with levosimendan early after the end of administration. Levosimendan reduced the risk of worsening heart failure, whereas increased the incidence of new onset atrial fibrillation in comparison to dobutamine treatment [18]. However, in patients with a previous history of CHF and on beta-blocker on admission, levosimendan seemed to have beneficial effect on short-term mortality [18]. In conclusion, the role of levosimendan in the improvement of short- or long-term survival in patients with ADHF is rather conflicting, and further studies are undoubtedly required, in contrast to the clinical and hemodynamic beneficial effects that are well documented [3, 8, 55]. An overview of the clinical trials mentioned earlier is shown in Table 2. Regarding the cost of levosimendan versus dobutamine in the management of ADHF, there are only few data derived from LIDO trial and a small Portuguese study concerning patients admitted with severe congestion in intensive care unit [62, 63]. Despite the higher price per vial of levosimendan, the global cost of the treatment was lower [62] or similar [63] for patients who were treated with levosimendan than that for patients who were treated with dobutamine. A potential explanation for this observation is the fact that levosimendan reduces the in-hospital length of stay of ADHF patients more effectively than dobutamine [62, 63]. However, the financial analysis of larger SURVIVE trial will give the final answer in this very important issue.
Clinical evidence According to the clinical evidence, levosimendan improves left ventricular contractility and also has anti-inflammatory, anti-apoptotic, vasodilatory, and lusitropic properties that lead to amelioration of clinical and hemodynamic status in patients with advanced heart failure. The survival advantage that was demonstrated in earlier mortality studies seems to crumble by the outcome of recent largescale trials. These findings may be attributed to the heterogeneity of the study population, to the absence of discrimination between ADHF and de novo AHF, as well as to the concomitant medical treatment and dosage of levosimendan, which may provoke hypotension and fatal
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Table 2 Large-scale randomized clinical trials comparing the effects of levosimendan with dobutamine or placebo treatment in patients with acutely decompensated chronic heart failure (modified from reference [3]) Trial acronym
N
Treatment arms
Duration of therapy
Primary end-point
Survival
RUSSLAN
504
Levosimendan vs. Placebo in Post-MI cardiac failure
Loading dose ? 6-h infusion
Hypotension or myocardial ischemia
; Risk of death or worsening of heart failure at 6 and 24 h ; mortality at 14 days and at 180 days
LIDO
203
Levosimendan vs.
Loading dose ? 24-h infusion
Hemodynamic improvement
; Mortality at 180 days (retrospectively)
Dobutamine in Decompensated heart failure REVIVE-1
100
Levosimendan vs. placebo in Decompensated heart failure
10-min loading dose ? 50-min infusion ? 23-h infusion (if well-tolerated)
Clinical outcome
; ‘‘Worsening’’ (including death) at 24 h and at 5 days
REVIVE-2
600
Levosimendan vs. placebo in Decompensated heart failure
Loading dose (6–12 mcg/ kg) ? 24-h infusion (0.1–0.2 mcg/kg/min)
A composite of clinical signs and symptoms of acute decompensated heart failure over 5 days
Neutral effects on mortality at 90 days (secondary endpoint) Improvement of primary end-point and length of hospitalization Reduction of BNP
SURVIVE
1327
Levosimendan vs. dobutamine in Decompensated heart failure
Loading dose (12 mcg/ kg) ? 24-h infusion (0.1–0.2 mcg/kg/min)
Survival at 5, 15, 30 and 180 days
No significantly different effects compared with dobutamine on mortality Greater reduction of BNP than dobutamine (secondary end-point)
Fig. 2 A proposed algorithm to treat acutely decompensated chronic heart failure (ADHF) patients with levosimendan according to systolic blood pressure (SBP) and NT-proBNP levels [65–67]
Levosimendan treatment according to SBP and NTproBNP levels in ADHF ADHF: volume overload Inpatient Rx
NT-proBNP>10000 ng/L SBP>100mmHg Rx: plus bolus 6µg/kg
NT-proBNP>7000 ng/L SBP>90 mmHg Rx: Levosimendan (continuous 0.1µg/kg/min)
Goal
Relief of symptoms NT-proBNP 30% reduction Yes
Outpatient Rx
Goal
NT-proBNP levels
arrhythmias [3, 8, 64]. It has also been demonstrated that treatment with beta-blockers may interact favorably with levosimendan, in comparison to beta-agonists [1, 20]. Finally, the percent reduction of B type natriuretic peptides after levosimendan administration is considered to have
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Discharge
No
Consider Levosimendan pulsed infusions every 3 weeks
Optimization of oral medications (ACE, β-blockers, Aldo antagonists)
Reverse remodeling
↓ NT-proBNP
