Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.
IN addition to administration of oxygen, diuretics, vasodilators, and anticoagulants, the support of severely impaired myocardial contractile function with positive inotropic agents represents a mainstay of therapy in critically ill patients. Irrespective of whether used in patients with acute decompensation of chronic heart failure (CHF), contractile dysfunction after myocardial infarction, or stunning after cardiac surgery, these drugs frequently improve contractility and relieve symptoms. Regarding clinical outcome, however, the results of many trials suggest substantial limitations of such drugs in the treatment of myocardial contractile dysfunction.1With the exception of digoxin, which has neutral effects on overall mortality,2currently available positive inotropic substances, including β1-adrenoceptor agonists and phosphodiesterase (PDE) III inhibitors, have been found detrimental in the long-term treatment of heart failure because they contribute to the development of malignant ventricular tachyarrhythmias and increase the incidence of sudden cardiac death.3,4In addition, recent studies also indicate that short-term administration of PDE III inhibitors is associated with a high incidence of treatment-related complications, e.g. , atrial fibrillation and hypotension,5particularly when concomitant ischemia is present as in patients with ischemic cardiomyopathy.6The reasons for these disappointing findings may be related to the fact that, despite different primary sites of action, all of these drugs eventually enhance myocardial contractility by increasing intracellular levels of cyclic adenosine monophosphate (cAMP) in myocytes, whether generated by an increased rate of synthesis (β1-adrenoceptor agonists) or by a decreased rate of degradation (PDE III inhibitors), which promotes the release of Ca2+from the sarcoplasmic reticulum (SR) to the cytosol. Augmentation of intracellular Ca2+subsequently produces a temporary improvement in contractility at the expense of an increased myocardial energy consumption and oxygen demand,7which finally accelerates myocardial cell death. Furthermore, increased concentrations of cAMP and the subsequent change in intracellular Ca2+turnover are cardiotoxic and enhance electrophysiologic mechanisms that result in rhythm disturbances.8
Accordingly, considerable research has been devoted to develop new approaches to positive inotropic therapy independent of the potentially deleterious mechanism of augmenting intracellular Ca2+availability. Theoretically, such approaches should enhance contractile force without increasing myocardial oxygen demand or the risk of cardiac arrhythmias. As the relation of intracellular Ca2+and corresponding tension of cardiac myofilaments may be impaired during pathophysiological conditions such as ischemia, acidosis, sepsis, or hypothermia, drugs have been developed that modulate this relation without actual alteration of intracellular Ca2+levels.9All of these “myofilament Ca2+sensitizers,” including levosimendan, pimobendan, EMD 57033, ORG 30029, MCI-154, and others, share the ability to enhance contractility by increasing the sensitivity of the myofilaments to calcium although with different potencies, through diverse mechanisms and sites of action, and with varying degrees of parallel PDE inhibitory effects.10Among these, levosimendan is promising in the management of both acute and chronic left ventricular (LV) failure, because it is a potent Ca2+sensitizer,10has no negative impact on diastolic function,11has little potency for additional PDE inhibition at clinically recommended concentrations,12has neutral effects on heart rhythm,13and has advantages over dobutamine in long-term survival.14Levosimendan was first approved in Sweden in 2000 and is currently in clinical use in approximately 30 countries, predominately in Europe and South America. The drug is in large phase III clinical studies in the United States (REVIVE) and Europe (SURVIVE) and has been granted fast-track status by the Food and Drug Administration. The European Society of Cardiology has adopted its use in the treatment of acute heart failure in 200115and assigned it a class of recommendation IIa (i.e. , conflicting evidence with weight in favor of usefulness), level of evidence B (i.e. , data derived from a randomized clinical trial) in the treatment of symptomatic low–cardiac output heart failure secondary to cardiac systolic dysfunction without severe hypotension in 2005,16which is superior to catecholamines or PDE III inhibitors for this indication.
This review compares the different actions of standard positive inotropic drugs and Ca2+sensitizers. It also summarizes the current experimental and clinical knowledge of the use of levosimendan and gives practical recommendations with a special focus on the perioperative setting.
Mechanism of Myocardial Excitation–Contraction Coupling
When the myocyte sarcolemma depolarizes, extracellular Ca2+enters the cell, primarily through sarcolemmal voltage-gated L-type Ca2+channels. This action on its own is insufficient to produce contraction of the myofilaments but triggers the (passive) release of larger amounts of Ca2+from the SR to the cytosol (“calcium-induced Ca2+release”),17which subsequently initiates contraction. Contraction is performed by interaction of a variety of structural and regulatory proteins, including myosin, actin, tropomyosin, and the troponin complex (TnC, TnI, TnT). When cytosolic Ca2+is low during relaxation (approximately 10−7m), tropomyosin inhibits interaction between actin and myosin. Contraction is initiated when cytosolic Ca2+increases (approximately 10−5m), binds to TnC, and causes a conformational change of this protein. Subsequent activation of TnT removes tropomyosin and TnI from the adenosine triphosphate (ATP) reactive site, thus allowing actin to interact with myosin, a process known as cross-bridging. As long as Ca2+is bound to TnC, this energy-dependent process is repeatedly performed (“cross-bridge cycling”) to generate contractile force. During basal states, Ca2+does not saturate the myofilaments, i.e. , approximately 25% of full activation is achieved. This reserve of activation can be mobilized by increasing either the amount of Ca2+available for binding or the sensitivity of myofilaments to Ca2+. Relaxation is initiated both by phosphorylation of TnI and rapid removal of cytosolic Ca2+predominately by reuptake into the SR through the (energy-requiring) sarcoplasmic endoplasmic reticulum calcium adenosine triphosphatase isoform 2 (SERCA2). With each contraction-relaxation cycle, there is no net gain or loss of cellular Ca2+.
Importantly, the response of myofilaments to a specific intracellular concentration of Ca2+may be attenuated (i.e. , “desensitization”) by a variety of pathophysiologic conditions, including acidosis,18hypothermia,19,20increased inorganic phosphate,21sepsis,22ischemia–reperfusion injury,23and myocardial stunning,24but also by pharmacologic β-adrenergic stimulation25–27or the presence of CHF with increased neurohormonal activation. Conversely, the sensitivity of contractile proteins to Ca2+may increase, e.g. , by α-adrenergic receptor stimulation27or by administration of myofilament calcium sensitizers.10
Mechanism of Action of Standard Inotropic Drugs
Drugs currently used to achieve positive inotropic effects in the perioperative setting include catecholamines, e.g. , dobutamine, and PDE III inhibitors, e.g. , milrinone. Although these substances have different sites of action, they ultimately initiate a cascade of events that stimulate contractility by increasing intracellular Ca2+concentration (fig. 1). Binding of catecholamines to β1-adrenergic receptors on the surface of myocytes activates adenylate cyclase, which generates cAMP from ATP. cAMP activates protein kinase A, which subsequently phosphorylates (i.e. , attaches a phosphate group to) intracellular targets, including the voltage-gated L-type Ca2+channel, phospholamban, and TnI. Phosphorylation of sarcolemmal voltage-gated L-type Ca2+channels enhances Ca2+entry into the cytosol. The increased activity of these channels further increases “trigger calcium,” leading to greater activation of the calcium release channel (RyR2) in the SR and subsequent contraction (i.e. , positive inotropic action of catecholamines and PDE III inhibitors). In contrast, phosphorylation of phospholamban activates SERCA2. This action increases the rate of Ca2+transport from the cytosol back into the SR during diastole and is therefore responsible for the positive lusitropic actions of catecholamines and PDE III inhibitors. Although this lusitropic action enhances relaxation, it is also crucial to ensure sufficient Ca2+availability from the SR for the next cellular depolarization and contributes to the overall gain in cardiac excitation–contraction coupling that adrenergic stimulation mediates. The consequences of this increased loading of the SR with Ca2+may be a key factor in the development of Ca2+-mediated arrhythmias.8Phosphorylation of TnI decreases the affinity of myofilaments for Ca2+and thereby also favors relaxation.28–30Together, these effects provide an integrated response to β-adrenergic stimulation that increases myocardial contractility, while in parallel supports myocardial relaxation by desensitizing myofilaments and augmenting the active removal of Ca2+from the cytosol.
Cardiac glycosides, e.g. , digoxin, selectively and reversibly inhibit the sarcolemmal Na+–K+adenosine triphosphatase in cardiac myocytes with a resultant modest increase in intracellular Na+. This increase of Na+subsequently inhibits extrusion of Ca2+from the cytosol into the extracellular compartment by the Na+–Ca2+exchanger. Ca2+not extruded from the cytosol by this mechanism is stored in the SR and allows increased release of Ca2+during the next contraction. Digoxin is commonly not used to increase myocardial contractility in the perioperative period because of only modest positive inotropic effects and a small therapeutic range. As digoxin decreases atrioventricular nodal conduction, it is, along with amiodarone, however, useful in the control of ventricular rate during refractory atrial fibrillation.31
Mechanism of Action of Levosimendan
Positive Inotropic Effects
Levosimendan enhances myocardial contractility by binding to the N-terminal lobe of cardiac TnC with a high affinity32–34and stabilizing the Ca2+-bound conformation of this regulatory protein.32Therefore, systolic interaction of actin-myosin filaments is prolonged without alteration of the rate of cross-bridge cycling. Other myofilament Ca2+sensitizers are bound to the TnC–Ca2+complex during both systole and diastole with improvement of systolic but possible impairment of diastolic function35due to facilitation of cross-bridging at diastolic Ca2+levels, whereas binding of levosimendan to TnC is dependent on the cytosolic Ca2+concentration, i.e. , increases during systole but is relatively unchanged during diastole, when Ca2+levels decrease.36This mechanism may be the reason for the parallel enhancement of myocardial contractility and improvement of LV diastolic function without promoting arrhythmogenesis or alteration of myocardial oxygen demand in experimental36–38and clinical11,39studies.
Phosphodiesterase III Inhibition.
In addition to myofilament Ca2+sensitization, levosimendan inhibits cardiac PDE, predominately PDE III,40in muscle strips from human hearts41and various animal models.12,40,42This effect is observed predominately at higher concentrations (> 0.3 μm),12,43but is not seen (0.03 μm) or is less pronounced (0.1–0.3 μm) at concentrations reflecting the clinically recommended therapeutic range of 0.03–0.3 μm (i.e. , 10–100 ng/ml).44,45Therefore, at concentrations of 0.03–0.1 μm, levosimendan does not alter heart rate, cAMP levels, myocardial relaxation,12and cytosolic Ca2+as assessed by aequorin light transients,37,41although it significantly increases myocardial contractility in guinea pig hearts12and shifts the graph of the relation between Ca2+and contractile force to the left.37These findings indicate that levosimendan mainly acts as a Ca2+sensitizer at concentrations of 0.03–0.1 μm. Although 0.1–0.3 μm levosimendan variably alters myocardial cAMP levels, heart rate, 32P incorporation into phospholamban,12and aequorin light transients,41concentrations exceeding 0.3 μm consistently increase heart rate, contraction (+dP/dt) and relaxation (−dP/dt) as well as partial phosphorylation of phospholamban12and aequorin light transients.41These findings suggest a contributing role of PDE inhibition at concentrations of levosimendan exceeding 0.3 μm.
Important experimental and clinical differences between levosimendan and classic PDE inhibitors (e.g. , milrinone), however, exist. First, milrinone has no Ca2+sensitizing effect,46but in contrast decreases the sensitivity of myofilaments to Ca2+through cAMP-dependent phosphorylation of TnI, whereas levosimendan has this action.12Second, milrinone consistently exerts positive inotropic effects in parallel with an increase in aequorin light emission (indicating influence on Ca2+transients),41whereas levosimendan at low concentrations does not have this effect despite production of positive inotropic effects, suggesting that levosimendan is more potent as a Ca2+sensitizer than as an inhibitor of PDE.12,47Third, metabolism of levosimendan produces a long-lasting active metabolite, OR-1896,48which has similar Ca2+sensitizing properties like the parent compound49but a significantly lower potential to inhibit PDE III (40-fold less potent, 3-fold less selective).40Because levosimendan has a relatively short elimination half-life and the infusion is usually discontinued after 24 h, the sustained positive inotropic effects observed thereafter50suggest an important role of Ca2+sensitization of this metabolite. Fourth, in clinical practice, levosimendan does not increase the incidence of arrhythmias,13worsen ischemia,51or negatively influence patient outcome,14,51whereas milrinone does.4–6
Levosimendan produces vasodilation in several vasculatures including coronary,52–54pulmonary,55renal,56splanchnic,56cerebral,56and systemic57,58arteries as well as saphenous,59portal,60and systemic57,58veins. The underlying mechanism of vasodilation has been extensively investigated54,55but has not yet been entirely clarified. Recent evidence proposes involvement of several systems or pathways in the vasodilating effects of levosimendan (fig. 2). An important mechanism in vascular smooth muscle of systemic, coronary,53,61and pulmonary55arteries is opening of potassium channels, including ATP-sensitive K+(KATP) channels in small resistance vessels and Ca2+-activated K+and voltage-dependent K+channels in large conductance vessels.62,63Opening of these channels hyperpolarizes the membrane, inhibits inward Ca2+current, and activates the Na+–Ca2+exchanger to extrude Ca2+. The resultant decrease in intracellular Ca2+produces vasorelaxation. Attenuation of levosimendan-induced dilation of coronary arteries during concomitant administration of the KATPchannel antagonist glibenclamide emphasizes the role of KATPchannels in this setting.53,61
A second mechanism involved in levosimendan-induced vasodilation is reduction of Ca2+sensitivity of the (TnC-lacking) contractile proteins in vascular smooth muscle.64This decrease in contractile force of vascular myofilaments occurs without a proportionate decrease in intracellular Ca2+. In addition, PDE inhibition has been proposed to contribute to levosimendan-induced vasodilation because of increases in cAMP in vascular smooth muscle.65This effect, however, predominately occurs at excessive doses (1 mm) of levosimendan,54whereas at 3 μm, vasorelaxation is different from milrinone64and not affected by inhibition of protein kinase A at concentrations of 0.01–1 μm.47Although the importance and relative contribution of each of these mechanisms of vasorelaxation is unclear and may be different in various vessels and dependent on the dose of levosimendan, an important role of K+channel opening is obvious, whereas the role of PDE inhibition remains to be defined.
Hemodynamic Effects of Levosimendan
Levosimendan consistently increases cardiac output in experimental and clinical studies. Possible theoretical mechanisms of this action are modification of heart rate, improvement of cardiac performance, and vasodilation.
Levosimendan dose-dependently (≥ 0.1 μm) increased heart rate in several animal experiments,12,38,42healthy volunteers,66and patients with New York Heart Association (NYHA) functional class II–IV heart failure of ischemic etiology.45The mechanism of the occasionally observed early levosimendan-induced increase in heart rate is unknown but may be produced by compensatory vasodilation-induced activation of baroreceptor reflexes,67particularly after administration of a bolus. Conversely, studies demonstrate an initial neutral effect on heart rate after abandonment of a bolus,68low bolus concentrations (3–12 μg/kg),51,66,69or oral administration of levosimendan.70In contrast, persistence of an increased heart rate after discontinuation of a 24-h infusion of levosimendan48,50or after extended infusions for 7 days71suggests an important role of OR-1896, a metabolite of levosimendan,48which continues to accumulate after withdrawal of levosimendan.50In clinical practice, treatment of patients with normal or reduced ejection fraction but within the recommended dosages (6- to 24-μg/kg bolus over 10-min, followed by an infusion of 0.05–0.2 μg · kg−1·min−1)45rarely produces positive chronotropy exceeding more than 10% from baseline45and is generally less marked in patients with severe heart failure. Accordingly, neutral or insignificant effects on heart rate were observed in patients with CHF,45cardiogenic shock,72and severe decompensated low-output heart failure14,58,73and after myocardial infarction,51but also in the perioperative period in patients undergoing surgical revascularization with normal39or compromised74ventricular function. In contrast, administration of high doses of levosimendan (36-μg/kg bolus and infusion of 0.3 μg · kg−1· min−1over 6 h) in patients with a normal ventricular function increased heart rate after cardiopulmonary bypass, particularly after the bolus (+24 beats/min) and during the first hour of infusion.75Therefore, changes in heart rate are obviously a function of dosage, intravascular volume status, and preexisting compromise of myocardial contractile function.76Taken together, modification of heart rate under clinical conditions and within the recommended doses45is unlikely to be an important mechanism of the increase in cardiac output produced by levosimendan.
Administration of levosimendan enhances cardiac performance in vitro ,41,in vivo ,76and in clinical studies.14,58For example, in patients with low-output heart failure, a 24-h administration of levosimendan (0.1–0.2 μg·kg−1·min−1) increased cardiac output by 1.09 l/min and decreased pulmonary capillary wedge pressure (PCWP) by 7 mmHg, whereas dobutamine (5–10 μg · kg−1·min−1) changed these parameters by 0.80 l/min and 3 mmHg, respectively (fig. 3).14These effects generally occur in a dose-dependent manner and are characterized by an increase in LV stroke volume and cardiac index in patients with severely compromised ventricular function.58In addition, improved cardiac performance has also been suggested by a significant decrease of circulating levels of amino terminal pro B-type natriuretic peptide after a 24-h infusion of levosimendan (0.1 μg·kg−1·min−1) in patients with decompensated CHF and a mean LV ejection fraction of approximately 25%.77Interestingly, the decrease of this neurohormonal marker was particularly pronounced 48 h after discontinuation of levosimendan treatment.
Although Ca2+sensitizers carry a potential risk of worsening diastolic function,35levosimendan decreased the time constant of isovolumic relaxation (τ) in various experimental38,76,78and clinical11settings, indicating improvement rather than deterioration of diastolic function. In addition to these beneficial effects at rest, levosimendan treatment also improved LV systolic and diastolic performance during exercise in dogs with pacing-induced CHF.79These positive lusitropic effects may be related to the Ca2+dependence of Ca2+-bound sensitization of cardiac TnC, i.e. , the contractile apparatus is sensitized in systole (when Ca2+is high) but not in diastole (when Ca2+is low) or alternatively due to PDE III inhibition.
Vasodilation observed with administration of levosimendan is followed by numerous consequences. Pulmonary vasodilation decreases right heart filling pressures,58which, in context with positive inotropic effects, could explain increases right ventricular contractility and performance observed with administration of levosimendan.80,81Systemic vasodilation decreases left heart filling pressures, enhances LV–arterial coupling,57and increases blood flow to various tissues, including myocardium, gastric mucosa,82renal medulla, small intestine, and liver.56In the splanchnic area, levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation82,83and increases portal venous blood flow and oxygen delivery in experimental septic shock.84Clinical consequences of levosimendan-induced vasodilation must be seen in context with the parallel improvement of cardiac performance. Although vasodilation may decrease mean arterial blood pressure, which compromises, for example, renal perfusion, the parallel increase in cardiac output frequently more than compensates this handicap. For example, renal function was improved after a 24-h infusion of levosimendan (0.1–0.2 μg · kg−1· min−1) in patients with low-output heart failure as demonstrated by decreases of serum creatinine levels (−9 μm) compared with infusions of dobutamine (5–10 μg·kg−1·min−1).14
Anti-ischemic Effects of Levosimendan
Particularly during ischemia and reperfusion, administration of catecholamines and PDE III inhibitors produce detrimental side effects, e.g. , atrial and ventricular tachyarrhythmias.5,6,85,86In this setting, availability of positive inotropic drugs with a neutral profile on cardiac rhythm and anti-ischemic effects would confer benefits.
Levosimendan opens both mitochondrial87,88and sarcolemmal89,90KATPchannels. Although the definite relevance of these actions is unknown, opening of mitochondrial KATPchannel has repeatedly been implicated in mediation of anti-ischemic actions.91Prevention of mitochondrial Ca2+overload, restoration and stabilization of mitochondrial membrane potential, preservation of high-energy phosphates, and regulation of mitochondrial matrix volume have been proposed as underlying mechanisms.92Interestingly, the positive inotrope levosimendan protected ischemic myocardium,85,93decreased myocardial infarct size when administered before and during myocardial ischemia in dogs,61and improved survival compared with placebo in patients with LV failure complicating acute myocardial infarction.51
Opening of sarcolemmal KATPchannels, however, has been implicated in both mediating cardioprotective effects94and exerting a theoretical proarrhythmic potential.95This detrimental action on heart rhythm is produced by the large outward repolarizing K+current that sarcolemmal KATPchannel opening initiates. Subsequent hyperpolarization of resting membrane potential and shortening of action potential duration decreases the effective refractory period96of the tissue and thereby increases the susceptibility to reentrant arrhythmias. Although levosimendan indeed hyperpolarized membrane potential,89shortened action potential duration in isolated cells,90and slightly shortened effective refractory period in patients,97experimental and clinical studies so far have demonstrated a neutral effect of this drug on heart rhythm rather than proarrhythmic potential.13,85,97
Effects of Levosimendan during Ischemia, Stunning, and Myocardial Infarction
Because levosimendan does not increase myocardial oxygen demand81and possibly exerts anti-ischemic effects,61,93,98efficacy and safety of this substance have been intensively tested before, during, and after ischemia–reperfusion injury in experimental and clinical studies. Levosimendan did not promote ischemia–reperfusion arrhythmias compared with dobutamine in guinea pig hearts85and in patients with stable moderate-to-severe ischemic cardiomyopathy when used in recommended clinical concentrations (6- to 24-μg/kg bolus over 10 min, followed by an infusion of 0.05–0.2 μg · kg−1· min−1) in a double-blinded, placebo-controlled, randomized, multicenter study.45Furthermore, the incidence of arrhythmias was not increased when levosimendan was compared with placebo in patients with acute myocardial infarction51or administered perioperatively in patients with coronary artery bypass grafting.75Although obviously having a neutral profile on heart rhythm, levosimendan consistently improved contractile function in the setting of global ischemia–reperfusion injury in experimental85,93,99,100and clinical studies.11,51,75
In contrast, two experimental studies using regional myocardial ischemia in pigs demonstrated detrimental effects of levosimendan during ischemia, i.e. , increase in the rate of ventricular arrhythmias101and worsening of the myocardial contractile function in the ischemic area.102An increased frequency of ventricular arrhythmias was also noted at levosimendan doses of 0.6 μg·kg−1· min−1(i.e. , 3 times higher than upper recommended dose) in patients with stable ischemic cardiomyopathy.45The reasons for these findings may be related to a decline in coronary perfusion pressure, redistribution of coronary blood flow producing coronary steal, and increase in myocardial oxygen consumption due to PDE III inhibition.103Therefore, as with any other positive inotropic drug, caution is advised with the use of levosimendan, especially in high doses, in patients who have ongoing myocardial ischemia.
Efficacy and safety of levosimendan have been demonstrated during states of myocardial stunning in experimental settings104,105and in patients with acute coronary syndrome undergoing angioplasty in a randomized, double-blinded, placebo-controlled trial.11Administration of levosimendan before or during myocardial stunning is of special interest not only because of the myofilament Ca2+sensitization of this drug. The decrease in myofilament responsiveness that characterizes stunning can also be prevented by ischemic preconditioning.24Because opening of myocardial KATPchannels plays a key role in the mediation of ischemic preconditioning, one may speculate that administration of the KATPchannel opener levosimendan before ischemia may also prevent or attenuate the negative effects of myocardial stunning. Levosimendan also has cardioprotective effects by opening KATPchannels in dogs with acute myocardial infarction. In this setting, levosimendan decreased myocardial infarct size while producing positive inotropic effects. These protective actions were blocked with glibenclamide without alteration of the hemodynamic effects of levosimendan.61
Pharmacokinetics, Metabolism, and Dosage
The pharmacologic profile of levosimendan and its metabolites in patients with normal and compromised myocardial contractile function has been reviewed extensively elsewhere.106Important pharmacokinetic data of levosimendan in healthy volunteers and patients with congestive heart failure are shown in table 1.
Although during CHF pharmacokinetics of many drugs may be altered because of reduction of central volume, fluid retention, and reduced blood flow to various organs, including liver and kidneys,107pharmacokinetic parameters of intravenous levosimendan are comparable when obtained in healthy volunteers and patients with mild108or NYHA functional class III or IV heart failure.44Levosimendan has a β elimination half-life, volume of distribution, and total body clearance of approximately 1 h, 20 l, and 300 ml/min, respectively. These parameters remain constant independent of the duration of infusion.71Because levosimendan at a pH of 7.4 is present primarily in the ionized form (pKa 6.26) and is 98% bound to plasma proteins, only trace amounts of the unchanged drug are found in erythrocytes and urine.108
The extensive metabolism of levosimendan yields biologically active metabolites (e.g. , OR-1855, OR-1896) that are eliminated in urine and feces. The clinically most relevant metabolite, OR-1896, also has Ca2+-sensitizing and weak PDE III–inhibiting properties49and exerts positive inotropic effects similar to the parent compound.109OR-1896, however, has an elimination half-life of 80–96 h,48reaches maximum plasma concentrations approximately 2 days after withdrawal of a 24-h infusion of levosimendan in patients with CHF (fig. 4), and is likely to be responsible for the sustained or greater hemodynamic effects observed after discontinuation of levosimendan.48,50Because of this accumulation of OR-1896, intravenous administration of levosimendan is therefore currently approved for 24 h. The effects of continuous infusions exceeding 24 h on plasma levels of levosimendan and its circulating metabolites and possible desired and undesired side effects, however, have recently been repeatedly investigated.50,71,110Pharmacokinetics of levosimendan were similar after single-dose administration and continuous infusion of 7 days,110whereas accumulation of OR-1896 was confirmed.71An extended infusion of 0.1 μg · kg−1· min−1over 7 days decreased systolic blood pressure (11 ± 14 mmHg) and substantially increased heart rate (26 ± 19 beats/min) on day 7 but was nevertheless well tolerated in patients with NYHA functional class III or IV symptoms of heart failure and ejection fractions below 40%.71
Administration of a 6- to 24-μg/kg bolus dose of levosimendan followed by a 24-h infusion of 0.05–0.2 μg · kg−1· min−1produces plasma concentrations of 10–100 ng/ml (0.035–0.35 μm) in patients with NYHA functional class II–IV heart failure44and can be considered as the therapeutic range to obtain favorable hemodynamic effects.45
Levosimendan generally is well tolerated by patients with moderate or severe heart failure, with an overall frequency of adverse events of 17–29%, which is similar to that of placebo (17–20%).45,51,58
Interaction with Concomitant Heart Failure Drugs
In most clinical trials that evaluated the effects of levosimendan in heart failure, patients were taking concomitant routine heart failure drugs.14,45,51,58For example, in a randomized multicenter trial, 89% of patients receiving levosimendan were using angiotensin-converting enzyme (ACE) inhibitors, 95% were using diuretics, 76% were using digoxin, and 37% were using β blockers.14Although additive responses particularly regarding vasodilation (i.e. , ACE inhibitors and levosimendan) and heart rate (i.e. , nitrates or β blockers and levosimendan) would be expected, clinical studies so far have not reported serious interactions when levosimendan was used within the recommended dose range and in patients with myocardial contractile impairment.
A subgroup analysis evaluating the concomitant effect of β blockade on hemodynamics revealed no reduction of the effects of levosimendan on cardiac output and PCWP, whereas the actions of dobutamine were attenuated.14This finding is in agreement with previous preclinical and clinical data demonstrating beneficial or neutral effects of parallel atenolol47or carvedilol111administration on the inotropic effects of levosimendan.
In another double-blinded, randomized, multicenter trial, the majority of patients received ACE inhibitors (5–20 mg enalapril), nitrates, and diuretics when various dose regimes of levosimendan were compared with dobutamine or placebo.45Although no direct comparisons were made between patients with or without these drugs, treatment with levosimendan within the recommended doses (0.05–0.2 μg · kg−1· min−1) in general was associated with only minor decreases in mean arterial blood pressure (3.5 ± 2.8 mmHg) after 24 h of treatment. Similarly, 50 mg captopril did not further decrease systolic or diastolic blood pressures when administered concomitantly with levosimendan in patients with NYHA functional class II or III after previous myocardial infarction.112Although no major additive hemodynamic effects of the combination of levosimendan and isosorbide-5-mononitrate compared with each drug alone were observed in healthy subjects at rest, an exaggerated circulatory response during an orthostatic test (i.e. , increase in heart rate by 40 beats/min; inability to stand upright) was observed with this combination of drugs.113In contrast, concomitant nitrate therapy in patients with acute myocardial infarction produced only marginal decreases in systolic blood pressure (5 mmHg) and minor increases in heart rate (4 beats/min).51Similarly, 5 mg felodipine, a dihydropyridine calcium antagonist, combined with oral levosimendan did not further increase heart rate and had no effect on blood pressure.114No exaggerated or attenuated hemodynamic side effects of levosimendan were further reported in the presence of furosemide (10 mg/h) and amiodarone.73
Hemodynamic Side Effects
Dose-dependent increases in heart rate and decreases in mean arterial blood pressure and total peripheral and pulmonary vascular resistance45may cause a variety of unfavorable hemodynamic effects, including myocardial ischemia, hypotension, cardiac arrhythmias, and hypoxemia. Treatment within the recommended doses of levosimendan, however, does not induce myocardial ischemia45,51and symptomatic or asymptomatic hypotension (> 10-mmHg pressure decrease).51Levosimendan-induced vasodilation may, however, be responsible for the increased frequency of headache, dizziness, and nausea observed in several clinical trials.14,45,113
Electrophysiologic Side Effects
Short-term intravenous administration (18-μg/kg bolus followed by 0.4 μg · kg−1· min−1) increases heart rate, shortens sinus node cycle duration and sinus node recovery time, and decreases atrioventricular nodal conduction interval and refractory periods.115These actions indicate that levosimendan enhances impulse formation and conduction, accelerates the recovery of excitability, and therefore may also increase the ventricular response rate during atrial fibrillation. Several clinical studies including patients with atrial fibrillation, however, have been performed,45,48,51,71and so far, no adverse effects related to this rhythm disorder have been reported.
Levosimendan may prolong the rate-corrected QT interval (QTc), depending on dose, duration of administration, patient profile, and mode of calculation. When used in recommended doses (12 μg/kg over 10 min followed by an infusion of 0.05–0.2 μg · kg−1· min−1), the QTc interval remained unaffected.45Single-bolus injections of 6.5 and 25 μg/kg without subsequent continuous infusion in healthy men produced QTc prolongations as assessed by the Bazett equation of +6 ms and +21 ms, respectively.116In contrast, administration of bolus doses of 24 and 36 μg/kg followed by continuous infusions of 0.4 and 0.6 μg · kg−1· min−1prolonged QTc duration by 15 ± 20 and 45 ± 10 ms in patients with NYHA functional class II–IV heart failure.45Continuous infusions of levosimendan in doses of 0.05–0.1 μg · kg−1· min−1but over 7 days increased mean QTc values by 38 ± 42 and 52 ± 40 ms.71
The impact of this proarrhythmic potential of levosimendan must be weighed against possible antiarrhythmic actions due to the lack of cytosolic Ca2+accumulation, maintenance of diastolic coronary blood flow, and neutral effect on myocardial oxygen consumption. To date, there is no evidence of an increase in the development of new supraventricular or ventricular tachyarrhythmias, including torsade de pointes, in healthy volunteers and patients with severe heart failure, suggesting little potential for the drug to provoke life-threatening proarrhythmic reactions.13
Other Side Effects
Clinical Trials with Possible Indications for Levosimendan
Currently, administration of levosimendan is approved for short-term treatment of acute decompensated CHF when conventional therapy with diuretics, ACE inhibitors, and digitalis is insufficient and inotropes are required. In addition, because of its interesting pharmacologic profile, several other possible indications for levosimendan have recently been explored, and the encouraging results of these trials may place levosimendan as a valuable expansion or replacement of standard therapy in the future.
Acute Decompensation of CHF
The LIDO study, a randomized, double-blinded, multicenter trial, compared the effects of levosimendan with dobutamine in 203 patients with acute decompensated low-output heart failure.14These patients had an LV ejection fraction of less than 35%, a cardiac index of less than 2.5 l · min−1· m−2, and a PCWP or 15 mmHg or greater on the basis of deterioration of severe CHF, heart failure after cardiac surgery, or acute heart failure related to a cardiac or noncardiac disorder of recent onset. A bolus of levosimendan of 24 μg/kg was infused over 10 min, followed by a continuous infusion of 0.1 μg · kg−1· min−1for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 μg · kg−1· min−1without a bolus. The infusion rate of each drug was doubled (i.e. , 0.2 μg · kg−1· min−1levosimendan and 10 μg · kg−1· min−1dobutamine) if the response was inadequate at 2 h. The primary endpoint was the proportion of patients with hemodynamic improvement (i.e. , increase of cardiac output of 30% or more and decrease of PCWP of 25% or more) at 24 h. All-cause mortality was assessed prospectively at 31 days and retrospectively at 180 days after randomization. Levosimendan treatment was superior to dobutamine in increasing cardiac output and decreasing PCWP (fig. 3), and a significantly greater proportion of patients in the levosimendan group achieved the primary endpoint compared with the dobutamine group (28% vs. 15%; P = 0.022). Although overall frequency of adverse events was similar, headache tended to be associated more frequently with levosimendan, whereas rhythm disorders and myocardial ischemia were more common with dobutamine. Administration of levosimendan was associated with both a significantly lower 31-day (8% vs. 17%; P = 0.049) and 180-day (26% vs. 38%; P = 0.029) mortality (fig. 5). Interestingly, levosimendan was equally effective in patients with concurrent β-blocker therapy, whereas the actions of dobutamine were attenuated, as expected. Interpretation of these encouraging results must include consideration that comparable hemodynamic effects might have also been achieved with higher infusion rates of dobutamine (although possibly with higher adverse events) and that, because of the lack of a placebo group, it cannot be derived whether this was a true beneficial effect of levosimendan or rather reflected a more adverse effect of dobutamine.
Beneficial hemodynamic effects of levosimendan were also observed in a 6-h short-term treatment of 146 patients with acute decompensated ischemic or dilated cardiomyopathy in a multicenter, double-blinded, placebo-controlled trial.58In these patients with NYHA functional class III or IV symptoms of heart failure and ejection fractions of 30% or less, levosimendan therapy was initiated with a bolus dose of 6 μg/kg, followed by a continuous infusion of 0.1 μg · kg−1· min−1. At hourly intervals, a repeat bolus of 6 μg/kg was given, and the infusion rate was up-titrated by increments of 0.1 μg · kg−1· min−1until a maximum rate of 0.4 μg · kg−1· min−1was achieved or a dose-limiting event (i.e. , heart rate > 130 beats/min or increase in heart rate of > 15 beats/min, symptomatic hypotension or a decrease in systolic blood pressure to < 75 mmHg, decrease in PCWP to ≤ 10 mmHg) occurred. The primary endpoint was the proportion of patients with an increase in stroke volume or a decrease in PCWP of 25% or more at 6 h. Levosimendan dose-dependently increased LV stroke volume (maximum 28% with the highest dose), cardiac index (maximum 39%), and heart rate (maximum 8%) and decreased PCWP (maximum 6 ± 1 mmHg) when compared with placebo.
Inotropic Support during and after Myocardial Ischemia
Safety, efficacy, and effects on mortality of various doses of levosimendan were investigated in the RUSSLAN study, when this drug or placebo was administered in 504 patients with LV failure complicating acute myocardial infarction in a randomized, double-blinded, multicenter trial.51In this investigation, four different dosing regimens of levosimendan were tested (6- to 24-μg/kg bolus infused over a period of 10 min, followed by 6 h infusions of 0.1–0.4 μg · kg−1· min−1). At the time of levosimendan administration, most patients were using nitrates and diuretics, approximately 40% were using ACE inhibitors or β blockers, and 17% had received thrombolysis. None of the patients had received percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. In the highest dosing group (24-μg/kg bolus followed by 0.4 μg · kg−1· min−1), a trend toward higher frequency of ischemia and hypotension was observed, but these effects were not evident at lower doses (0.1–0.2 μg · kg−1· min−1). Levosimendan-treated patients in general experienced a lower risk of death and worsening heart failure than patients receiving placebo during both the 6-h infusion (2.0% vs. 5.9%) and over 24 h (4.0% vs. 8.8%; P = 0.044). Furthermore, all-cause mortality among levosimendan-treated patients was significantly lower than with placebo for the 14-day period after the start of treatment (11.7% vs. 19.6%; P = 0.031) and exhibited a trend toward reduced mortality after 180 days of follow-up (22.6% vs. 31.4%; P = 0.053). This study suggests that levosimendan infusions of 0.1–0.2 μg · kg−1· min−1are favorable compared with higher doses, because they combine a low potential of side effects with a maintained positive effect on survival in patients with LV failure complicating acute myocardial infarction.
Although levosimendan also produced significantly fewer ischemic adverse side effects compared with dobutamine in the LIDO study,14did not aggravate ischemia in patients with stable coronary heart disease as assessed by a 24-h Holter electrocardiogram,114and enhanced cardiac output in patients with ischemic heart disease and LV dysfunction,69caution may be advised when this drug is administered in patients with critical coronary stenoses and regional myocardial ischemia. In this setting, despite improvement of overall contractile function, animal experiments demonstrated detrimental effects of levosimendan101,102that may have been due to declines in coronary perfusion pressure producing failure of autoregulation, coronary steal, or increased mechanical stress of myocytes between ischemic and nonischemic areas.103
Myocardial Stunning after Percutaneous Transluminal Coronary Angioplasty in Patients with Acute Coronary Syndrome
Improvement of the function of stunned myocardium after percutaneous transluminal coronary angioplasty was shown after infusion of levosimendan in 24 patients with acute coronary syndrome in a double-blinded, randomized, placebo-controlled trial.11Levosimendan (24 μg/kg over 10 min) was administered 10 min after successful coronary angioplasty, and LV and regional functions were assessed by pressure–volume loops and Slager wall motion analysis, respectively. In levosimendan-treated patients, systolic function improved and the number of hypokinetic segments decreased from 8.9 ± 0.9 to 6.5 ± 1.1 when compared with placebo (7.8 ± 1.0 to 8.5 ± 1.1). This action occurred without parallel impairment of diastolic function.
Although the efficacy of levosimendan has repeatedly been demonstrated in the perioperative setting, the number of patients investigated was rather small.14,74,117In a randomized, double-blinded, placebo-controlled study, levosimendan (18- or 36-μg/kg bolus and 0.2- or 0.3-μg · kg−1· min−1infusion) administered 15 min before separation of cardiopulmonary bypass and continued for 6 h had beneficial effects on cardiac performance in low-risk patients and had no detrimental effects on arterial oxygenation and perioperative arrhythmias.75In this study, administration of the 36-μg/kg bolus instantly increased heart rate, although this effect vanished after 1 h despite continuation of the infusion. Similarly, levosimendan (8 or 24 μg/kg administered as a 5-min bolus without continuous infusion) improved hemodynamic parameters without changing myocardial oxygen consumption or substrate extractions after coronary artery bypass grafting in patients with ejection fractions greater than 30%.39The high dose but not the low dose of levosimendan increased heart rate (maximum 11 beats/min) during the observation period of 1 h. In the setting of off-pump coronary artery bypass surgery, increases in stroke volume and cardiac output and decreases in systemic vascular resistance were observed when levosimendan was administered in two different bolus doses (12 or 24 μg/kg over 10 min) 20 min before the start of surgery in patients with normal preoperative ventricular function. Heart rate increased in both levosimendan-treated groups during the observation period of 1 h, whereas no differences in mean arterial blood pressure were demonstrated compared with placebo.118
In the presence of refractory cardiogenic shock (defined as cardiac index < 2.2 l · min−1· m−2, PCWP >16 mmHg, systolic blood pressure < 90 mmHg, and requirement of catecholamines), 0.1 μg · kg−1· min−1levosimendan for 24 h as add-on therapy favorably altered hemodynamic parameters by increasing cardiac index from 1.8 ± 0.4 to 2.4 ± 0.6 l · min−1· m−2and decreasing systemic vascular resistance from 1,559 ± 430 dyn · s · cm−5to 1,109 ± 202 dyn · s · cm−5, although it was administered without administration of a bolus in 10 patients. No significant changes in mean arterial blood pressure (78 mmHg to 73 mmHg), heart rate (96 to 101 beats/min), or adverse events were observed in this uncontrolled, retrospective study.72Similarly, in a case series of 10 patients with cardiogenic shock undergoing emergency surgical revascularization, levosimendan in addition to standard catecholamines produced favorable effects.74
Right Ventricular Dysfunction
Because levosimendan decreased PCWP more effectively than dobutamine,14the substance may be of value in patients with reversibly increased pulmonary pressures or right ventricular dysfunction, e.g. , in patients during and after heart transplantation. Using dynamic positive emission tomography, pulmonary artery catheterization, and echocardiography, improved right ventricular mechanical efficiency (+24%) was demonstrated after administration of an 18-μg/kg bolus and a 0.3-μg · kg−1· min−1continuous infusion of levosimendan in eight patients with NYHA functional class III or IV symptoms of heart failure in a double-blinded, crossover, placebo-controlled study.81Although clinical data are sparse, administration of levosimendan with positive inotropic effects and parallel decreases in pulmonary pressures is promising in the setting of right ventricular dysfunction119and could confirm the encouraging results of animal studies80in this setting.
Combination with Other Positive Inotropic Drugs
Numerous reports of the efficacy of levosimendan as add-on therapy to catecholamines exist regarding improvement in hemodynamic parameters68,72,74,117,120,121; clinical data evaluating specific combinations at specific doses, however, are lacking. Efficacy of addition of levosimendan (6-μg/kg bolus plus 0.2-μg · kg−1· min−1continuous infusion for 24 h) was shown in patients with NYHA functional class IV heart failure refractory to a continuous infusion of dobutamine (10 μg · kg−1· min−1) and furosemide.73In this study, combination of these positive inotropic drugs improved hemodynamics (increase in cardiac index 1.19 ± 0.66 l · min−1· m−2and decrease in PCWP 5.4 ± 8.7 mmHg) and consistently alleviated symptoms than when compared with dobutamine alone (increase in cardiac index 0.44 ± 0.32 l · min−1· m−2and increase in PCWP 1.0 ± 4.4 mmHg) after 24 h. This investigation confirmed an experimental study in conscious dogs that demonstrated superiority of a combination therapy of dopamine and levosimendan (i.e. , levosimendan potentiated the positive inotropic effects of dopamine while attenuating its deleterious action on chamber compliance) over treatment with dopamine alone.122Furthermore, addition of levosimendan to epinephrine during profound acidosis improved the attenuated efficacy of epinephrine in guinea pig hearts.123
Other Possible Indications
Efficacy and safety of intermittent, long-term, concomitant dobutamine and levosimendan infusions in severe heart failure refractory to dobutamine alone were evaluated in 36 patients in NYHA functional class IV who were resistant to a 24-h continuous infusion of dobutamine in an uncontrolled, nonrandomized trial. The 45-day survival rates were 6% and 61% in patients treated with weekly dobutamine infusions and biweekly levosimendan infusions, respectively.124
Data regarding the use of levosimendan in children, pregnancy, and circulatory failure due to septic shock are rare, but published experience gives an encouraging view beyond the treatment of acutely decompensated CHF.80,82–84,121,125–127
Currently, the clinically recommended administration of levosimendan is a single 24-h infusion, which is usually performed using one 12.5-mg vial with an average cost of approximately £700 ($875).
A cost-effectiveness analysis was performed for intravenous treatment with levosimendan compared with dobutamine in patients with severe low-output heart failure based on the data of the LIDO study.128Costs were based on study drug usage and hospitalization in the 6-month follow-up of the study, and the primary effectiveness measure was the gain in life expectancy. The mean survival in the LIDO study over 6 months was extrapolated (157 ± 52 and 139 ± 64 days for levosimendan- and dobutamine-treated patients, respectively). This assumed a mean additional lifetime of 3 yr based on the CONSENSUS trial129due to the similar patient population, and the gain in life expectancy was estimated at 0.35 yr/patient. Levosimendan increased the mean cost per patient by £1,108, which was attributable to the cost of the drug. Although the absolute difference in drug costs was relatively high (£1,024 vs. £41 for one treatment of levosimendan vs. dobutamine), the incremental cost per life-year saved was only £3,205 on European average, which is well below the acceptable threshold for cardiology therapies. Although the patients in the levosimendan group were alive for more days and thus at risk for a longer period of hospitalization, there was no increase in resource utilization with levosimendan treatment compared with dobutamine.
Levosimendan is a positive inotropic drug with vasodilating properties that has been extensively investigated in experimental studies and that is also increasingly the subject of clinical trials. Clinical trials that are currently under way in the United States (REVIVE study) and in Europe (SURVIVE study) aim to establish the role of levosimendan in short- and long-term therapy of patients with CHF. To date, clinical experience with levosimendan is encouraging because it combines several beneficial actions that considerably differ from other cardiotonic drugs. First, levosimendan enhances myocardial force without increasing intracellular Ca2+concentrations, which, in context with neutral effects on myocardial oxygen demand and heart rhythm, should be of benefit compared with catecholamines or PDE III inhibitors. Second, levosimendan does not impair myocardial relaxation, a possible limitation of other Ca2+sensitizers. Third, stimulation of ATP-sensitive potassium channels improves coronary blood flow, reduces preload and afterload, and may exert anti-ischemic actions. Finally, the drug has advantages on short- and long-term survival compared with standard inotropes and is safe, with a low incidence of adverse effects when used in appropriate concentrations. Therefore, part of the benefit of levosimendan may also be achieved because it allows other inotropic agents that may have adverse effects on clinical outcome to be reduced in dose or avoided.