The Journal of Clinical

Pharmacology
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Levosimendan: Implications for Clinicians

Brian F. McBride and C. Michael White
J. Clin. Pharmacol. 2003; 43; 1071
DOI: 10.1177/0091270003257217

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 THERAPEUTIC REVIEW

ARTICLE
MCBRIDE AND WHITE
10.1177/0091270003257217
LEVOSIMENDAN:
THERAPEUTIC REVIEW
IMPLICATIONS FOR CLINICIANS

Levosimendan: Implications for Clinicians

Brian F. McBride, PharmD, and C. Michael White, PharmD

Levosimendan is a novel calcium sensitizing agent in devel- levosimendan to open adenosine triphosphate (ATP)–
opment for the treatment of acute and chronic heart failure. sensitive potassium channels. In addition, the agent has not
The agent increases myocardial force without increasing been studied in patients with additional risks for torsades de
myocyte calcium concentrations, thus reducing the possibil- pointes. Levosimendan has been shown to have beneficial
ity for myocardial necrosis. In addition, the agent also causes survival effects in several populations; its use improves pa-
vasodilation of coronary and peripheral vessels to improve tient outcomes relative to the standard of care and has the po-
coronary blood flow and reduce afterload. The short half-life tential to reduce hospital costs associated with heart failure.
is a benefit for intravenous administration but could be prob-
lematic for the drug’s use in chronic heart failure. The risk of Keywords: Levosimendan; acute decompensated heart fail-
the development of arrhythmias from levosimendan ap- ure; pharmacokinetics; calcium sensitization
pears small secondary to an increase in the QTc interval of Journal of Clinical Pharmacology, 2003;43:1071-1081
15 msec but needs to be evaluated in light of the ability of ©2003 the American College of Clinical Pharmacology

C hronic heart failure (CHF) is a major health disor-

der in the United States. The annual cost of caring
for these patients approaches $5 billion annually.1 A
exploration of novel experimental agents that increase
inotropy without affecting myocardial calcium con-
centrations is warranted. This review will focus on the
large portion of these costs are attributed to the in- pharmacodynamics, pharmacokinetics, interactions,
hospital management of acute decompensated heart adverse events, and clinical data of levosimendan, a
failure (ADHF). ADHF is characterized by an increase calcium sensitizing agent, for the treatment of ADHF.
in neurohormonal activation that is associated with
systemic congestion, pulmonary congestion, and a de- MYOCARDIAL PHYSIOLOGY
cline in ejection fraction (EF) from baseline levels.
ADHF etiology is usually multifactorial and involves A review of myocardial physiology is essential to ap-
patient socioeconomic status, noncompliance with preciate the novel mechanism of action of
diet and medication, and less aggressive medical care levosimendan. The key proteins involved in myocar-
during the initial hospitalization when ADHF is diag- dial contraction are myosin, actin, tropomyosin, and
nosed.2-6 Pharmacologic therapy for ADHF targets the the troponin complex (see Figure 1).
reversal of congestive symptoms (e.g., diuretics, vaso- Myosin is a large helical protein consisting of four
dilators) and improvement in ventricular function light chains and two heavy chains. At one end of each
(e.g., inotrope therapy). Unfortunately, currently heavy chain, the amino acid sequence forms a globular
available inotrope therapy may increase mortality and myosin head. These heads exhibit enzymatic activity
is associated with a high incidence of ventricular that converts adenosine triphosphate (ATP) to
arrhythmias.7-9 Since these agents (i.e., catecholamines adenosine diphosphate (ADP) and free energy. This
and phosphodiesterase inhibitors) increase inotropy free energy, along with intracellular magnesium, al-
via increases in myocardial calcium concentrations, lows myosin to bind tightly to actin filaments. By bind-
ing to ADP-mediated active sites, the myosin heads
From the Hartford Hospital Drug Information Center, Hartford, Connecti- “walk along” the actin filament, causing muscle con-
cut, and the University of Connecticut School of Pharmacy, Storrs, Con- traction by increasing the overlap between actin and
necticut. Submitted for publication February 22, 2003; revised version ac- myosin filaments. ADP-mediated active sites are
cepted June 15, 2003. Address for reprints: C. Michael White, PharmD,
Hartford Hospital Drug Information Center, 80 Seymour Street, P.O. Box
blocked by another protein known as tropomyosin,
5037, Hartford, CT 06102-5037. which must be removed by the troponin complex for
DOI: 10.1177/0091270003257217 myocardial contraction to occur.

J Clin Pharmacol 2003;43:1071-1081 1071

 MCBRIDE AND WHITE

Figure 1. Interaction of the

troponin/tropomyosin complex
with the actin filament. During di-
astole, troponin I covers the
adenosine triphosphate (ATP) re-
active site on the actin filament.
When calcium binds to troponin C
during systole, a conformational
change causes troponin T to lift
tropomyosin and troponin I away
from the ATP reactive site to permit
actin and myosin interaction.

The troponin complex consists of three proteins: PHARMACODYNAMICS

troponin I, troponin T, and troponin C. Troponin I
serves as the anchor protein to the actin filament, while Calcium Sensitization
troponin T is bound to tropomyosin. Finally, troponin
C binds calcium, which is necessary for the troponin
complex to remove tropomyosin.10 Agents currently available for the treatment of ADHF
Troponin C is an EF hand protein that has four bind- increase myocardial concentrations of cAMP, which
ing sites for calcium. As calcium binds, the ultimately causes an inotropic effect by increasing
conformational shape of the protein is altered and lifts myocardial concentrations of calcium.15,16 Catechola-
tropomyosin from the ADP-mediated active site on the mines such as dobutamine stimulate beta-1
actin filament, thus permitting contraction. During adrenoceptors on the myocardial cells, causing in-
ventricular systole, calcium concentrations are high creases in cAMP, while phosphodiesterase inhibitors
enough to induce this conformational change. As con- such as milrinone prevent the breakdown of cAMP by
centrations decline during diastole, troponin C re- phosphodiesterase. In contrast, levosimendan re-
turns to its resting state and permits inhibition by duces the calcium-binding coefficient of troponin C
tropomyosin.11 by stabilizing the conformational shape of the protein
Myocardial calcium concentrations increase in sys- in its active form (see Figure 2). This enhances myo-
tole and decrease in diastole. Longstanding CHF is cardial contraction similar to traditional agents but
known to decrease myocardial calcium concentrations with lower intracellular calcium concentration re-
in systole because beta-1 receptor down-regulation quirements. Even though levosimendan does not en-
prevents endogenous catecholamines from causing hance intracellular calcium, there is a concentration-
inotropy, which contributes to the reduced cardiac out- response relationship between intracellular calcium
put by the mechanism described.12-14 and inotropy.

1072 • J Clin Pharmacol 2003;43:1071-1081

 LEVOSIMENDAN: IMPLICATIONS FOR CLINICIANS

Figure 2. Protein structure of troponin C. In the absence of levosimendan (left panel), higher calcium concentrations are required to overcome
the sterically hindered active sites. Levosimendan causes an opening of the active sites to permit calcium binding at lower concentrations (right
panel).

The increase in cAMP provided by catechol- ATP-Sensitive Potassium

amines and phosphodiesterase inhibitors causes an Channel Activation
up-regulation in the activity of protein kinase C, which
increases the calcium current into myocytes during The opening of ATP-sensitive potassium (KATP) chan-
systole to cause an increased inotropic effect. During nels by levosimendan provides three beneficial effects
diastole, the activity of protein kinase C enhances the (peripheral vasodilation, coronary artery dilation, and
outward calcium current to enhance lusitropy.17 myocyte mitochondrial activation) that work synergis-
Levosimendan offers the advantage of increasing tically with calcium sensitization to improve myocar-
systolic force without compromising coronary perfu- dial performance. In the normal heart, protein kinases
sion due in part to a synergistic mechanism of action that generate vasodilatory substances open these chan-
(see below).18,19 These effects were demonstrated by a nels. However, the imbalance between endogenous
study of human myocardial specimens in which ad- vasodilatory and vasoconstrictive substances in heart
ministration of levosimendan (10–7 M) caused an in- failure reduces their activity.21
crease in the developed force (Fdev) compared to control Levosimendan’s effect on the activation of ATP-
(13.84 ± 3.27 vs. 16.40 ± 3.57 mN/mm2, p < 0.05) while sensitive potassium (KATP) channels was investigated
decreasing diastolic force (Fdia) compared to baseline using an in vitro preparation of rat arterial myocytes.
(5.32 ± 0.67 mN/mm2 vs. 4.94 ± 0.61 mN/mm2, p < The myocytes were exposed to 10–6 M of levosimendan.
0.05).20 Application of the agent produced a significant in-

THERAPEUTIC REVIEW 1073

 MCBRIDE AND WHITE

crease in resting membrane potential (–44.3 ± 2.2 mV cial, opening KATP channels on the myocardium has
vs. +19.4 ± 3.5 mV, p < 0.05). To confirm that been shown to cause ventricular fibrillation in animals
levosimendan was acting on the KATP channels, a sec- secondary to a shortening of the ventricular action po-
ond experiment was conducted with the myocytes in- tential duration. However, the ability of levosimendan
cubated in a solution of glibenclamide, a known inhibi- to prolong the ventricular action potential may reduce
tor of K AT P. In the presence of the inhibitor, the risk of arrhythmia induced by opening of the KATP
levosimendan did not cause hyperpolarization. The channels (see below). Clearly, more research is needed
study also noted that levosimendan had no effect on to provide a more complete understanding of the
the L-type calcium channels located in the peripheral electropharmacologic profile of levosimendan.
vasculature.22 However, the phase I clinical trials dis-
cussed below demonstrate that the agonism of KATP Inhibition of Phosphodiesterase III
channels causes vasodilation, which translates into a
reduction in afterload-enhancing cardiac output. As described above, high doses of a pure phospho-
Mitochondrial calcium cycling is also affected by diesterase III (PDE III) inhibitor (e.g., milrinone) have
levosimendan. Opening of KATP channels in the mito- been shown to increase intracellular levels of cyclic
chondria promotes the use of mitochondrial calcium, AMP. Low levels of PDE III inhibition provide positive
thus decreasing the need for extracellular calcium to lusitropic activity with a reduced chance of developing
cause contraction. When these channels are activated, an arrhythmia. Although levosimendan exhibits antag-
it causes a reduction in transmembrane potential. In an onist activity against PDE III, the extent of this activity
in vitro model of arterial myocytes, levosimendan re- does not cause an increase in the intracellular levels of
duced transmembrane potential in a concentration- cAMP.16,24,25
dependent fashion when compared to control (6.5%
for levosimendan 0.7 mcM and 40.4% for PHARMACOKINETICS
levosimendan 2.6 mcM; no p-value reported).19 This ef-
fect could positively affect the safety profile of Levosimendan is rapidly absorbed from the gastroin-
levosimendan relative to other inotropic therapy since testinal tract and demonstrates an 85% bio-
myocardial calcium concentration is not altered. availability compared to the intravenous formulation.
Currently available inotropic therapy increases Levosimendan exhibits a modest volume of distribu-
myocardial oxygen demand.15 This is especially prob- tion (27 ± 5.3 L), which could enhance its effects as a
lematic in patients with concomitant ischemic heart peripheral vasodilator.26
disease. Precipitating myocardial ischemia is a known The primary route of metabolism is via the hepatic
trigger for ventricular tachyarrhythmias. In addition, glutathione system, and metabolism is rapid, as evi-
ischemia causes myocardial cells in the ischemic zone denced by its short half-life (0.94 h). Since the urinary
to attenuate or stop contracting until adequate blood and fecal recovery of radiolabeled drug and metabo-
flow has been reestablished. This has been shown to lites only totaled 70% of the administered dose, the
compromise cardiac output, which can exacerbate presence of a third tissue-specific metabolic pathway
CHF. Therefore, agents that could reduce oxygen de- must be considered.26 Studies comparing healthy vol-
mand while increasing pumping activity would be ad- unteers and those with heart failure have shown no sig-
vantageous in the heart failure population. nificant differences in the pharmacokinetic profile of
In normal myocardium, endogenous protein kinase levosimendan.26 Although no published studies of the
enzymes with vasodilatory activity have been shown to impact on renal disease on the pharmacokinetics of
activate KATP channels on the coronary arteries, which levosimendan are available, a review by Figgit et al27
increases diastolic coronary flow velocity (DCFV). quotes data from the manufacturer as saying that renal
However, the increase in vasoconstricitve substances disease has no impact on the pharmacokinetic profile
associated with ADHF prevents the opening of these of the agent. The rapid clearance of intravenous
channels and contributes to a reduced DCFV. levosimendan is advantageous since the effects can be
Levosimendan has been shown to significantly in- rapidly terminated after therapy discontinuation.
crease DCFV through activation of the KATP channels lo- While the short half-life would be a disadvantage for
cated on the coronary vasculature.22 Early trials have oral administration of the agent, the feasibility of trans-
also shown that opening of the KATP channels in the cor- dermal or controlled-release formulations could cir-
onary vasculature can also reduce the size of an infarc- cumvent this issue.26,28
tion by dilating collateral vessels.23 While the ability to Levosimendan’s high (98%) protein binding may
dilate coronary arteries via this mechanism is benefi- create the potential for pharmacokinetic drug interac-

1074 • J Clin Pharmacol 2003;43:1071-1081

 LEVOSIMENDAN: IMPLICATIONS FOR CLINICIANS

tions. Since the levosimendan molecule has both pro- of these findings, one would predict that the half-life of
ton donor and proton acceptor sites, this interaction warfarin should increase since an inverse relationship
could affect drugs that bind to both positively and neg- exists between half-life and Vd when clearance is un-
atively charged plasma proteins such as albumin and changed. However, levosimendan caused a significant
alpha-1-acid glycoprotein.29 Protein-binding interac- decrease in half-life of warfarin (40.8 ± 8.1 vs. 37.3 ± 7.8
tions with other highly bound agents have been found h, p < 0.05). This indicates that the metabolism of war-
to have a minor impact on blood concentrations chron- farin is altered. Since the individual components of
ically as the increase in the free fraction of the drugs en- clearance (e.g., hepatic, renal) and the steady-state
hances elimination. Agents that demonstrate this effect clearance of warfarin were not evaluated, one can only
include warfarin, lithium, and valproic acid. Whether speculate about why a paradoxical relationship be-
the same will be true for levosimendan remains to be tween half-life and Vd exists during concomitant
established. administration.
This study exhibits limited external validity for sev-
DRUG INTERACTIONS eral reasons. First, a single dose of warfarin was stud-
ied. Warfarin inhibits the carboxylation of the vitamin
Anticoagulants K–dependent clotting proteins and has no effect on the
proteins that have already been carboxylated.31 There-
fore, the effect of warfarin on the TT-SPA or interna-
Since anticoagulants are commonly used to prevent
tional normalized ratio (INR) would not be seen for up
thrombosis in heart failure, concerns regarding the dis-
to 6 days. While the TT-SPA was analyzed at 12 time
placement of warfarin and heparin by levosimendan
points for up to 6 days, the authors did not specify
have been raised. While no studies with levosimendan
which time point is reported for the TT-SPA in the re-
and heparin are available, a small crossover study of
sults. Second, the TT-SPA is too specific and does not
warfarin and levosimendan has been reported. Partici-
measure the effect of factor IX. To make the study more
pants (n = 10; age = 26 years, mean weight = 72 kg) re-
relevant to clinical practice, the authors should have
ceived either a single 25-mg dose of warfarin or 9 days
used a prothrombin time (PT) and INR. Third, the aPTT
of therapy with oral levosimendan 500 mcg every 6
is not specific for vitamin K–dependent clotting factors
hours and a single 25-mg dose of warfarin administered
VII, IX, X, II (i.e., the SNOT factors) and likely remained
on the 4th day of the combination phase. Pharma-
unchanged since most of the factors represented by the
cokinetic parameters (maximum concentration, Cmax;
aPTT remained uninhibited.31 More information re-
time to maximum concentration, tmax; area under the
garding the effects of levosimendan on the pharma-
curve, AUC; total clearance; and plasma protein bind-
cokinetics of warfarin could have been provided if the
ing) for both agents were reported. The effect of combi-
study had been designed to evaluate the effects of
nation therapy on the pharmacokinetics of both agents
levosimendan on therapeutic warfarin therapy.
was also reported. The level of anticoagulation was
measured by the activated partial thromboplastin time
(aPTT) and the thromboplastin time (TT-SPA). There Vasodilators
was no difference in the aPTT or TT-SPA with concom-
itant administration of levosimendan and warfarin. There are two reasons clinicians need to be concerned
Concomitant administration did not alter the protein about additive vascular effects with levosimendan and
binding of warfarin at 2 hours after warfarin adminis- other vasodilators such as beta-adrenergic antagonists,
tration (98.7% ± 0.3% vs. 98.8% ± 0.1%; p-value not re- angiotensin-converting enzyme inhibitors (ACEIs),
ported). This effect was nearly identical 4 hours follow- and nitrates. First, patients receiving the intravenous
ing warfarin administration. The protein binding of form of levosimendan for ADHF will eventually be ti-
levosimendan was also not altered at 2 or 4 hours after trated to oral vasodilator therapy. Study in this area is
levosimendan administration (97.0% ± 0.6% vs. 96.5% warranted because if nitrates are titrated too quickly in
± 1.0% [p-value not reported] and 96.5% ± 0.5% vs. the presence of levosimendan, a rapid drop in pulmo-
96.5% ± 0.6% [p-value not reported]). Cmax, tmax, total nary capillary wedge pressure (PCWP) could compro-
clearance, and AUC for both levosimendan and warfa- mise cardiac output (CO). Second, the potential for
rin were not significantly different when the agents levosimendan to be used as a chronic therapy exists.
were administered separately or concomitantly. The Therefore, the addition of oral or transdermal
Vd of warfarin was increased when given with levosimendan to current standards of care for CHF
levosimendan (40.8 ± 8.1 vs. 37.3 ± 7.8, p < 0.05). Total must be examined.26,28 In a placebo-controlled cross-
clearance was not significantly different.30 On the basis over study of 12 healthy volunteers, the coadministra-

THERAPEUTIC REVIEW 1075

 MCBRIDE AND WHITE

tion with isosorbide dinitrate did not produce additive the effects of the agent on HR, SBP, CO, EF, and cor-
effects on heart rate (HR), CO, systemic vascular resis- rected QT interval (QTc). In addition, 24-hour Holter
tance (SVR), and systolic blood pressure. Similar re- monitoring was performed. Last, the effects of drug ad-
sults were reported when levosimendan was adminis- ministration on plasma levels of neurohormones were
tered with captopril.32 Although no published data examined. Resting HR was not influenced by either
about the interaction of levosimendan with beta- dose of levosimendan (65 ± 12 bpm for placebo, 64 ± 10
adrenergic antagonists are available, Figgit et al27 cited bpm for 6.5 mcg/kg, p = ns; 63 ± 11 for placebo, 67 ± 10
manufacturer data showing no interaction between bpm for 25 mcg/kg, p = ns). Systolic blood pressure was
levosimendan and cardvedilol, a nonselective beta- not reduced by study drug administration (134 ± 9
receptor antagonist with alpha antagonist properties. mmHg vs. 135 ± 9 mmHg at 6.5 mcg/kg, p = ns, and 133 ±
7 mmHg vs. 134 ± 8 at 25 mcg/kg). Cardiac output was
HEMODYNAMIC AND increased with both doses (7.6 ± 1.6 L/min vs. 7.8 ± 1.9
ELECTROPHYSIOLOGIC EFFECTS L/min, p = 0.01, for 6.5 mcg/kg and 7.2 ± 1.3 L/min vs.
8.6 ± 1.3 L/min for 25 mcg/kg, p < 0.001). EF was ele-
In an evaluation of myocardial efficiency, 8 patients vated in a similar fashion to the cardiac output (57.3%
with CHF (6 male, age 59 ± 9 years) were randomized to vs. 60.2%, p = 0.05, for 6.5 mcg/kg and 57% ± 4% vs.
receive placebo or levosimendan (18 mcg/kg bolus, 0.3 62.5% for 25 mcg/kg, p < 0.001). There were no indica-
mcg/kg/min infusion). On the 2nd day, patients were tions of proarrythmic activity following examination of
crossed over to the other treatment. Patients’ myocar- the Holter monitor recordings. Neurohormones were
dial and hemodynamic response to levosimendan was not affected by drug administration. QTc interval was
measured by echocardiography and Swan-Ganz cathe- not altered with the 6.5-mcg/kg dose (402 ± 24 msec vs.
ter monitoring, respectively. Positron emission tomog- 408 ± 14 msec, p = ns), but after receiving the 25-mcg/kg
raphy (PET) was used to evaluate myocardial blood dose, the QTc interval was significantly prolonged
flow and oxygen consumption. Global myocardial (394 ± 25 msec vs. 415 ± 17 msec, p < 0.01).34 The clini-
blood flow increased 32% with active treatment (p = cal significance of the 15-ms elevation in the QTc inter-
0.032). The distribution of the increase in blood flow val is thought to be minimal because the risk of fatal
was evenly distributed between the septal, anterior, ventricular arrhythmias (e.g., torsades de pointes) is
and lateral regions of the heart. This is an important significant when the interval is greater than 30 msec or
finding because improvements in coronary blood flow when the absolute value exceeds 500 msec.35,36 It is to
could reduce the risk for an arrhythmia, as discussed the drug’s benefit that the QTc interval increase was the
earlier. Therapy also produced a modest but significant maximum increase seen throughout the day by ambu-
increase in heart rate (73 ± 5 vs. 78 ± 5 bpm, p = 0.015). latory ECG monitoring in study participants and not
Similar to previous studies, levosimendan caused an the increase noted by the performance of random ECGs,
increase in CO (4.1 ± 0.4 vs. 5.0 ± 0.6 L/min) and EF which frequently underestimate the true degree of in-
(33% ± 4% vs. 40% ± 6%, p = 0.025). PCWP and SVR crease in the QTc interval produced by a drug. In addi-
were also reduced (21 ± 4 mmHg vs. 17 ± 4 mmHg, p = tion, use of levosimendan in severe hypokalemia,
0.013, and 1611 ± 152 dynes*s/cm5 vs. 1193 ± 144 hypomagnesemia, myocardial hypoxia, systemic aci-
dynesxs/cm5, p < 0.001). Interestingly, systolic blood dosis, and other factors that, by themselves, can pro-
pressure (SBP) and diastolic blood pressure (DBP) were mote QTc interval prolongation has not been studied,
not altered by levosimendan administration.33 Despite and caution in these patients is warranted until further
the promising results observed in this trial, the number data are available. In addition, whether levosimendan
of patients is very small and warrants further studies to exhibits reverse use dependence and has an accentu-
see if the improvement in hemodynamics translates ated QTc interval effect at lower heart rates, like class Ia
into improved safety relative to other agents currently and III antiarrhythmic drugs (with the exception of
available. amiodarone and ibutilide), is not known.37
The hemodynamic effects of levosimendan were The electrophysiologic effects of levosimendan
also investigated in a phase I open-label crossover trial were further evaluated in a study of 10 patients (no de-
(n = 14; age = 20-29 years, weight = 67-84 kg). Patients mographic information) who were being evaluated for
were administered placebo followed by a bolus dose of syncope or paroxysmal supraventricular tachycardia.
levosimendan using one of two regimens (i.e., 6.5 mcg/ All participants had no evidence of structural heart dis-
kg or 25 mcg/kg) administered over 10 minutes. On day ease and had normal liver and renal function tests.
2, patients were administered a placebo and the alter- Levosimendan was administered as an 18-mcg/kg
native dose of levosimendan. Investigators examined bolus over 10 minutes followed by a continuous infu-

1076 • J Clin Pharmacol 2003;43:1071-1081

 LEVOSIMENDAN: IMPLICATIONS FOR CLINICIANS

sion of 0.4 mcg/kg/min (two to four times the continu- ment of future therapies will be evaluated for their ef-
ous infusion rate used in clinical trials). Investigators fects on hemodynamics and neurohormonal levels.
examined the effects of the study drug on the atrial-His The effects of levosimendan on neurohormonal re-
(AH) and His-ventricular (HV) intervals, ventricular lease were evaluated as a substudy of a phase II clinical
mean action potential duration (VAPD), and effective trial. Patients (n = 79, 82% male, mean age = 59 years)
refractory period (VERP). The QTc interval was also with New York Heart Association (NYHA) class III or
measured. There was a significant increase in the sinus IV CHF had a PCWP > 15 mmHg and a cardiac index
rate from baseline values (62 ± 9 bpm vs. 71 ± 10 bpm, (CI) < 2.5L/min/m2. The endpoint of the study was the
p < 0.05), which corresponds with a significant de- influence of levosimendan (6 mcg/kg intravenous
crease in sinus node recovery time (average decrease of bolus followed by a continuous infusion of 0.1 mcg/kg/
160-280 ms, p < 0.001). During the phase of the study in min to 0.4 mcg/kg/min) or placebo on endothelin-1
which patients were in sinus rhythm, there was no in- (ET-1) and norepinephrine concentrations in the
crease in the VAPD. There was a significant effect on plasma. After 6 hours of therapy, ET-1 levels were re-
the QTc interval during sinus rhythm (395 ± 23 msec vs. duced by 11% versus baseline (8.32 ± 4.84 vs. 7.17 ±
420 ± 28 msec, p < 0.001). During the pacing phase, 4.03 pg/mL, p = 0.008 vs. levosimendan, and 7.17 ±
there was an increase in the VAPD by an average of 9 to 4.03 vs. 8.99 ± 6.33 pg/mL, p < 0.001 vs. placebo). After
17 msec (p < 0.001 for 50% VAPD; p = 0.07 for 90% 24 hours, ET-1 was reduced 27% versus baseline (p <
VAPD at both the 500-msec and 600-msec cycle 0.001). The reductions in ET-1 showed a trend toward a
length). VERP was significantly reduced during pacing correlation, with the reductions in PVR provided by
(251 ± 17 msec vs. 246 ± 23 msec at the 600-msec cycle levosimendan (p = 0.06, r = 0.067). Norepinephrine
length, p < 0.01).38 Since the effect of levosimendan on levels were not significantly altered.44
the VERP is not reported during sinus rhythm, it is not Further evaluation of the neurohormonal implica-
known if the reduction in VERP will enhance the risk of tions arising from levosimendan administration was
arrhythmia associated with QTc interval prolongation. investigated in a dose-ranging study of patients (n =
More definitive studies in patients with CHF are 151, 87.4% male, 93% NYHA class III CHF) with
needed to demonstrate the electrophysiologic safety of NYHA class II to IV CHF. Inclusion was limited to pa-
levosimendan in light of the ability of the agent to open tients with ischemic etiology of CHF. Patients received
ATP-sensitive potassium channels. open-label dobutamine (active control), placebo, or
Despite concern regarding the elevation in the QTc levosimendan as a continuous infusion at one of five
interval, most arrhythmias in the CHF patient occur as doses (0.05, 0.1, 0.2, 0.4, or 0.6 mcg/kg/min). Plasma
a result of electrical-mechanical aberrations, levels of atrial natriuretic peptide (ANP), norepinephrine,
bradyarrhythmias, or an acute ischemic event.39 Cur- epinephrine, and renin were measured at baseline and
rently available therapy can increase the risk for an ar- at 8 and 26 hours. Patients receiving levosimendan did
rhythmia by contributing to myocardial ischemia not demonstrate a sustained lowering of ANP,
(e.g., dobutamine) or by causing electrical aberrations norepinephrine, epinephrine, or renin. However,
(e.g., milrinone). In light of the data presented, norepinephrine did increase throughout the duration
levosimendan would be less likely to cause an ar- of the 0.05- and 0.1-mcg/kg/min infusions, becoming
rhythmia since it does not cause an accumulation of statistically significant at the 26-hour endpoint. Plasma
cAMP (electrical aberration), alter heart rate renin activity became significantly elevated at the 0.4-
(bradyarrhythmias), or decrease coronary blood flow and 0.6-mcg/kg/min rates.45 Although the data between
during diastole (acute ischemic event).31,36 these two groups and the patients receiving
dobutamine are similar, no direct comparisons were
NEUROHORMONAL EFFECTS made between the active control and levosimendan at
any dose.
Elevation of neurohormones (e.g., norepinephrine,
renin, endothelin-1, and brain natriuretic peptide EFFICACY TRIALS
[BNP]) in CHF has been associated with a worsening
prognosis.40-43 Despite producing a hemodynamic ben- Bypass Surgery
efit, the clinical utility of currently available inotropic
therapy is limited because these agents increase mor- Since reperfusion injury is a frequent complication of
tality.7-9 At this point, it is unclear if drug-induced in- cardiopulmonary bypass surgery, the use of inotropes
creases in neurohormone levels contribute to drug- is frequently employed to reverse myocardial
induced increases in mortality. Therefore, the develop- hypokinesis. Unfortunately, the use of inotropes can

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 MCBRIDE AND WHITE

produce an increase in myocardial oxygen consump- ventricular fibrillation, atrial fibrillation with a rapid
tion secondary to a shift toward increased fatty acid ventricular response, right ventricular infarction, SBP
metabolism.46,47 In a study from Finland, patients (n = < 90 mmHg, and the use of a beta agonist within 30
23, mean age = 57 years) scheduled for elective coro- minutes of enrollment.48 The number of subjects
nary artery bypass surgery with a PCWP of 8 to 20 achieving the primary endpoint was not significantly
mmHg and a CI greater than 1.71 L/min/m2 were ran- different among the individual groups (p = 0.319).
domized to receive either placebo or levosimendan 8 When an on-treatment analysis was performed, the ef-
mcg/kg or levosimendan 24 mcg/kg (administered as a fect of levosimendan on the primary endpoint was still
slow infusion over 5 min). Pertinent exclusion criteria comparable to placebo (10.8% vs. 13.4%, p = 0.456). A
included second- or third-degree atrioventricular nonsignificant trend in the primary endpoint toward a
block, valvular stenosis, type I diabetes mellitus, or dose response was observed (p = 0.054). Assignment to
antiarrhythmic use. The primary endpoints were the the active drug also reduced heart failure–associated
effects of levosimendan on mean arterial pressure, mortality at 24 hours (4.0% vs. 8.0%, p = 0.044), re-
SVR, PVR, CO, HR, stroke volume (SV), and right atrial duced all-cause mortality at 14 days (11.7% vs. 19.6%,
pressure from baseline to 60 minutes after reperfusion. p = 0.031), and exhibited a trend toward reduced mor-
The investigators found a significant increase in HR tality at 180 days (22.6% vs. 31.4%, p = 0.053). When
(+11 beats/min) and SV among those receiving high- the individual doses were compared against placebo
dose levosimendan (p < 0.05 for the trend on both HR using a Cochran-Mantel-Haenszel test for dose relation,
and SV relative to placebo). Right atrial pressure and significance was lost, which could have been due to the
myocardial oxygen consumption were not affected. selection of an inappropriate statistical test.48
High-dose levosimendan produced a significant im-
provement in cardiac output throughout the trial (no Acute Decompensated
mean reported; p < 0.05 for the trend). SVR was re- Heart Failure
duced with both dosing regimens (no means reported;
p < 0.05 for the trend). There was a trend toward im- Patients with ADHF (n = 146; EF, 21% ± 1%; age, 58 ± 1
proved coronary hemodynamics with both doses, as years [active]/56 ± 2 years [placebo]) with ADHF re-
evidenced by a decreased coronary vascular resistance ceived levosimendan or placebo in a randomized,
(35 mL/min, p = 0.0539).46 A study with a similar pa- double-blind fashion. Pertinent inclusion criteria in-
tient population that was conducted in the United cluded the following: ACE inhibitor treatment, CI < 2.5
States produced similar results.47 These trials indicate L/min/m2, PCWP > 15 mmHg, and EF < 30%. Stable
that levosimendan would be an adequate alternative to doses (at least 7 days) of beta-adrenergic antagonists,
improve hemodynamics following bypass surgery. calcium channel antagonists, and amiodarone (2
However, no direct comparison exists between agents months of stable dosing) were permitted. Class IC
such as dobutamine or milrinone in this setting. antiarrhythmics are contraindicated in patients with
structural heart disease, including heart failure.37 In-
Postmyocardial Infarction vestigators used exclusion criteria, therefore, that were
similar to previous phase II trials, including treatment
The RUSSLAN trial evaluated the effect of with a class IC antiarrhythmic, since the electrophy-
levosimendan therapy in patients (n = 504) who experi- siologic safety of the agent was being evaluated.
enced a myocardial infarction that caused left ventricu- Levosimendan was administered as an initial 6-mcg/kg
lar failure. The study was designed to evaluate the intravenous bolus followed by a 0.1-mcg/kg/min infu-
safety of the agent in this population, which was as- sion that could be titrated to 0.4 mcg/kg/min. The pri-
sessed by the presence of ischemia or hypotension. mary endpoint was a 25% decline in SV and PCWP rel-
Worsening heart failure at 6 hours and 24 hours after ative to placebo when subjects were evaluated at 6
the start of the infusion and mortality were evaluated as hours. The study did not have a power analysis for this
secondary outcomes.48 Patients were randomized to re- endpoint. CI, the time-dependent change in PCWP and
ceive levosimendan at one of four doses (6-mcg/kg SV, right atrial pressure, mean arterial pressure, SVR,
bolus, 0.1-mcg/kg/min infusion; 12-mcg/kg bolus, 0.2- PVR, and symptom severity were evaluated relative to
mcg/kg/min infusion; 24-mcg/kg bolus, 0.3-mcg/kg/ placebo. Compared with placebo, levosimendan in-
min infusion; 24-mcg/kg bolus, 0.4-mcg/kg/min infu- creased SV (no means reported; p < 0.001) starting 60
sion) or matching placebo. Pertinent exclusion criteria minutes after the beginning of the infusion. The benefit
were as follows: sustained ventricular tachycardia or was also seen in those who received 0.1 mcg/kg/min.

1078 • J Clin Pharmacol 2003;43:1071-1081

 LEVOSIMENDAN: IMPLICATIONS FOR CLINICIANS

The 25% reduction in PCWP was achieved by more pa- when compared with levosimendan (13 vs. 4, p =
tients receiving levosimendan relative to placebo (43% 0.023).50
vs. 15%, p < 0.001).49 Although means were not re-
ported, the other hemodynamic variables were signifi- CONCLUSION
cantly decreased (p < 0.001 for the trend) at 6 hours. Pa-
tient self-assessment was improved among those Sensitization of troponin C to calcium with
receiving the study drug (p = 0.037), which was similar levosimendan offers a novel and safe method to in-
to the physician assessment. No ventricular crease myocardial force without increasing
arrhythmias were reported, and headache was the most intracellular calcium concentrations. The stimulation
common adverse event among patients receiving the of ATP-sensitive potassium channels contributes to im-
study drug.49 provements in coronary blood flow, as well as reduc-
Follath et al50 performed the first comparison of tions in afterload and preload. The weak inhibition
levosimendan to standard-of-care therapy (i.e., of phosphodiesterase III increases myocardial
dobutamine). The primary endpoints were hemody- lusitropy. Levosimendan has predictable first-order
namic effects and 6-month mortality. Inclusion and ex- pharmacokinetics and is able to be given by several
clusion criteria closely resembled those of prior trials. routes of administration. The short half-life will pro-
A total of 203 patients admitted for ADHF (86.6% male) vide for easy titration of the product in the event of a
received either 5 mcg/kg/min of dobutamine or suboptimal therapeutic response or adverse drug
levosimendan (24-mcg/kg intravenous bolus plus 0.1- event. Despite providing beneficial effects on
mcg/kg/min infusion). Investigators were instructed to hemodynamics and mortality, the electrophysiologic
double the dose of both agents if an increase in CO of profile of the agent requires further investigation due to
30% did not occur within 2 hours from the initiation of conflicting reports. Levosimendan is currently avail-
therapy. Patients experiencing a dose-limiting event able in Sweden and, if approved in the United States,
(HR > 140 beats/min or SBP < 80 mmHg) were allowed could supplant all currently available inotropic treat-
to continue the protocol at one-half their initial dose. A ment modalities due to favorable outcome studies that
30% increase in cardiac output and a > 25% reduction show decreases in mortality relative to placebo and
in PCWP were defined as the primary endpoint. CI, SV, standard-of-care treatment. The effect on the QTc inter-
pulmonary artery pressure, HR and peripheral resis- val is mild and unlikely to have clinical significance in
tance at 24 hours, number of patients needing open- a majority of patients, but specific patient populations
label inotropic support or vasodilator or diuretic sup- with cofactors for QTc interval prolongation (e.g., pa-
port, number of days alive and out of the hospital, the tients with CHF) should be treated with caution until
rate of death or worsening heart failure, and the effect of further safety evaluations are performed.
beta-blocker therapy were evaluated as secondary
endpoints. The authors wish to thank Mr. Daniel Small of Hartford Hospital
for his technical expertise designing the figures presented in this
More patients in the levosimendan arm achieved the manuscript.
primary endpoint (28% vs. 15%, p = 0.022) at 24 hours.
Patients who received the study drug achieved a
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