Pharmacology & Therapeutics 114 (2007) 184 – 197
www.elsevier.com/locate/pharmthera
Levosimendan: Beyond its simple inotropic effect in heart failure
Charalambos Antoniades ⁎, Dimitris Tousoulis, Nikolaos Koumallos,
Kyriakoula Marinou, Christodoulos Stefanadis
Athens University Medical School, 1st Cardiology Department, Hippokration Hospital, Vasilissis Sofias 114, 115 28, Athens, Greece
Abstract
Classic inotropic agents provide short-term haemodynamic improvement in patients with heart failure, but their use has been associated with
poor prognosis. A new category of inotropic agents, the Ca2+ sensitizers, may provide an alternative longer lasting solution. Levosimendan is a
relatively new Ca2+ sensitizer which offers haemodynamic and symptomatic improvement by combining a positive inotropic action via Ca2+
sensitization and a vasodilatory effect via adenosine triphosphate(ATP)-sensitive K+ (KATP), Ca2+-activated K+ (KCa2+) and voltage-dependent K+
(KV) channels activation. Levosimendan also seems to induce a prolonged haemodynamic improvement in patients with heart failure as a result of
the long half-life of its active metabolite, OR-1896. Furthermore, there is also evidence that levosimendan may have additional antiinflammatory
and antiapoptotic properties, affecting important pathways in the pathophysiology of heart failure. Despite the initial reports for a clear benefit of
levosimendan on short- and long-term mortality in patients with severe heart failure, the results from the recent clinical trials are rather
disappointing, and it is still unclear whether it is superior to dobutamine in affecting survival of patients with severe heart failure. In conclusion,
levosimendan is a promising agent for the treatment of decompensated heart failure. As further to its positive inotropic effect, it affects multiple
pathways with key roles in the pathophysiology of heart failure. The results of the ongoing trials examining the effect of levosimendan on
mortality in patients with heart failure will hopefully resolve the controversy as to whether levosimendan is superior to classic inotropic agents for
the treatment of severe heart failure.
© 2007 Elsevier Inc. All rights reserved.
Keywords: Levosimendan; Heart failure; Ca2+ sensitizers; Myocardial function
Abbreviations: ace, angiotensin-converting enzyme inhibitor; BNP, NT-pro-brain natriuretic peptide; CASINO, calcium sensitizer or inotrope or none in low output
heart failure study; CHF, congestive heart failure; KATP, ATP-sensitive K+ channels; KCa2+, Ca2+-activated K+ channels; KV, voltage-dependent K+ channels; LIDO,
levosimendan infusion versus dobutamine in severe low output heart failure study; NYHA, New York Heart Association functional class; NF-κB, nuclear factor
kappa B; PCWP, pulmonary capillary wedge pressure; PDE, phosphodiesterase; REVIVE, randomized multicenter evaluation of intravenous levosimendan efficacy
versus placebo in the short-term treatment of decompensated heart failure; RUSSLAN, randomised study on safety and effectiveness of levosimendan in patients
with left ventricular failure after an acute myocardial infarct; sFAS, soluble FAS; SURVIVE, survival of patients with acute heart failure in need of intravenous
inotropic support study.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . .
Pharmacokinetics and metabolism of levosimendan . .
Levosimendan: molecular mechanisms of action . . . .
3.1. Levosimendan as an inotropic agent . . . . . .
3.2. Levosimendan and phosphodiesterase inhibition
3.3. Levosimendan and cardiac arrhythmias . . . . .
3.4. Levosimenan as a vasodilator . . . . . . . . . .
⁎ Corresponding author.
E-mail address: antoniades@panafonet.gr (C. Antoniades).
0163-7258/$ - see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.pharmthera.2007.01.008
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C. Antoniades et al. / Pharmacology & Therapeutics 114 (2007) 184–197
3.5.
3.6.
Antiinflammatory and antiapoptotic effects of levosimendan
Levosimendan and ischemic heart disease: cardioprotective
myocardium . . . . . . . . . . . . . . . . . . . . . . . .
3.6.1. Levosimendan and stunned myocardium . . . . .
4. Haemodynamic effects. . . . . . . . . . . . . . . . . . . . . . .
4.1. Results from clinical trials . . . . . . . . . . . . . . . . .
5. Effects of levosimendan on heart failure symptoms . . . . . . . .
5.1. Results from clinical trials . . . . . . . . . . . . . . . . .
6. Effects of levosimendan on morbidity and mortality . . . . . . .
6.1. Results from recent and ongoing clinical trials. . . . . . .
7. Side effects of levosimendan—interactions with other drugs . . .
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Heart failure is characterised by decreased cardiac output,
resulting in both pulmonary congestion and peripheral hypoperfusion; it is accompanied by neurovascular activation,
enhancement of systemic inflammatory process and cachexia
(Thackray et al., 2001). The currently used combined therapy
for heart failure [with beta-blockers, angiotensin-converting
enzyme (ACE) inhibitors, aldosterone antagonists and highdose loop diuretics] offers symptomatic relief and improves the
short-term prognosis of patients with heart failure. Although the
currently used inotropic agents seem to be useful for the shortterm treatment of acute heart failure, evidence suggests that
their use is associated with increased mortality and several side
effects (Thackray et al., 2001). As a general principle, the
classic inotropic agents operate through the adrenergic nervous
signaling pathway, the sodium–potassium pump, or the
inhibition of phosphodiesterase (PDE), leading to the increase
of intracellular Ca2+ levels (Thackray et al., 2001), but they can
induce dangerous arrhythmias (Majerus et al., 1989). Ca2+
sensitizers, a relatively new category of inotropic agents, exert
their inotropic action by increasing the sensitivity of the
myocardial contractile system to intracellular Ca2+ (Ukkonen et
al., 2000; Koumallos et al., 2006). The most commonly used
agent of this category, the class III Ca2+ sensitizer levosimendan, seems to offer new therapeutic opportunities to patients
with heart failure, since, further to the simple inotropic effect, it
has a number of additional beneficial effect in heart failure
patients by acting as a vasodilator in resistance vessels and
modifying critical pathways implicated in the pathophysiology
of heart failure.
2. Pharmacokinetics and metabolism of levosimendan
Levosimendan has high oral bioavailability, but in clinical
practice it has only been developed for intravenous administration. Steady state is achieved within 5 hr of a constant dose
infusion. It has an elimination half-life of ∼1 hr and body
clearance ∼300 mL/min (Haikala & Linden, 1995; Sandell et
al., 1995; Antila et al., 1999; Kivikko et al., 2002a,b). Only a
small proportion (∼4%) of the drug is free in plasma, since
>90% is bound to albumin. After infusion, levosimendan is
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effect on
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acetylated to form 2 biologically active metabolites, OR-1896
and OR-1855, with much longer elimination half-lives (Kivikko
et al., 2002a,b; Antila et al., 2004) than levosimendan itself,
while their pharmacologic effects persist for ∼1 week. OR1855, an intermediate metabolite in the conversion of
levosimendan to OR-1896, is formed by the acetylation of
levosimendan by intestinal bacteria, and is excreted by the
biliary route. Approximately 40% of these metabolites are also
bound to plasma proteins, while they are eliminated in urine and
feces.
The most clinically relevant metabolite is OR-1896, which
has similar pharmacodynamic properties as the parent drug
(Kristof et al., 1998). This metabolite has an elimination halflife ∼80 hr, whereas for 24-hr infusions it reaches its maximum
concentrations 2 days after the end of infusion (Kivikko et al.,
2002a,b). Therefore, this metabolite is probably responsible for
the prolonged haemodynamic effects of levosimendan, which
seem to persist for many days after infusion (Kivikko et al.,
2002a,b). This long half-life of OR-1896 seems to lead to its
accumulation after prolonged infusions, exceeding 24 hr
(Kivikko et al., 2002a,b). Although prolonged infusion of
levosimendan (up to 1 week at a dosage of 0.1 μg/kg/min) may
lead to accumulation of OR-1896, it does not seem to have any
dangerous side effects (Kivikko et al., 2002a,b). However, the
recommended dosage for levosimendan has been set to an initial
6–24 μg/kg of bolus administration followed by a 24-hr
infusion of 0.05–0.2 μg/kg/min (Toller & Stranz, 2006). This
leads to the optimum haemodynamic effects (Nieminen et al.,
2000). Pharmacokinetic studies have demonstrated that 24-hr
levosimendan infusion (0.2 μg/kg/min) achieves maximal free
(nonprotein bound) plasma concentrations 6 nM for levosimendan and 12 nM for OR-1896 (Kivikko et al., 2002a,b).
These concentrations are of major importance, since the
pharmacologic effects of these 2 molecules are largely
dependent on the achieved concentrations.
Renal dysfunction prolongs the elimination half-life of OR1896, but it has little effect on the plasma concentration of
levosimendan. On the other hand, liver cirrhosis does prolong
the elimination half-life of levosimendan, although its effects on
production or metabolism of OR-1896 are unknown (Kivikko et
al., 2002a,b). Finally, no tolerance to the effects of levosimendan has been observed, even after infusions lasting for as long
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C. Antoniades et al. / Pharmacology & Therapeutics 114 (2007) 184–197
as 7 days (Kivikko et al., 2002a,b). Furthermore, no rebound
decline in haemodynamic variables has been observed after
withdrawal of levosimendan.
3. Levosimendan: molecular mechanisms of action
3.1. Levosimendan as an inotropic agent
Levosimendan is a “Ca2+ sensitizer” with multiple mechanisms of action. It exerts its inotropic effect by increasing the
affinity of troponin-C for Ca2+, directly stabilising the Ca2+induced conformation of troponin-C, or acting distal to the
troponin-C molecule (Fig. 1) (Haikala & Pollesello, 2000). It
binds in a Ca2+-dependent manner to the N-terminal domain of
troponin-C, thus magnifying the extent of the contraction
produced by troponin-C when it is Ca2+-activated (Haikala &
Linden, 1995). This leads to a positive inotropic effect without
impairing diastolic relaxation (Pagel et al., 1994; Haikala et al.,
1995; Hasenfuss et al., 1998) or causing cytosolic Ca2+ ion
overload, which might provoke cardiac myocyte dysfunction,
arrhythmogenesis, and cell death. Indeed, in contrast to other
myofilament Ca2+ sensitizers which are bound to the troponin
C-Ca2+ complex during both systole and diastole, impairing
diastolic function (Hajjar et al., 1997), levosimendan's binding
to troponin C is dependent on cytosolic Ca2+, and it is
significantly weaker (causing a minimum Ca2+ sensitization)
during diastole, when intracellular Ca2+ levels are low (Haikala
et al., 1995). This is the reason why levosimendan enhances
myocardial contractility and improves LV diastolic function
with relatively low arrhythmogenesis or alteration of myocardial oxygen demands in human myocardium (Lilleberg et al.,
1998).
Similar effect on Ca2+ sensitization has also been demonstrated with levosimendan's active metabolite OR-1896 (Szilagyi et al., 2004). In guinea pig permeabilized myocyte-sized
preparations (Szilagyi et al., 2004), the Ca2+ -sensitizing
potential of levosimendan was illustrated by an EC50 ∼8 nM
and by a maximal increase in isometric force production (Emax)
∼51% (for pCa2+ 6.2). On the other hand, the EC50 for OR1896 was ∼36 nM, for an Emax of ∼52%. Furthermore, it was
demonstrated that levosimendan has an EC50 of ∼15 nM for the
increase of left ventricular pressure signal in guinea pig
Langendorff-perfused hearts (Emax, ∼26%), while the EC50
for OR-1896 in the same model is ∼25 nM (Emax, ∼25%).
Despite the strong preclinical evidence that OR-1896 has a
similar pharmacodynamic effect as levosimendan (although at
relatively high concentrations), it is still unclear whether this is
also valid in humans. The long-lasting positive inotropic effect
of levosimendan (lasting for several days after a 24-h infusion;
Lilleberg et al., 2006) has been explained by the longer semi-life
of OR-1896, but there has been no clinical study examining the
effect of OR-1896 infusion on myocardial function in humans.
In conclusion, levosimendan exerts its inotropic action
mainly by increasing the sensitization of contractile system to
Ca2+, although a possible effect on PDE activity and intracellular
Ca2+ levels can not be excluded (see next paragraph).
Fig. 1. (A) Levosimendan as an inotropic agent. Levosimendan binds to troponin C during systole, increasing the sensitivity of myofilaments to Ca2+ levels. This
phenomenon increases the contractility of myocardium during systole, but it does not affect diastolic function. (B) In more details, levosimendan leads to an opening of
the active sites of troponin C, increasing in this way its sensitivity to Ca2+ (Pollesello et al., 1994).
C. Antoniades et al. / Pharmacology & Therapeutics 114 (2007) 184–197
3.2. Levosimendan and phosphodiesterase inhibition
Both levosimendan and its active metabolite OR-1896
appear to have structural similarities with a family of PDE
inhibitors. Therefore, it has been hypothesized that levosimendan and OR-1896 may exert part of their action via inhibition of
PDE. Indeed, in preliminary ex-vivo experiments conducted
25 years ago (Raasmaja et al., 1991), it was shown that
levosimendan inhibits PDE activity selectively and even more
potently than milrinone. It was also shown that levosimendan
increases cAMP levels in isolated guinea pig intact-hearts and
enhances heart rate and the amplitude of the L-type Ca2+-current
(ICa,L), implying that at least in that experimental model,
levosimendan exerted part of its action via a cAMP-dependent
mechanism (Raasmaja et al., 1991; Edes et al., 1995; Boknik et
al., 1997). On the other hand, it has also been suggested that
levosimendan had no effect on the ICa,L at concentrations
between 0.2–10 μM (Yokoshiki et al., 1997a,b), a finding which
was questioned by other studies suggesting that levosimendan
has an EC50 of ∼54 nM for the enhancement of ICa,L in isolated
human cardiac myocytes (Ajiro et al., 2002). PDE inhibition
would increase the intracellular cAMP level and thus the
amplitude of the intracellular Ca2+ transient, similarly to the
effects of β-adrenoreceptor agonists (Hasenfuss et al., 1994).
However, a clear dose–effect relation between levosimendaninduced positive inotropy and the intracellular cAMP elevation
could not be established (Edes et al., 1995; Boknik et al., 1997).
Moreover, several studies have demonstrated that levosimendan
either did not increase the intracellular Ca2+ concentration at all
(Lancaster & Cook, 1997; Hasenfuss et al., 1998; Brixius et al.,
2002) or not to levels high enough to explain its positive
inotropic effect (Hasenfuss et al., 1998; Sato et al., 1998; Chen et
al., 2003). It is more likely that levosimendan is associated with a
moderate elevation of intracellular Ca2+ which may partly
contribute to its overall positive inotropic effect in combination
with its ability to improve the responsiveness of the contractile
system to Ca2+. The extent to which this elevation of intracellular
Ca2+ could have any significant side effects (e.g., by inducing
arrhythmias) is still unclear.
This controversy about the inhibitory effect of levosimendan
and OR-1896 on PDE inhibition was partly addressed by recent
reports, suggesting that they are both selective inhibitors of PDE
type III (Szilagyi et al., 2004). The half-maximal inhibition of
PDE III is achieved at a concentration (IC50) of 2.5 nM for
levosimendan and 94 nM for OR1896 (Szilagyi et al., 2004). On
the other hand, half-maximal inhibition of PDE IV is achieved
at much higher concentrations of levosimendan (24 μM) or OR1896 (286 μM) (Szilagyi et al., 2004), which are not achieved in
vivo.
Evidence suggests that a marked increase in the ICa,L (and
positive inotropism through cAMP signaling) is observed if
multiple PDE subtypes are inhibited at the same time, while
when only 1 PDE isoenzyme is selectively inhibited, cAMP
may presumably be metabolized by other PDE isoenzymes,
thereby minimizing a large increase in cAMP at intracellular
level (Shahid & Nicholson, 1990; Verde et al., 1999) Although
PDE III is the most abundant PDE in the human heart, recent
187
evidence suggest that even a modest hyperactivity of PDE IV
may result in an appreciable blunting of the cAMP response to
catecholamines, whereas a reduced activity of PDE IV may lead
to exaggerated responses in terms of amplitude and duration
(Zaccolo, 2006). Therefore, since the inhibition of PDE IV
requires significantly higher concentrations of levosimendan or
OR-1896 than their maximal free (nonprotein bound) plasma
concentration achieved after 24 hr levosimendan infusion
(0.2 μg/kg/min), which are 6 nM for levosimendan and
12 nM for OR-1896, it can be hypothesized that in a clinical
setting, the selective PDE III inhibition may lead to moderate
but not critical elevation of intracellular cAMP (Kivikko et al.,
2002a,b). This hypothesis along with the finding that OR-1896
requires concentrations higher (∼94 nM) than those observed in
clinical practice (∼12 nM) to effectively inhibit PDE III
(Szilagyi et al., 2004), partly explain previous observations,
suggesting that at normal dosage, levosimendan does not induce
serious arrhythmias (Lilleberg et al., 2004) and does not have a
negative effect on clinical outcome, as other inotropic agents do
(Moiseyev et al., 2002).
3.3. Levosimendan and cardiac arrhythmias
It is well known that the use of PDE inhibitors or dobutamine
is limited by their arrhythmogenic effect (Packer et al., 1991;
Nony et al., 1994). In particular, PDE inhibition induces
nonsustained ventricular tachycardias (VT), and increases
overall mortality (Nony et al., 1994). In preliminary reports
from pigs, levosimendan increased the number of VT and
ventricular fibrillation during regional ischemia(du Toit et al.,
2001). However, in those studies the elevation of intracellular
cAMP in ventricular myocardium was not higher in levosimendan treated animals, compared with controls. Furthermore,
in other experimental models of ischemia, levosimendan had no
effect on the incidence of ischemia-induced ventricular
arrhythmias(Du Toit et al., 1999; Nijhawan et al., 1999). In
recent animal studies of ischemia, levosimendan was proved to
be clearly superior than the PDE inhibitor milrinone, since it
was associated with fewer ventricular premature beats and less
incidence of tachycardia or ventricular fibrillation (Papp et al.,
2006).
In patients, it seems that levosimendan does not induce
significant ventricular arrhythmias (Lilleberg et al., 2004;
Mebazaa, 2005), despite the existing evidence that it selectively
inhibits PDE III at clinically relevant concentrations (Szilagyi et
al., 2004). Indeed, clinical evidence suggests that standard
infusion of levosimendan (at a dose 12 μg/kg for 10 min,
followed by steady infusion 0.05–0.2 μg/kg/min for 24 h) did
not increase the occurrence of nonsustained VT or the frequency
of its episodes in patients with heart failure. Furthermore, in the
same study it was demonstrated that levosimendan did not
increase the QT interval, although the QT interval corrected
using Bazett's formula was slightly prolonged (Toivonen et al.,
2000). Levosimendan increased ventricular monophasic action
potential duration by 9–17 ms at 50% and by 5–15 ms at 90%
levels of repolarization on average. Furthermore, levosimendan
was found to increase heart rate by 9 beats/min on average and
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to shorten the sinus node recovery time. Although the
underlying mechanisms by which levosimendan affects heart
rate are still obscure, it is likely that the activation of
baroreceptor reflexes induced by vasodilation could also lead
to tachycardia (Harkin et al., 1995).
Furthermore, levosimendan seems to shorten the effective
refractory periods in the atrioventricular node by 40–63 ms, in
the atrium by 22–33 ms, and in the ventricle by 5–9 ms on
average (Toivonen et al., 2000). These observations indicate
that levosimendan in short-term administration induces impulse
formation and conduction in cardiac nodal tissue, enhances
recovery of excitability in the myocardium, and may delay
ventricular repolarization.
It is now believed that the effects of levosimendan on the
ventricle are not substantial, and the likelihood of provoking
serious cardiac arrhythmias is not high (Singh et al., 1999;
Toivonen et al., 2000; Lilleberg et al., 2004; Mebazaa, 2005),
However, the interpretation of all these clinical trials is
particularly difficult, since in most of these studies, patients
with documented sustained ventricular arrhythmias were
excluded. It is therefore likely that a selection bias was
introduced in all these studies. Indeed, a recently presented
clinical trial (randomized multicenter evaluation of intravenous
levosimendan efficacy versus placebo in the short-term
treatment of decompensated heart failure, REVIVE-II) observed
a slightly higher incidence of VT in patients treated with
levosimendan compared with placebo (25% vs. 17%; Packer,
2005), although this incidence was the same as with dobutamine
(survival of patients with acute heart failure in need of
intravenous inotropic support [SURVIVE]-W study) (Mebazaa,
2005). Finally, in both SURVIVE and REVIVE-II studies,
levosimendan infusion was associated with an increased risk for
atrial fibrillation (Mebazaa, 2005; Packer, 2005; Cleland et al.,
2006); and this finding requires further evaluation in the future.
We should therefore wait for the results of further large
randomized clinical trials to conclude whether levosimendan
induces dangerous arrhythmias in heart failure patients
compared with conventional inotropic agents.
3.4. Levosimenan as a vasodilator
Levosimendan not only increases cardiac performance but
has also been shown to induce arteriolar and venous dilatation
because of its ability to open ATP-sensitive potassium channels
in vascular smooth muscle cells (SMC; Bowman et al., 1999;
Pataricza et al., 2000; Kaheinen et al., 2001). In more detail,
levosimendan stimulates the ATP-sensitive K+ channels (KATP)
in resistance vessels and the Ca2+-activated (KCa) and voltagedependent K+ channels (KV) in large conductance vessels
(Pataricza et al., 2003; Yokoshiki & Sperelakis, 2003). Therefore, it leads to the hyperpolarization of the membranes,
inhibiting the inward L-type Ca2+ (ICa-L) current and promoting
the forward mode of Na+–Ca2+ exchanger (Yokoshiki &
Sperelakis, 2003; Toller & Stranz, 2006). These mechanisms
lead to a decrease of intracellular Ca2+-inducing vasorelaxation
(Fig. 2).
An additional mechanism by which levosimendan induces
vasodilation independently from intracellular Ca2+ levels is the
reduction of contractile system's sensitivity to Ca2+ in vascular
SMC (Bowman et al., 1999; Fig. 2). Finally, levosimendan may
also affect vascular tone via its PDE inhibitory effect. At high
concentrations (∼ 1 mM; Gruhn et al., 1998), levosimendan
inhibits PDE, leading to an increase of intracellular cAMP in
vascular SMC and vasorelaxation (Haikala & Linden, 1995;
Gruhn et al., 1998). Although the inhibitory effect of
levosimendan on PDE III is now believed to occur at clinically
Fig. 2. Levosimendan as a vasodilator. In small resistance vessels, levosimendan stimulates the KATP channels in vascular SMC; whereas in large conductance vessels
it activates KCa and KV channels. These effects result in the hyperpolarization of the membranes of SMC, thereby inhibiting the inward ICa-L and promoting the
forward mode of Na+/Ca2+ exchanger. These changes lead to the decrease of intracellular Ca2+ levels, inducing vasorelaxation. Furthermore, levosimendan may
directly decrease the sensitivity of the contractile system to intracellular Ca2+.
C. Antoniades et al. / Pharmacology & Therapeutics 114 (2007) 184–197
relevant concentrations (Szilagyi et al., 2004), the contribution
of this mechanism to the overall vasodilatory effect of this drug
in humans remains to be defined.
The vasodilatory effect of levosimendan has been demonstrated in several vasculatures including coronaries in animal
models (Kaheinen et al., 2001) and humans (Michaels et al.,
2005): pulmonary artery (De Witt et al., 2002), systemic arteries
and veins (Pagel et al., 1996; Slawsky et al., 2000), saphenous
veins (Hohn et al., 2004) and others. Improved contractile
performance and vasodilatation leads to a reduction in both
preload and after load in the failing heart with reduced
myocardial oxygen consumption (Todaka et al., 1996; Michaels
et al., 2005). Combined with coronary vasodilatation, this
reduction may also have anti-ischemic effects (Lilleberg et al.,
1998).
Further to the direct vasodilatory effects of levosimendan
itself, very little is known about the effect of its metabolite OR1896 on vasomotion. In a very recent report (Erdei et al., 2006), it
was demonstrated that OR-1896 is a strong vasodilator in both
coronary and skeletal muscle arterioles from Wistar rats. In the
same study, OR-1896 appeared to be a more potent vasodilator in
the coronary than in the gracilis muscle arterioles, an effect not
observed with levosimendan itself. It has also been suggested
(Erdei et al., 2006) that OR-1896 exerts its vasodilating action
again via its interactions with K+ channels and especially via
interactions with KATP channels in skeletal muscle arterioles and
the large conductance KCa2+ channels in the coronaries. It is
therefore important to point out that the relative contribution of
different K+ channels to the OR-1896-induced vasodilation may
vary depending on the vessel type and size.
3.5. Antiinflammatory and antiapoptotic effects of levosimendan
The failing myocardium is a major source of proinflammatory cytokines (Adamopoulos et al., 2001; Moiseyev et al.,
2002) which contribute to the pathophysiology of heart failure
(Anker et al., 1997; Adamopoulos et al., 2001; Tentolouris et
al., 2004). Cytokines promote the transition from asymptomatic
to symptomatic heart failure (Ceconi et al., 1998) since they
depress myocardial contractility (Yokoyama et al., 1993),
whereas they also promote cardiomyocyte apoptosis and
subsequent cardiac remodeling (Krown et al., 1996).
We (Parissis et al., 2004; Trikas et al., 2006) have recently
shown that levosimendan administration causes a significant
reduction of the circulating proinflammatory cytokine interleukin6 (lasting for at least 1 month after infusion) and soluble apoptosis
mediators, such as the apoptotic marker soluble FAS (sFAS) and
Fas ligand in patients with decompensated heart failure. The
improved haemodynamics may partly explain the decreased
expression of cytokines from the failing myocardium, whereas
levosimendan also seems to inhibit the stimuli for myocardial
cytokine production and spillover into circulation (Hasenfuss et
al., 1995, 1998). Additionally, levosimendan improves systolic
function and induces peripheral vasorelaxation, which attenuate
peripheral tissue hypoperfusion, leading to down-regulation of
cytokine extracardiac production by transcriptional factors, such
as nuclear factor kappa B (NF-κB) (Yokoshiki et al., 1997a,b;
189
Adamopoulos et al., 2001). These immunomodulatory effects
may lead to improvement of symptoms and echocardiographic
markers of cardiac contractile performance (Paraskevaidis et al.,
2005; Parissis et al., 2005, 2006).
3.6. Levosimendan and ischemic heart disease:
cardioprotective effect on ischaemic myocardium
There is evidence that levosimendan may have beneficial
effects on ischaemic myocardium since the activation of KATP
channels may occur in ischaemic myocardial regions where the
intracellular ADP is increased and the ATP is decreased
(Kopustinskiene et al., 2004; De Luca et al., 2006a,b). It has
been reported that levosimendan opens the KATP channels in
both liver (Kopustinskiene et al., 2001) and cardiac (Kopustinskiene et al., 2004) mitochondria, which has been suggested
as a cardioprotective mechanism (Oldenburg et al., 2002) linked
to the preconditioning in response to oxidative stress (Yokoshiki
et al., 1997a,b; De Luca et al., 2006a,b). Indeed, the proposed
underlying mechanisms of this effect include the prevention of
mitochondrial Ca2+ overload, the preservation of high energy
phosphates, the restoration and stabilization of mitochondrial
membrane potential and the regulation of mitochondrial matrix
volume (Peart & Gross, 2002; Gross & Peart, 2003). It is
therefore possible that the activation of these channels partly
explains the cardioprotective effect of levosimendan on
ischaemic myocardium (Rump et al., 1994; Du Toit et al.,
1999). On the other hand, the very existence of mitochondrial
KATP channels has recently been questioned (Hanley & Daut,
2005). Although there is strong evidence for the existence of K+
channels in the mitochondrial inner membrane and there is
growing consensus that ion channels are involved in the
regulation of matrix volume, matrix Ca2+ and respiratory rate,
the properties ascribed to mitochondrial KATP channels on the
basis of pharmacological experiments should not be considered
as established facts. It is not yet clear whether the mitochondrial
inner membrane is endowed with channels that bear any
resemblance to surface KATP channels, and alternative hypotheses for the cellular defense mechanisms against ischemic
damage are now being considered (Hanley & Daut, 2005).
Further to its possible effect on mitochondrial KATP
channels, levosimendan may also activate sarcolemmal KATP
channels, which have been associated with both a cardioprotective (Gross & Fryer, 1999) and a possible proarrhythmic
effect (Fischbach et al., 2004). Theoretically, this effect of
levosimendan on the sarcolemmal KATP channels could lead to
arrhythmias as a result of the increased outward repolarizing K+
current. This may lead to hyperpolarization of resting
membrane potential and shortening of action potential duration,
which finally could decrease the effective refractory period
(Wilde & Janse, 1994) of myocardial cells promoting
arrhythmogenesis. However, despite the observed membrane
hyperpolarization (Yokoshiki et al., 1997a,b) and the shortening
of action potential duration in isolated cardiomyocytes
(Yokoshiki et al., 1997a,b), levosimendan seems to have a
rather neutral proarrhythmic effect, although the findings from
clinical trials are rather conflicting (see Section 3.3).
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3.6.1. Levosimendan and stunned myocardium
Levosimendan may also have beneficial effects on myocardium in patients with myocardial stunning. Myocardial
stunning is probably the result of decreased sensitivity of the
myofibrils to Ca2+ caused by either the generation of oxygenderived free radicals (radical hypotheses) or by a transient
calcium overload on reperfusion (calcium hypotheses; Bolli &
Marban, 1999). In these patients systolic dysfunction is usually
combined with marked diastolic dysfunction. Calcium sensitization by levosimendan may therefore directly improve the
function of stunned myocardium (Soei et al., 1994; Sonntag et
al., 2004) especially if we consider that levosimendan improves
systolic function without affecting diastolic function (Haikala &
Linden, 1995). Furthermore, levosimendan has been shown to
improve local coronary blood supply to ischemic myocardial
areas (Kersten et al., 2000), increase the coronary flow
(Kaheinen et al., 2001) and diminish infarct size (Rump et al.,
1994; Kersten et al., 2000), whereas other studies have showed
an oxygen-sparing effect of this drug (Kaheinen et al., 2004)
and a neutral effect on the energy balance after ischemia/
reperfusion(Eriksson et al., 2004).
These antiischemic properties of levosimendan may have an
impact on the drug-induced arrhythmogenesis as it has been
suggested recently (Papp et al., 2006). This may explain the
observation that arrhythmias were not increased when levosimendan was compared with placebo in patients with acute
myocardial infarction (Moiseyev et al., 2002) or when
administered perioperatively in patients having coronary artery
bypass grafting (Nijhawan et al., 1999). However, increased
frequency of ventricular arrhythmias was observed when highdose levosimendan was used in patients with stable ischemic
cardiomyopathy (Nieminen et al., 2000), suggesting that
attention must be paid when the drug is being used at high
doses in patients who have ongoing myocardial ischemia.
4. Haemodynamic effects
It is now believed that levosimendan increases cardiac output
by several mechanisms, involving its effects on heart rate,
improvement of cardiac performance and vasodilation (Lilleberg et al., 1995; Nieminen et al., 2000; Slawsky et al., 2000;
Follath et al., 2002; Kivikko et al., 2002a,b). Cardiac output is
increased by 0.4–0.8 L/min (by increasing both stroke volume
and heart rate), pulmonary capillary wedge pressure (PCWP) is
reduced by 4–6 mm Hg and systemic vascular resistance is
reduced while transpulmonary gradient remains unchanged
(Table 1). In addition, improved cardiac performance has also
been suggested by the decrease of circulating levels of amino
terminal pro-B-type natriuretic peptide after 24-hr infusion of
levosimendan (0.1 μg/kg/min) in patients with decompensated
congestive heart failure (CHF) and a mean left ventricle ejection
fraction at ∼25% (Kyrzopoulos et al., 2005; Parissis et al.,
2006).
Theoretically, levosimendan could increase cardiac output
partly by increasing heart rate (Todaka et al., 1996), an effect
observed in patients with ischemic heart failure with New York
Heart Association (NYHA) functional class II–IV (Nieminen et
al., 2000). Although the exact mechanism of the effect of
levosimendan on heart rate is unknown, it seems to be partly
mediated by compensatory vasodilation-induced activation of
baroreceptor reflexes (Harkin et al., 1995). However, the effect
of levosimendan on heart rate is a function of dosage,
intravascular volume status and the degree of preexisting
impairment of myocardial contractility (Pagel et al., 1997). At a
clinical level, modification of heart rate under clinical
conditions and within the recommended doses is unlikely to
be an important mechanism of the increase in cardiac output
produced by levosimendan (Toller & Stranz, 2006).
4.1. Results from clinical trials
In the levosimendan infusion versus dobutamine in severe
low output heart failure (LIDO) study Follath et al., 2002), a
randomized double-blinded clinical trial, levosimendan
increased cardiac output and reduced PCWP to a greater extent
than dobutamine. Levosimendan also reduced systolic blood
pressure more and tended to cause more vasodilatation. The
haemodynamic effects of levosimendan, unlike those of
dobutamine, were not attenuated by the concomitant use of βblockers. This finding is important, in view of the increasing
evidence for the usefulness of β-blockers in the management of
severe heart failure.
The dose-ranging study (Nieminen et al., 2000) has
demonstrated that all the used dosages of levosimendan caused
a greater reduction in PCWP than placebo or dobutamine, while
high doses of levosimendan had stronger effect on heart rate and
cardiac output. A fall in mean systemic arterial pressure of 5–
10 mm Hg was noted with higher doses of levosimendan, while
the effects on pulmonary haemodynamics were also reported
(Table 1).
Respective improvements of haemodynamics after levosimendan infusion were also observed in the dose escalation
study (Slawsky et al., 2000), the 7-day study (Kivikko et al.,
2002a,b, 2003), and the bolus study (Lilleberg et al., 1995).
These haemodynamic effects of levosimendan seem to persist
for at least 24 hr after discontinuation of a 24-hr infusion
(Kivikko et al., 2002a,b), while there is also evidence that
combined infusion of dobutamine and levosimendan may also
improve haemodynamics in end-stage heart failure (Nanas et
al., 2004).
In conclusion, evidence suggests that levosimendan infusion
leads to an improvement of haemodynamics in patients with
heart failure, an effect which lasts for several days/weeks after
the infusion. However, it is still unclear whether this haemodynamic benefit obtained by levosimendan can be translated into
better short- and long-term outcome of these patients.
5. Effects of levosimendan on heart failure symptoms
The effects of levosimendan on heart failure symptoms have
been assessed in several studies such as the randomized study
on safety and effectiveness of levosimendan in patients with
left ventricular failure after an acute myocardial infarct
(RUSSLAN) study (Moiseyev et al., 2002), the LIDO study
C. Antoniades et al. / Pharmacology & Therapeutics 114 (2007) 184–197
191
Table 1
Levosimendan: clinical trials
Study
In ischemic heart disease
Moiseyev et al., 2002
(RUSSLAN trial)
De Luca, 2005
Sonntag et al., 2004
De Luca et al., 2006a,b
In heart failure patients
Follath et al., 2002
(LIDO study)
Study protocol
Conclusions
Population: 504 patients with left ventricle failure
complicating acute myocardial infarction
Design: double-blind placebo-controlled trial
examining the effect of levosimendan infusion
0.1–0.4 μg/kg/min on composite clinical end points
Population: 26 patients with acute myocardial infarction
Design: double-blind placebo-controlled trial examining
the effect of bolus infusion of levosimendan 12 μg/kg,
on haemodynamics and coronary flow velocities after
primary angioplasty
Population: 24 patients with acute coronary syndrome
Design: double-blind placebo-controlled trial examining
the effect of bolus infusion of levosimendan 24 μg/kg
on left ventricle function after coronary angioplasty
Population: 52 patients with anterior acute myocardial
infarction undergoing primary angioplasty
Design: double-blind placebo-controlled trial,
evaluating the effects of levosimendan on left
ventricular diastolic function
The mortality was lower in patients treated with
levosimendan at 14 and 180 days, although the
incidence of ischemia and/or hypotension was
similar in all treatment groups
Population: 203 patients with severe chronic
heart failure
Design: infusion of levosimendan or dobutamine over
a period of 24 hr; measurements after 30 hr
Nieminen et al., 2000
(Dose-ranging study)
Population: 151 patients with NYHA class II to IV
heart failure
Design: compared 5 different doses of levosimendan with
a placebo and with dobutamine when infused over a
period of 24 hr
Slawsky et al., 2000
(Dose escalation study)
Population: 146 patients with NYHA class III to IV
heart failure
Design: infusion of levosimendan followed by hourly
increments up to a maximum of 0.4 μg/kg/min; patients
randomized to levosimendan then received open-label
drug for the remainder of the 24 hr; subsequently,
patients were randomized to continue levosimendan for
24 hr or to have it withdrawn; further haemodynamic
measurements were made at 48 hr
Kivikko et al., 2002a,b
(7-day study)
Population: 24 patients with NYHA class III to IV
heart failure
Design: randomized to an infusion of 0.05 or
0.1 μg/kg/min
for 7 days during which time, heart rate, blood pressure
and ECG were monitored
Lilleberg et al., 1995
(Bolus study)
Population: 24 patients with severe chronic heart failure
Design: 5-min bolus infusions of levosimendan ranging
from 0.25 to 4 mg
Population: 146 patients with decompensated heart failure
Design: randomized placebo controlled trial, using
levosimendan infusion 6 μg/kg bolus, followed by
0.1–0.4 μg/kg/min continuous infusion for 24/48 hr
Kivikko et al., 2003
Levosimendan induced an improvement of coronary
flow reserve and haemodynamics
Levosimendan improved the function of stunned
myocardium
Levosimendan improved the Doppler echocardiographic
parameters of left ventricular diastolic function,
after primary angioplasty in patients with anterior acute
myocardial infarction
Levosimendan reduced systolic blood pressure more
and tended to cause more vasodilatation than dobutamine.
It increased cardiac output and reduced PCWP to a greater
extent than dobutamine; 6 hr after discontinuing infusion,
the effects of dobutamine had disappeared, but those of
levosimendan persisted
Although both drugs exerted similar effects on stroke
volume, all doses of levosimendan exerted a greater
reduction in PCWP than placebo or dobutamine;
systemic vascular resistance was decreased equally
with levosimendan and dobutamine, but further
vasodilatation occurred with higher doses of
levosimendan; pulmonary vascular resistance declined
with higher doses of levosimendan, while the
transpulmonary gradient remained unchanged
Levosimendan increased stroke volume and cardiac
index with significant effects even at the lowest dose;
it also increased heart rate by an average of 6 bpm at
higher doses, while systemic and pulmonary vascular
resistance were declined and mean systemic arterial
pressure was dropped by 4 mm Hg; haemodynamic
effects persisted or increased over the subsequent 48 hr
for those who remained on the infusion, but
transpulmonary gradient was not affected; only 70% of
patients were titrated to the maximum dose of
levosimendan
Metabolite concentrations reached their peak about
24 hr after cessation of therapy and were still detectable
at therapeutic levels 2 weeks later; heart rate was increased
by up to 18 bpm and 26 bpm, respectively, while
blood pressure dropped by 6 mm Hg and 11 mm Hg,
and returned to baseline within 3 days of cessation of
therapy in contrast to the heart rate, which remained
increased even 14 days after cessation of infusion
Heart rate and cardiac output were increased while
the filling pressures were reduced; the peak was reached
after 10 min and the results were dose related
The haemodynamic effects of levosimendan maintained
during 48-hr continuous infusion and for at least 24 hr
after discontinuation of a 24-hr infusion
(continued on next page)
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Table 1 (continued)
Study
Study protocol
Conclusions
Nanas et al., 2004
Population: 18 patients with end-stage heart failure,
refractory to dobutamine and furosemide
Design: compared the infusion of dobutamine
(10 μg/kg/min) with bolus infusion of levosimendan
6 μg/kg followed by 0.2 μg/kg/min infusion as
adjunctive therapy
Population: 1327 patients with severe heart failure
(ejection fraction < 30%)
Design: randomized controlled trial, comparing the effect
of levosimendan (n = 664, with bolus 12 μg/kg followed
by stepped dose regiment of 0.1–0.2 μg/kg/min for
24 hr) and dobutamine (n = 663, 5 μg/kg/min for 24 hr or
more) on clinical end points
This study evaluated the magnitude and duration of
haemodynamic effects of combined infusion of
dobutamine and levosimendan in end-stage heart failure,
and demonstrated that the combined treatment
improves haemodynamics and symptoms for 24 hr
Mebazaa, 2005;
Cleland et al., 2006
(SURVIVE-W study)
Packer, 2005;
Cleland et al., 2006
(REVIVE-II study)
Population: 600 patients with acute decompensated heart
failure and ejection fraction < 30%, unresponsive to diuretics
and vasodilators
Design: multicenter, randomized placebo controlled trial,
examining the effect of levosimendan (initial bolus, 12 μg/kg
followed by a stepped dose regimen of levosimendan,
0.1–0.2 μg/kg/min for 24 hr) on a complex clinical end point;
the treatment was on top of standard therapy; patients
followed-up for 4 days after the end of infusion
Cleland et al., 2004;
Zairis et al., 2004
(CASINO study)
Population: 299 patients with decompensated low-output
heart failure (ejection fraction < 35%)
Design: patients randomized to receive 24 hr infusion
with levosimendan or placebo or dobutamine; the primary
end-point was the composite of or rehospitalization because
of heart failure deterioration death
Although there was a trend for an improved short-term
survival after levosimendan infusion, this was only from
the period of haemodynamic efficacy of the drug, and
it was not significantly better than dobutamine; patients
who received levosimendan were more likely to
experience atrial fibrillation (9.1% vs. 6.1%) and less
likely to show worsening of heart failure (12.3% vs. 17%)
compared with dobutamine
The primary complex end-point was achieved
(19.4% experienced improvement with levosimendan
vs. 14.6% in placebo, p = 0.015); although plasma BNP
was decreased and the duration of hospitalization
was shortened by ∼2 days (7.9 vs. 8.9 days in
placebo, p = 0.001), this was not accompanied by a
reduction of mortality; furthermore, there were more
reports of hypotension (50% vs. 36%), VT (25% vs.
17%) and atrial fibrillation (8% vs. 2%) in
levosimendan-treated patients compared with placebo
The study was designed to recruit 600 patients, but it
was stopped after 299 patients had been recruited, as
a result of the clear superiority of levosimendan versus
the other treatments (6 months mortality was 18% for
levosimendan, 42% with dobutamine and 28.3%
for placebo)
PCWP: pulmonary capillary wedge pressure; BNP: NT-pro-Brain Natriuretic Peptide.
(Follath et al., 2002), the dose escalation study (Slawsky et al.,
2000) and others.
5.1. Results from clinical trials
The RUSSLAN study (Moiseyev et al., 2002) randomized
504 patients with acute pulmonary edema after myocardial
infarction to 4 different 6-hr dosing regimens of levosimendan
or placebo in addition to conventional background therapy with
the exception of other intravenous inotropic agents. The
objective of the study was to examine the safety of
levosimendan in this high-risk population, targeting the risk
of ischemia and hypotension. Levosimendan did not exacerbate
these problems except at the highest dose. Overall, levosimendan did not affect symptoms. However, worsening heart failure
was less likely with levosimendan than with placebo at 6 hr and
24 hr. Also, patients treated with levosimendan experienced less
dyspnea and fatigue.
Similarly, in the dose escalation study (Slawsky et al.,
2000), the symptoms were more often improved on levosimendan than on placebo at the end of the 6-hr, double-blind
phase. Similar trends were observed for fatigue. However, in
the LIDO study (Follath et al., 2002), nonsignificant trends
towards greater improvement in breathlessness and fatigue
were noted among patients receiving levosimendan compared
with dobutamine.
The effect of levosimendan on symptomatic relief in heart
failure patients was also examined in the recently presented
REVIVE-II trial (Packer, 2005), which was actually the first
large, prospective, randomized, double-blind, controlled trial
comparing the effects of levosimendan plus standard therapy to
the effects of standard therapy alone over the clinical course of
patients with acute decompensated heart failure. Importantly,
the REVIVE-II showed an improvement of the composite endpoint (Table 1) compared with placebo. The 3-stage “composite
end-point” of this study consisted of 3 ranking clinical features:
“improved” (defined as moderately or markedly improved
patient global assessment at 6 hr, 24 hr, 5 days and no
worsening), “unchanged” (defined as neither improved nor
worse) or “worse” (defined as death from any cause, persistent
or worsening heart failure requiring intravenous medications
such as diuretics, vasodilators or inotropes at any time or
moderately/markedly worse patient global assessment at 6 hr,
24 hr and 5 days). In the REVIVE II it was demonstrated that
levosimendan improves symptoms, decreases the duration of
hospitalization and decreases NT-pro-brain natriuretic peptide
(BNP) levels (Table 1).
Although the outcome of clinical trials regarding the effect of
levosimendan on heart failure symptoms is still controversial, it
seems that levosimendan is indeed a therapeutic option to relief
symptoms of heart failure, improving in this way the quality of
life in these patients.
C. Antoniades et al. / Pharmacology & Therapeutics 114 (2007) 184–197
6. Effects of levosimendan on morbidity and mortality
The initial evidence suggested that levosimendan is superior
to any other inotropic agent currently used in clinical practice,
regarding its effects on morbidity and mortality (De Luca et al.,
2006a,b). Indeed, in the RUSSLAN study (Moiseyev et al.,
2002), the composite outcome of death or worsening heart
failure at 24 hr was significantly reduced from 8.8% to 4.0%.
All-cause mortality at 14 days was again significantly reduced
from 19.6% to 11.7%, whereas at 180 days, mortality on
levosimendan was 22.6% compared with 31.4% on placebo.
The reduction in mortality was similarly independent of the
dose of levosimendan used in the study. Similar effects were
also observed in the LIDO study (Follath et al., 2002), since
1 month after levosimendan infusion, there was a significantly
lower mortality with levosimendan than with dobutamine and a
reduction in the composite endpoint of death or worsening heart
failure. In addition to improving haemodynamic performance,
lower mortality was seen in the levosimendan group than in the
dobutamine group for up to 180 days (26% vs. 38%, 0.57
[0.34–0.95]; p = .029). A reduction in the composite outcome
(death or hospitalization with heart failure or an increase in days
alive and out of hospital) during 6 months of follow-up was also
observed. The results of that study have led to much
speculation. Dobutamine may have had an adverse effect on
survival. Acute exposure to powerful adrenergic stimulants may
not only provoke arrhythmias but also accelerate programmed
cell death of cardiac myocytes, worsening both short-term and
long-term outcome. On the other hand levosimendan might
exert a sustained beneficial effect on haemodynamics, with
possible secondary neuroendocrine benefits with relatively
lower hazards of arrhythmogenesis, cellular Ca2+ overload, and
induction of cell death.
193
consisted of relatively young (mean age, 63 years) patients,
mainly males (73%). Therefore, we should wait for publication
of these results before any definite conclusion is made.
In a third clinical trial, the calcium sensitizer or inotrope or
none in low-output heart failure (CASINO) study (Zairis et al.,
2004), a clear benefit of levosimendan on 6 months of survival
was demonstrated in patients who received levosimendan
compared with placebo (Table 1) (Cleland et al., 2004). The
superiority of levosimendan in the CASINO study was so clear
that the study was stopped early after recruitment of 299
patients (out of 600 patients scheduled to be recruited in the
initial study design; Cleland et al., 2004).
A more critical view of the existing data regarding the impact
of levosimendan on mortality in heart failure leads to the
conclusion that the high heterogeneity of the few published
studies does not allow any safe conclusions for the moment.
Previous studies comparing the effects of levosimendan versus
dobutamine were referred mainly to patients with severe chronic
heart failure, who were more likely to be under treatment with
beta-blockers, which seems to interact favorably with levosimendan compared with dobutamine (Follath et al., 2002). The
rather conflicting results of the recently published clinical trials
are reflected in a recent meta-analysis (Cleland et al., 2006)
which indicated a nonsignificant trend towards better short-term
survival with levosimendan compared with placebo (OR [95%
CI]: 0.79 [0.58–1.08]) and a borderline significant difference
compared with dobutamine (OR (95%CI): 0.75 [0.60–0.93]).
In conclusion, the ability of levosimendan to improve shortor even long-term survival in patients with severe heart failure is
still a topic of controversy, and further studies are needed to
document such an effect.
7. Side effects of
levosimendan—interactions with other drugs
6.1. Results from recent and ongoing clinical trials
The SURVIVE study (Mebazaa, 2005) is actually the first
clinical trial examining the short- and long-term survival after
levosimendan infusion in high-risk patients with severe heart
failure (ejection fraction < 30%), compared with dobutamine
(Table 1). The major end point was 180-day all-cause mortality;
and despite the trend towards greater improvements with
levosimendan early after the end of infusion, this did not reach
significance (Table 1). Although the full details of the study
have not been published yet, it seems that levosimendan also
reduced BNP to a greater extent than dobutamine during the
first week after infusion. Furthermore, it was associated with
lower risk of heart failure worsening but higher risk for atrial
fibrillation compared with dobutamine. Interestingly, the
proportion of other side effects, such as hypotension and VT,
was similar in both study groups (Mebazaa, 2005).
On the other hand, in the REVIVE-II study (Packer, 2005),
levosimendan had no effect on 90-day mortality, although it
seems that it induced some side effects, such as hypotension and
arrhythmias (Table 1). However, it is important to point out that
the REVIVE-II was not designed to examine the effect of
levosimendan on mortality, whereas the study population
Levosimendan is generally well tolerated by patients.
However, decrease in vascular resistance, which is induced by
the drug, can lead to various haemodynamic effects.
Hypotension is probably one of the most common side effect
observed after levosimendan administration in the clinical
practice (Nieminen et al., 2000; Mebazaa et al., 2005; Packer,
2005). Indeed, REVIVE-II study(Packer, 2005) reported a
higher incidence of hypotension in the levosimendan group
compared with the placebo group (50% vs. 36%). Consequently hypotension may cause myocardial ischemia, cardiac
arrhythmias, and hypoxemia. However, these side effects are
not common when the treatment remains within the
recommended doses (Nieminen et al., 2000; Moiseyev et
al., 2002). The vasodilatory effects of the drug may be
responsible for headache (5% of patients), dizziness (1–10%
of patients), and nausea (1–10% of patients) (Slawsky et al.,
2000; Sundberg & Lehtonen, 2000; Follath et al., 2002;
Moiseyev et al., 2002).
Levosimendan may also affect cardiac rhythm. It may
increase sinus rate, shorten sinus node recovery time and
decrease atrioventricular nodal conduction interval (see Section
3.3; Toivonen et al., 2000). Levosimendan may prolong the
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rate-corrected QT interval, an effect which seems to be dose
related (Nieminen et al., 2000) and largely also dependent on
the patient's clinical profile (Lilleberg et al., 1995; Sundberg et
al., 1995). Despite this proarrhythmic potential of levosimendan, most of the clinical studies provided no evidence of
increased life-threatening ventricular tachyarrhythmias after
levosimendan administration in the clinical practice (Lilleberg
et al., 2004). However, 2 recent clinical trials, the REVIVE-II
and SURVIVE studies, have shown that patients receiving
levosimendan were more likely to experience atrial fibrillation
compared with placebo and dobutamine (Mebazaa, 2005;
Packer, 2005).
Another interesting issue with levosimendan is its interaction
with other heart failure drugs. Most patients with heart failure
being treated with levosimendan are usually taking other routine
heart failure drugs concomitantly such as ACE inhibitors,
diuretics, nitrates, beta-blockers and digoxin. In the LIDO study
(Follath et al., 2002) 89% of patients receiving levosimendan
were using ACE inhibitors, 76% were using digoxin and 95%
were using diuretics. However, clinical studies so far have not
reported serious interactions when levosimendan was used
within the recommended dose range. Similarly, concomitant use
of levosimendan and beta-blockers was shown to have
beneficial or neutral effects on the inotropic efficacy of the
drug (Haikala et al., 1997; Follath et al., 2002; Lehtonen &
Sundberg, 2002), while the actions of dobutamine were
attenuated (Follath et al., 2002). Furthermore, the combination
of levosimendan with angiotensin converting enzyme inhibitors
has been associated with only minor decreases in mean arterial
blood pressure when levosimendan was used within the
recommended dose range (Antila et al., 1996; Nieminen et al.,
2000). On the other hand its combination with nitrates increased
heart rate by 40 beats/min in healthy subjects during an
orthostatic test (Sundberg et al., 1995) but produced only
marginal decreases in systolic blood pressure (5 mm Hg) and
minor increases in heart rate (4 beats/min) in patients with acute
myocardial infarction (Moiseyev et al., 2002). Finally no
increase in heart rate and no effect on blood pressure were
observed when coadministered with furosemide, amiodarone
(Nanas et al., 2004) and calcium antagonists (Poder et al.,
2003). Taken together, all these data suggest that levosimendan
does not appear to have any serious interactions with the
currently used medication in heart failure. And this may provide
an important advantage against dobutamine, especially when
beta-blockers are co-administered.
8. Conclusions
Levosimendan is a Ca2+ sensitizer in myocardium and KV/
KCa2+/KATP channel opener in vascular SMC that has a dual
inotropic and vasodilatory effect. It provides both symptomatic
and haemodynamic improvement within a few hours of
treatment initiation, while these benefits are achieved with a
minimum increase of myocardial oxygen requirements and
without impairing diastolic relaxation. Furthermore, it seems to
have beneficial effects in ischemic heart disease, since further to
its effect as a vasodilator, it also seems to have direct cyto-
protective effects on ischemic myocardium, while it also has
antiinflammatory and antiapoptotic properties.
Despite the initial reports for a positive effect of levosimendan on short- and long-term survival in patients with severe
heart failure, the results of the recently presented large-scale
clinical trials provided rather controversial results. Although
levosimendan is considered to induce fewer arrhythmias than
classic inotropes, recent studies suggested that levosimendan
infusion may be associated with higher incidence of atrial
fibrillation in patients with heart failure.
In several countries, levosimendan is already routinely used
in patients with heart failure requiring inotropic support. If
future studies confirm its beneficial effect on mortality, it is
likely to become the inotropic agent of first choice in severe
heart failure in the near future.
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