Journal of Cardiac Failure Vol. 13 No. 7 2007
A 6-Month Follow-up of Intermittent Levosimendan
Administration Effect on Systolic Function, Specific Activity
Questionnaire, and Arrhythmia in Advanced Heart Failure
SOPHIE MAVROGENI, MD, FESC, GREGORY GIAMOUZIS, MD, EVANGELIA PAPADOPOULOU, MD,
SOPHIA THOMOPOULOU, MD, ATHANASIOS DRITSAS, MD, GEORGE ATHANASOPOULOS, MD,
ELIAS ADREANIDES, MD, IOANNIS VASSILIADIS, MD, KONSTANTINOS SPARGIAS, MD,
DIMOSTHENIS PANAGIOTAKOS, MD, AND DENNIS V. COKKINOS, PROF.
Athens, Greece
ABSTRACT
Background: Levosimendan (LS) improves cardiac contractility without increasing myocardial oxygen
demand. We administrated LS on a monthly intermittent 24-hour protocol and evaluated the clinical effect
after 6 months in a randomized, open, prospective study.
Methods and Results: Fifty patients (age 45e65 years) with LV systolic dysfunction and New York
Heart Association (NYHA) III or IV were randomized in 2 groups. LS group (n 5 25) was compared
with a control group (n 5 25) matched for sex, age, and NYHA class. LS was given monthly on a
24-hour intravenous protocol for 6 months. Patients were evaluated by specific activity questionnaire
(SAQ) and echocardiography (ECHO) before and 3 to 5 days after last drug administration, whereas
24-hour Holter recording was performed before and during last drug administration. Patients in LS and
control group had same baseline SAQ, ECHO, and Holter parameters. At the end of the study, a larger
proportion of patients in the levosimendan group reported improvement in symptoms (dyspnea and
fatigue) (65% versus 20% in controls, P ! .01). After 6 months, the LS group had a significant increase
in LV ejection fraction versus controls (28 6 7 versus 21 6 4 %, P 5 .003), LV shortening fraction (15 6
3 versus 11 6 3 %, P 5 .006) and a decrease in mitral regurgitation (1.5 6 0.8 versus 2.7 6 0.6,
P 5 .0001). There was no increase in supraventricular or ventricular beats or supraventricular tachycardia
and VT episodes in LS group, compared with controls. Two patients from the LS group died in the
6-month follow-up period, compared with 8 patients in the control group (8% versus 32%, P ! .05).
Conclusions: A 6-month intermittent LS treatment in patients with decompensated advanced heart failure
improved symptoms and LV systolic function. (J Cardiac Fail 2007;13:556e559)
Key Words: Heart failure, levosimendan.
Levosimendan (LS), a novel calcium sensitizer, improves
cardiac contractility (inotropic effect) without increasing
myocardial oxygen demand (vasodilatory properties).1,2
This is due possibly to stabilization of troponin-C in a configuration that enhances the calcium sensitivity of cardiac
myofilaments3,4 and activation of adenosine triphosphatesensitive Kþ channels in the heart and systemic arteries5
In severe low-output heart failure, levosimendan improves
cardiac function and has been reported to decrease mortality in some6 but not all studies. Randomized Multicenter
Evaluation of Intravenous Levosimendan Efficacy Versus
Placebo in the Short-Term Treatment of Decompensated
Heart Failure (REVIVE-1) revealed that LS induced a significantly higher rate of clinical improvement compared
with placebo. REVIVE-2 showed improvement of clinical
signs and symptoms of acute decompensated heart failure
with neutral effects on mortality at 90 days. Survival of
Patients With Acute Heart Failure in Need of Intravenous
Inotropic Support (SURVIVE) revealed no significantly
different effects compared with dobutamine on mortality.1
The results of these studies provide now some more firm
conclusions regarding the potential beneficial effects of levosimendan on clinical status of patients with acute
decompensated heart failure. Additionally, LS administration offers renal protection, improves hemodynamics,
From the Onassis Cardiac Surgery Center, Athens, Greece.
Manuscript received April 29, 2006; revised manuscript received March
24, 2007; revised manuscript accepted April 17, 2007.
Reprint requests: Sophie Mavrogeni, MD, FESC, 50 Esperou Street,
175-61 P. Faliro, Athens, Greece.
Data were presented in abstract form in the 2005 ESC Heart Failure
meeting.
1071-9164/$ - see front matter
Ó 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.cardfail.2007.04.004
556
Follow-up of Levosimendan in Heart Failure
myocardial wall stress and peripheral organ perfusion,7 and
is beneficial even in patients whose syndrome is refractory to
traditional inotropes.8
Our aim was to apply the administration of levosimendan
in end-stage heart failure patients and repeat the drug
administration on a monthly base for 6 months. Evaluation
of patients was performed at baseline (immediately before
the drug administration) and 3 to 5 days after the last drug
administration using echocardiography and specific activity
questionnaire (SAQ). A 24-hour Holter recording was performed at baseline and during the last drug administration.
Mavrogeni et al
557
Table 1. Baseline Clinical Characteristics of Patients
Treated With Levosimendan (LS) and Controls
Male/female
Age (y)
Cardiomyopathy type (%):
ischemic/dilated/valvular
Medication (%): Angiotensin-converting
enzyme inhibitor or AT1
b-blockers
Diuretics
Digitalis
Aldosterone antagonist
Amiodarone
Nitrates
LS
Controls
20/5
62 6 20
52/32/16
20/5
61 6 19
50/33/17
96
97
92
100
32
52
25
30
94
100
35
49
28
26
Patients and Methods
The study population consisted of 50 patients with systolic LV
dysfunction and New York Heart Association Class III or IV
symptoms of heart failure. Patients were currently on treatment
with angiotensin-converting enzyme inhibitors, b-blockers, aldosterone antagonist, amiodarone, and diuretics. They had documented LV ejection fraction of !30% and a cardiac index !2.5
L/min/m2. Exclusion criteria were acute or chronic infectious or
inflammatory diseases, recent myocardial infarction (!8 weeks)
or active ischemia, hepatic or renal impairment (creatinine O2.5
mg/d), use of immunosuppressive drugs, serious arrhythmias,
and supine systolic blood pressure !85 mm Hg. The investigation
conformed to the principles outlined in the Declaration of Helsinki. The study was approved by Onassis Cardiac Surgery Center
ethics committee, and written consent was given by each patient.
The patients who received LS were informed about the drug
effect, while the staff that performed the study and analyzed the
data was blinded to drug given and to group characteristics.
The design of the study was open, prospective. Of the 50 patients, 25 were randomized to receive additionally to standard
treatment intravenous levosimendan; the rest (n 5 25) served as
controls and did not receive any additional infusion. Controls
underwent monthly visits for routine clinical evaluation. Randomization was based on a sequence of binary numbers. In detail, for
each consecutive patient of our clinic we assigned a sequence of
random binary numbers (ie, 1,1,1,0,1,0,1,1,0,1.) that assisted
to allocate participants into the 2 treatment arms. For example if
a patient was assigned to number 1, he/she was treated with levosimendan, if he/she was assigned to number 0, he/she was not
treated with levosimendan. No blocking or stratification was performed. The treatment code was not known to the physician of the
study. The randomization system was created by a special software (STATA, STATA Corp, College Station, Texas 77845 USA,
data command: sample # [if exp] [in range] [, count by (groupvars)])’’. The 2 groups had similar baseline clinical characteristics
(Table 1).
Levosimendan was given as a 10-minute intravenous bolus of 6
mg/kg followed by continuous infusion, initially at a rate of 0.1 mg/
kg/min. Up-titration was done until a maximum rate of 0.2 mg/kg/
min was achieved or a dose-limiting event occurred, as previously
described.9 The same protocol was applied every month for six
months in the levosimendan group. Diuretics dose was halved
on the day of infusion.
Symptoms (evaluated using SAQ) and left ventricular volumes
per body surface area (mL/m2), LV ejection fraction (%), mitral
regurgitation grade (scale 1e4), and right ventricular systolic pressure (mm Hg) were analyzed at baseline and 3 to 5 days after the
last drug administration over a 6-month study period. A 24-hour
Holter recording was performed and analyzed at baseline and during the last dose of drug administration for LS group and during
hospitalization after 6 months for the control group.
A Vivid General Electric Ultrasound System was used to perform the study. Complete 2-dimensional echocardiographic study
was performed by the use of a mechanical and phased-array sector-scanner with a 3.5-MHz transducer. Long axis and parasternal
short axis views at the mid-ventricular level were used to derive
the left-ventricular end-systolic and end-diastolic diameters. The
echocardiographic study was read by 1 experienced cardiologist,
who was blinded to the treatment group.
Ambulatory 24-hour Holter echocardiographic recording were
obtained in a standard fashion with a portable tape recorder and
modified V1 and V5 leads. Holter echocardiographic recordings
were scanned on a DelMar Reynolds AccuPlus (Del Mar Reynolds
Medical, Irvine, California). In each case the arrhythmias were
verified by an experienced cardiologist, who was blinded to the
clinical, echocardiographic, and follow-up data.
The SAQ is composed of 13 questions based on everyday activities. Each activity corresponds to metabolic equivalents, 1 metabolic equivalent 5 3.5 mL O2$kg$min, predicted for a given type
of activity (Table 2). SAQ was performed in person during hospitalization and subsequently analyzed by personnel blinded to the
treatment group.
Death and its cause, at any time during the 6-month interval,
were recorded.
All values are mean 6 SD. Repeated measures analysis of variance was used to evaluate the differences in variables (inclusion
versus 6 months) between levosimendan and control group.
Comparisons between qualitative variables were performed by
chi-square test. A P value ! .05 was considered statistically
significant.
Results
All of the patients in the levosimendan group achieved
the maximum rate of 0.2 mg$kg$min. Only 2 patients presented a dose-limiting event (hypotension), but this was
temporary and they managed to reach also the maximum
infusion rate. All LS patients completed successfully the
6 cycles of drug administration.
Patients in the LS and the control groups had same
baseline SAQ, echocardiogram, and Holter parameters
558 Journal of Cardiac Failure Vol. 13 No. 7 September 2007
Table 2. The Specific Activity Questionnaire (SAQ)
Can you Complete the Following Activities Without
Symptoms?
MET
Values
1. Dress without stopping because of symptoms?
2. Do moderate work around the house like vacuum, sweep floors,
or carry groceries?
3. Walk down a flight of stairs unassisted and without stopping?
4. Do heavy work around the house like make the beds,
hang out washing, or wash the car?
5. Do moderate gardening like weed or rake the leaves?
6. Push an electric or petrol mower on level ground?
7. Participate in moderate activities like walk at a normal pace
(4 km/h) or play golf and carry the clubs?
8. Walk briskly around an oval?
9. Do outdoor work like split wood or dig in the garden?
10. Carry an 8-kg weight (load of wet washing) up 8 steps?
11. Carry at least 10 kg (eg, a suitcase) up 8 steps?
12. Carry objects that weight at least 35 kg
13. Participate in vigorous activities like swimming (crawl),
jogging (8 km/h), cycling (17 km/h), singles tennis?
2.00
2.50
3.00
3.25
4.25
4.50
4.75
5.00
5.50
6.00
7.00
7.50
9.00
(Table 3). After 6 months of treatment, the mean SAQ values
improved in the LS group, but were not significantly different after repeated measures analysis of variance analysis.
However, a larger proportion of patients in the levosimendan
group reported improvement in symptoms (dyspnea and
fatigue) (65% versus 20% in controls, P ! .01).
At the end of the 6 months, the LS group had a significant
increase in LV ejection fraction versus controls (28 6 7 versus 21 6 4 %, P 5 .003) and LV shortening fraction
(15 6 3 versus 11 6 3 %, P 5 .006), respectively. There
was also a decrease in end-systolic volume versus controls
(82 6 20 versus 107 6 21 mL/m2, P 5 .044), end-diastolic
volume (120 6 20 versus 157 6 25 mL/m2, P 5 .0001),
mitral regurgitation (1.5 6 0.8 versus 2.7 6 0.6,
P 5 .0001), and a borderline decrease in RV systolic pressure (50 6 13 versus 63 6 14 mm Hg, P 5 .052), respectively. There was no increase in supraventricular or
ventricular beats or supraventricular tachycardia and
ventricular tachycardia episodes in LS group, compared
with controls. Two patients from the LS group died in the
6-month follow-up period, compared with 8 patients in
the control group (8% versus 32%, P ! .05).
In the control group, there was a worsening at the end of the
6-month study period (versus baseline) of both mitral regurgitation grade (2.7 6 0.6 versus 2.5 6 0.6, P ! .05) and RV
systolic pressure (63 6 14 versus 61 6 14, P ! .05).
Concerning mortality, 2 patients from the LS group died
in the 6-month follow-up period because of acutely decompensated heart failure and cardiac arrest, compared with 8
patients in the control group (8% versus 32%, P ! .05).
Discussion
This study focused on the follow-up of patients with endstage heart failure after intermittent administration of levosimendan during a 6-month period. We evaluated clinical
symptoms, echocardiographic indexes of cardiac contractility, and 24-hour Holter recording.
Clinical symptoms, such as dyspnea and fatigue, were
improved in a larger proportion of our patients in the levosimendan group compared with controls. Score derived
from SAQ is strongly correlated with maximal overall aerobic capacity expressed by peak VO2 measured by exercise
spirometry.10 This effect, already described after acute
administration,11,12 is also observed after an intermittent
6-month levosimendan administration. A decrease in mean
pulmonary artery pressure in the levosimendan group
was considered responsible for the improvement of symptoms.13,14 In this study, the mean SAQ values improved in
the levosimendan group, but the difference did not reach
statistical significance. This may be explained by the
small population of the study.
An increase in shortening and injection fraction with simultaneous improvement of functional mitral regurgitation
Table 3. Comparison of ECHO, Holter, and SAQ Parameters in Patients Treated With Levosimendan and Controls
at Inclusion and After 6 Months Treatment
Levosimendan
Parameter
FS (%)
LVEF (%)
EDV (mL/m2)
ESV (mL/m2)
MR grade
RVSP (mm Hg)
Max HR
Min HR
Mean HR
SVB
PVB
Couplets
NSVT
SAQ (METS)
Inclusion
12
22
138
98
2.4
61
95
61
78
393
1535
89
8
1.7
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
6
20
25
1.0
16
21
10
13
115
1256
57
5
1.6
Controls
6 Months
15
28
120
82
1.5
50
108
58
79
358
2010
104
12
2.7
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
7
20
20
0.8
13
16
19
6
63
1188
88
6
1.2
Inclusion
12
22
145
99
2.5
61
93
58
80
402
1610
95
10
2.2
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
5
30
28
0.6
14
15
8
13
120
1150
40
7
1.1
RANOVA
6 Months
11
21
157
107
2.7
63
98
61
82
415
1710
100
13
1.7
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
4
25
21
0.6
14
20
8
10
180
1190
45
6
1.6
P Value*
.006
.003
.0001
.044
.0001
.052
.134
.917
.348
.319
.689
.899
.190
.423
ECHO, echocardiogram; SAQ, specific activity questionnaire; FS, shortening fraction of left ventricle; LVEF, left ventricular ejection fraction; EDV, enddiastolic volume of left ventricle; ESV, end-systolic volume of left ventricle; MR, mitral regurgitation; RVSP, right ventricular systolic pressure; HR, heart
rate; SVB, supraventricular beats; PVB, premature ventricular beats; NSVT, nonsustained ventricular tachycardia (*P value for repeated measures analysis of
variance [RANCOVA] [inclusion vs. 6 months] between levosimendan and controls).
Follow-up of Levosimendan in Heart Failure
was documented in levosimendan-treated patients. This
might be the result of drug-induced increase of myocardial
contractility.15
There were no dose-limiting events in the levosimendan
group, except for 2 patients that presented transient hypotension. This may be explained by the reduction of diuretic
dose during levosimendan infusion. In the levosimendan
group, no increase in heart rate or arrhythmias on Holter recording was found. This is in agreement with previous studies, showing that levosimendan has no significant effects on
heart rate, when data were pooled from the 24-hour electrocardiograms of patients receiving various dose levels.16 The
absence of tachycardia may also be attributed to the fact
that the patients were already on maximal doses of bblockers. However, these findings are notably different
from the REVIVE experience,1 where there was a significant excess of atrial fibrillation, ventricular tachycardia,
and death. In view of the conflicting findings, there is
need for more information to establish safety.
At the moment, there is rarity of studies on the effects of
an intermittent long-term protocol of intravenous administration of levosimendan. However, a recent study17 confirmed the beneficial effects of our protocol in LV
performance, neurohormonal, and immune indices.
It should be noted that the 2 major trials, REVIVE and
SURVIVE, failed to provide much evidence of efficacy
and both raise concerns of safety. In REVIVE, the primary
outcome was substantially driven by the lesser use of
diuretics rather than real evidence of clinical improvement.
The previously impressive LIDO trial probably reflects excessively high doses of dobutamine, because the mortality
data were not reproduced in SURVIVE. Other published
studies are not as well blinded or controlled and only included small numbers of outcomes or very short followup. Overall, the clinical (versus hemodynamic) efficacy of
this agent remains uncertain and needs to be confirmed in
a large randomized, double-blind, placebo-controlled outcome study. In this perspective, our data support the potential use of intermittent infusions in such a trial.
Limitations of the Study
This is a report of an intermittent protocol of levosimendan administration in decompensated heart failure and the
results seem encouraging. Although the small number of
patients is not powerful to perform risk assessment, these
findings suggest that a double-blind, placebo-controlled
study with larger number of patients should be performed.
The open design of the current study may have influenced
the SAQ response. Although mortality rate was smaller in
the LS group, no early conclusions should be drawn.
Further studies are needed to establish the exact duration
of such a protocol, the possible benefit in different New
York Heart Association classes and the long-term survival.
In conclusion, this study presents the results of intermittent levosimendan administration during a 6-month period.
The beneficial effect on symptoms and systolic function in
Mavrogeni et al
559
the LS group, coming from these early results, justifies the
prospective of more detailed studies about a long-term
intermittent administration of the drug.
References
1. Parissis J, Filippatos G, Farmakis D, Adamopoulos S, Paraskevaidis I,
Kremastinos D. Levosimendan for the treatment of acute heart failure
syndromes. Expert Opin Pharmacother 2005;6:2741e51.
2. Todaka K, Wang J, Yi GH, et al. Effects of levosimendan on myocardial contractility and oxygen consumption. J Pharmacol Exp Ther
1996;279:120e7.
3. Kiviko M, Antila S, Eha J, Lehtonen L, Pentikainen P. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and
its metabolites during an extended infusion in patients with severe
heart failure. J Clin Pharmacol 2002;42:43e51.
4. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H.
Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation
1998;98:2141e7.
5. Yokoshiki H, Katsube Y, Sunagawa M, et al. Levosimendan, a novel
Ca2þ sensitizer, activates the glibenclamide- sensitive Kþ channel
in rat arterial myocytes. Eur J Pharmacol 1997;333:249e59.
6. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous
levosimendan compared with dobutamine in severe low-output heart
failure (the LIDO study: a randomized double-blind trial). Lancet
2002;360:196e202.
7. Follath F, Franco F, Cardoso JS. European experience on the practical
use of levosimendan in patients with acute heart failure syndromes.
Am J Cardiol 2005;96:80Ge5G.
8. Nanas JN, Papazoglou PP, Terrovitis JV, Kanakakis J, Dalianis A,
Tsolakis E, et al. Hemodynamic effects of levosimendan added to dobutamine in patients with decompensated advanced heart failure
refractory to dobutamine alone. Am J Cardiol 2004;94:1329e32.
9. Kiviko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects
of intravenous levosimendan. Circulation 2003;107:81e6.
10. Chryssanthopoulos S, Dritsas A, Cokkinos D. Activity questionnaires;
a useful tool in accessing heart failure patients. Int J Cardiol 2005;105:
294e9.
11. Parissis J, Adamopoulos S, Antoniades C, et al. Effects of levosimendan on circulating proinflammatory cytokines and soluble apoptosis
mediators in patients with decompensated advanced heart failure.
Am J Cardiol 2004;93:1309e12.
12. Spargias K, Anifantakis A, Papadakis M, et al. Preliminary clinical
experience with the repetitive administration of levosimendan in
patients with end-stage heart failure. Ital Heart J 2003;4(Suppl 2):
45Se9S.
13. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and
clinical effects of levosimendan in patients with severe heart failure.
Circulation 2000;102:2222e7.
14. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients
with congestive heart failure. J Am Coll Cardiol 2000;36:1903e12.
15. Janssen PML, Datz N, Zeitz O, et al. Levosimendan improves diastolic
and systolic function in failing human myocardium. Eur J Pharmacol
2000;404:191e9.
16. Singh BN, Lilleberg J, Sandell EP, Ylonen V, Lehtonen L, Toivonen L.
Effects of levosimendan on cardiac arrhythmia: electrophysiologic and
ambulatory electrocardiographic findings in phase II and phase III
clinical studies in cardiac failure. Am J Cardiol 1999;83:16e20.
17. Parissis JT, Adamopoulos S, Farmakis D, et al. Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of
myocardial injury and neurohormonal and immune activation in patients
with advanced heart failure. Heart 2006;92:1768e72.