Review Article
Effects of levosimendan on mortality and hospitalization.
A meta-analysis of randomized controlled studies*
Giovanni Landoni, MD; Giuseppe Biondi-Zoccai, MD; Massimiliano Greco, MD; Teresa Greco, MSc;
Elena Bignami, MD; Andrea Morelli, MD; Fabio Guarracino, MD; Alberto Zangrillo, MD
Objective: Catecholaminergic inotropes have a place in the
management of low output syndrome and decompensated heart
failure but their effect on mortality is debated. Levosimendan is a
calcium sensitizer that enhances myocardial contractility without
increasing myocardial oxygen use. A meta-analysis was conducted to determine the impact of levosimendan on mortality and
hospital stay.
Data Sources: BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for pertinent studies. International experts and the manufacturer were
contacted.
Study Selection: Articles were assessed by four trained investigators, with divergences resolved by consensus. Inclusion criteria were random allocation to treatment and comparison of
levosimendan vs. control. There were no restrictions on dose or
time of levosimendan administration or on language. Exclusion
criteria were: duplicate publications, nonadult studies, oral administration of levosimendan, and no data on main outcomes.
Data Extraction: Study end points, main outcomes, study design, population, clinical setting, levosimendan dosage, and treatment duration were extracted.
T
here are indications both from
individual studies and metaanalyses that use of intravenous inotropes may be associated with a worsened longer-term
prognosis (1–5). However, this view is
*See also p. 702.
From the Department of Anesthesia and Intensive
Care (GL, MG, TG, EB, AZ), Università Vita-Salute San
Raffaele, Milano, Italy; Interventional Cardiology, Division of Cardiology (GBZ), University of Turin, Turin,
Italy; Department of Anesthesiology and Intensive Care
(AM), University of Rome, “La Sapienza,” Rome, Italy;
Cardiothoracic Department (FG), Azienda Ospedaliera
Universitaria Pisana, Pisa, Italy.
Supplemental digital content is available for this
article. Direct URL citations appear in the printed text
and are provided in the HTML and PDF versions of this
article on the journal’s Web site (www.ccmjournal.org).
The authors have not disclosed any potential conflicts of interest.
For information regarding this article, E-mail:
landoni.giovanni@hsr.it
Copyright © 2012 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e318232962a
634
Data Synthesis: Data from 5,480 patients in 45 randomized
clinical trials were analyzed. The overall mortality rate was 17.4%
(507 of 2,915) among levosimendan-treated patients and 23.3%
(598 of 2,565) in the control group (risk ratio 0.80 [0.72; 0.89], p
for effect <.001, number needed to treat ⴝ 17 with 45 studies
included). Reduction in mortality was confirmed in studies with
placebo (risk ratio 0.82 [0.69; 0.97], p ⴝ .02) or dobutamine (risk
ratio 0.68 [0.52– 0.88]; p ⴝ .003) as comparator and in studies
performed in cardiac surgery (risk ratio 0.52 [0.35; 0.76] p ⴝ .001)
or cardiology (risk ratio 0.75 [0.63; 0.91], p ⴝ .003) settings.
Length of hospital stay was reduced in the levosimendan group
(weighted mean difference ⴝ ⴚ1.31 [ⴚ1.95; ⴚ0.31], p for effect ⴝ .007, with 17 studies included). A trend toward a higher
percentage of patients experiencing hypotension was noted in
levosimendan vs. control (risk ratio 1.39 [0.97–1.94], p ⴝ .053).
Conclusions: Levosimendan might reduce mortality in cardiac
surgery and cardiology settings of adult patients. (Crit Care Med
2012; 40:634 – 646)
KEY WORDS: anesthesia; cardiac surgery; heart failure; inotropic
support; intensive care; levosimendan; mortality; survival
subject to a number of qualifications and
limitations. First, the population of patients is heterogeneous, and it is plausible (even likely) that the effect of inotropes may differ considerably from one
population to another. Furthermore, inotrope therapy tends to be reserved for
patients in extremis: associations with
poor long-term outcomes in nonrandomized studies may be coincidence rather
than a demonstration of cause and effect.
Variations in clinical practice, such as
timing of intervention, may also influence results. Above all, assessment of the
true effects of inotropes on survival is
hampered by the fact that many of the
published studies have been either too
small to produce robust results or of low
quality.
These concerns attach primarily to
inotropes acting via the ␤-receptor/cyclic
adenosine monophosphate pathway,
which may increase myocardial oxygen
demand, favor the development of cardiac
arrhythmias, and compromise coronary
perfusion pressure. Agents that stimulate
inotropy through nonadrenergic mechanisms may therefore offer survival advantages over traditional agents. One such
alternative agent is levosimendan, which
improves cardiac contractility primarily
through a calcium-sensitizing effect. This
agent is claimed to have a net neutral
effect on myocardial oxygen consumption
and to enhance cardiac mechanical efficiency, and has recently been reported to
cause no increase in sympathetic nervous
activity (6). Furthermore, levosimendan
has two sites of action, opening potassium
channels in both vascular smooth muscle
and cardiomyocyte mitochondria (7).
Early clinical studies suggested improved survival with levosimendan compared with dobutamine or placebo in patients with acute heart failure (LIDO,
RUSSLAN, and CASINO trials) (8 –10),
but two large clinical trials in acute decompensated heart failure (SURVIVE and
REVIVE II) (11, 12) did not confirm a
definite survival advantage from levosiCrit Care Med 2012 Vol. 40, No. 2
mendan. Recent published meta-analyses
(13, 14) suggest a modest survival benefit
from levosimendan, but have been limited by the lack of a complete dataset
from clinical trials.
We therefore devised an updated
meta-analysis of all the randomized clinical trials of levosimendan to reach a definitive conclusion about the role of this
agent in the management of patients requiring inotropic drugs. The analysis was
strengthened by the inclusion, for the
first time, of the results of all the large
clinical studies: SURVIVE (11, 15–18),
LIDO (8, 19, 20), RUSSLAN (9), CASINO
study (10, 21, 22), and REVIVE I and II
(12, 17, 23–25). In addition, we analyzed
mortality and hospital length of stay
(LOS) in different settings (i.e., cardiology and cardiac surgery) and in subsets of
studies in which levosimendan was compared to dobutamine or to placebo.
MATERIALS AND METHODS
Search Strategy
Pertinent studies were independently
searched in BioMedCentral, PubMed, Embase,
and the Cochrane Central Register of clinical
trials (updated November first 2010) by four
trained investigators. The full PubMed search
strategy was developed according to BiondiZoccai et al (26), available in the Appendix,
and aimed to include any randomized study
ever performed with levosimendan in any clinical setting in humans. In addition, we employed backward snowballing (i.e., scanning of
references of retrieved articles and pertinent
reviews) and contacted international experts
and the manufacturer for further studies. No
language restriction was enforced.
Study Selection
References obtained from database and literature searches were first independently examined at a title/abstract level by four investigators, with divergences resolved by
consensus, and then, if potentially pertinent,
retrieved as complete articles.
The following inclusion criteria were used
for potentially relevant studies: random allocation to treatment and comparison of levosimendan vs. control. There were no restrictions on dose or time of administration.
The exclusion criteria were: duplicate publications either acknowledged or not (in this
case we referred to the first article published
while retrieved data from the article with the
longest follow-up available), nonadult studies,
oral administration of levosimendan, and lack
of data on mortality. Two investigators inde-
Crit Care Med 2012 Vol. 40, No. 2
pendently assessed compliance to selection
criteria and selected studies for the final analysis, with divergences finally resolved by consensus.
Data Abstraction and Study
Characteristics
Baseline, procedural, and outcome data were
independently abstracted by four trained investigators, with divergences resolved by consensus. Specifically, we extracted potential sources
of significant clinical heterogeneity, such as
study design, sample size, clinical setting/
indication, levosimendan bolus dose, infusion
dose and duration, control treatment, and follow-up duration, as well as primary study end
points and other key outcomes. If a trial
reported multiple comparisons, the control
group was considered as a whole in the
overall analysis and single groups were considered separately in subset analysis. At least
two separate attempts at contacting original
authors were made in cases of missing data.
The primary end point of the present
review was mortality at the longest follow-up available. The secondary end point
was LOS.
Internal Validity and Risk of
Bias Assessment
The internal validity and risk of bias of
included trials was appraised by two independent reviewers according to Cochrane
Collaboration methods (27), with divergences resolved by consensus. Publication
bias was assessed by visually inspecting funnel plots, by analytical appraisal based on
the Peters regression asymmetry test and on
the Begg adjusted-rank correlation test for
publication bias, and finally, with trim and
fill method (28 –30).
According to the Peters (28) or Begg (29)
methods for publication bias evaluation, a
two-sided p value of .10 or less was regarded as
significant. Sensitivity analyses were performed by sequentially removing each study
and reanalyzing the remaining dataset (producing a new analysis for each study removed), by selecting each individual subset
(defined by setting and control drug), and by
analyzing only data from studies with low risk
of bias.
Data Analysis and Synthesis
Computations were performed with Stata
(Stata Statistical Software: Release 11, College
Station, TX) and RevMan 5 (a freeware available from The Cochrane Collaboration) (31).
Hypothesis of statistical heterogeneity was
tested by means of Cochran Q test, with statistical significance set at the two-tailed .10
level, whereas extent of statistical consistency
was measured with I2, defined as 100% ⫻
(Q-df)/Q, where Q is Cochran’s heterogeneity
statistic and df the degrees of freedom. Binary
outcomes from individual studies were analyzed to compute individual and pooled risk
ratios (RRs) with pertinent 95% confidence
intervals (with equivalence set at 1, RR ⬍1
favoring the first treatment, and RR ⬎1 favoring the second treatment), by means of inverse
variance method and with a fixed-effect model
in case of low statistical inconsistency (I2
ⱕ25%) or with random-effect model (which
better accommodates clinical and statistical
variations) in case of moderate or high statistical inconsistency (I2 ⬎25%). In addition, we computed the number needed to
treat (NNT) with corresponding 95% confidence intervals for the primary end point.
Weighted mean differences (WMD) and 95%
confidence intervals were computed for continuous variables using the same methods as
just described (27).
To explore the relation between log-risk
mortality and the length of study follow-up,
we performed univariate metaregression
analyses.
Statistical significance was set at the twotailed 0.05 level for hypothesis testing. Unadjusted p values are reported throughout. This
study was performed in compliance with The
Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines (27, 32).
RESULTS
Database searches, snowballing, and
contacts with experts yielded a total of
541 articles. Excluding 453 nonpertinent
titles or abstracts, we retrieved in complete form and assessed 88 studies according to the selection criteria (Fig. 1).
Twenty-four studies were excluded because there were no outcome data and
further details could not be obtained by
the authors (33–56), two, including the
PERSIST study (57, 58), because levosimendan was administrated orally, six because they were not randomized (5, 59 –
63), ten because of duplicate publication
(15, 16, 20, 25, 64 – 69), and one because
it involved a pediatric population (70).
Ultimately, therefore, we identified 45 eligible randomized clinical trials for inclusion in the analysis (8 –12, 23, 71–109).
Study Characteristics
The 45 included trials randomized
5,480 patients (2,915 to levosimendan
and 2,565 receiving control) (Table 1).
Seventeen studies reported data on LOS.
Clinical heterogeneity was mostly due to
setting, dose, control treatment, and fol635
Figure 1. Flow diagram for selection of articles.
low-up duration. Indeed, 23 studies (8 –
12, 23, 71, 77, 78, 81, 82, 84, 88, 90, 96,
98, 99, 101, 103–105, 108, 109) used levosimendan in a cardiological setting (decompensated heart failure); four of these
studies used intermittent 24-hr infusions
of levosimendan (77, 90, 96, 99). Seventeen studies used levosimendan in cardiac surgery (73, 76, 79, 80, 83, 87, 89,
91, 93–95, 97, 102, 106, 107), two trials
were performed in septic patients (72,
100), two in an interventional cardiology
setting (85, 86), and one in vascular surgery (92). Thirty-six authors administered a bolus (8 –12, 23, 71, 73–78, 81–
83, 85– 87, 90 –95, 97, 99, 101, 102, 104 –
109, 112), and 41 authors used a
continuous infusion (8 –12, 23, 71–75,
77– 86, 88 –105, 108, 109), 32 of them
following bolus (8 –12, 23, 71, 73–75, 77,
78, 81– 83, 85, 86, 90 –95, 97–99, 101,
102, 104, 105, 108, 109). Dose varied between 3 and 36 ␮g/kg as intravenous bolus and between 0.05 and 0.6 ␮g/kg/min
as a continuous infusion. Seventeen studies were multicentered (8 –12, 23, 78, 83,
90, 93–97, 100, 101, 104). Study quality
appraisal indicated that studies were of
variable quality (Table 2) and that 13 of
them had a low risk of bias.
Quantitative Data Synthesis
Overall analysis showed that the use of
levosimendan was associated with a significant reduction in mortality at the longest follow-up available (507 of 2,915
[17.4%] in the levosimendan group vs.
636
598 of 2,565 [23.3%] in the control arm,
RR ⫽ 0.80 [0.72; 0.89], p for effect ⬍ .001,
Q ⫽ 51.98, p for heterogeneity ⫽ .191,
I2 ⫽ 15.4%, NNT ⫽ 17 with 5,480 patients and 45 studies included) (Fig. 2).
The reduction in mortality was confirmed
when studies with at least 30, 90, and 180
days of follow-up were analyzed (Table 3,
and supplemental data [Supplemental
Digital Material 1–3, http://links.lww.com/
CCM/A342]). Furthermore, a univariate
metaregression of average follow-up
against log-risk mortality showed no significant effects for time on mortality (n ⫽
45, slope coefficient ⫽ 0.01 [-0.01, 0.03];
p ⫽ .36) (see supplemental data [Supplemental Digital Material 4, http://links.lww.
com/CCM/A342]). A reduction in mortality was also found when studies with
short-term follow-up (ⱕ30 days) were analyzed, and when studies with follow-up
longer than 30 days were analyzed (see
supplemental data [Supplemental Digital
Material 5 and 6, http://links.lww.com/
CCM/A342]).
The reduction in mortality was confirmed when only the studies comparing
levosimendan to placebo were included
(233 of 1581 [14.7%] vs. 205 of 1097
[18.7%], RR ⫽ 0.82 [0.69; 0.97], p for
effect ⫽ .02, Q ⫽ 21.95, p for heterogeneity ⫽ .582, I2 ⫽ 0% with 25 studies
included, NNT ⫽ 25; see supplemental
data [Supplemental Digital Material 7,
http://links.lww.com/CCM/A342]), and
when only the studies comparing levosimendan with dobutamine were included
(280 of 1383 [15.0%] vs. 361 of 1305
[27.7%], RR ⫽ 0.68 [0.52– 0.88]; p for
effect ⫽ .003, Q ⫽ 27.74, p for heterogeneity ⫽ .023, I2 ⫽ 45.9% with 16 studies
included, NNT ⫽ 13; see supplemental data
[Supplemental Digital Material 8, http://links.
lww.com/CCM/A342]).
Furthermore, the reduction in mortality was confirmed in the cardiac surgery
setting (37 of 635 [5.8%] in the levosimendan group vs. 77 of 598 [12.9%] in
the control arm, RR ⫽ 0.52 [0.35; 0.76],
p ⫽ .001, Q ⫽ 13.69, p for heterogeneity ⫽ .622, I2 ⫽ 0% with 17 studies included, NNT ⫽ 14; see supplemental data
[Supplemental Digital Material 9, http://
links.lww.com/CCM/A342]), in the cardiology setting (441 of 2207 ([20.0%] in the
levosimendan group vs. 484 of 1893
[25.6%] in the control group, RR ⫽ 0.67
[0.51; 0.86], p ⫽ .002, RR ⫽ 0.75 [0.63;
0.91], p ⫽ .003, Q ⫽ 29.51, p for heterogeneity ⫽ .131, I2 ⫽ 25.5% with 23
studies included, NNT ⫽ 18; see supplemental data [Supplemental Digital Material 10, http://links.lww.com/CCM/A342]),
and in those patients undergoing revascularization, either surgical or percutaneous (Table 3 and Supplemental Digital
Material 11, http://links.lww.com/CCM/
A342).
Numerous other subanalyses on risk
of mortality were conducted and are summarized in Table 3 and as supplemental
data (Supplemental Digital Material 1217, http://links.lww.com/CCM/A342). A
significant reduction in mortality for levosimendan-treated patients was found
when only studies on patients on mechanical ventilation, only studies with
mortality as a primary end point, and
only studies with ⬎100 patients were included in the analysis. A subanalysis including only blind studies found a significant reduction in mortality favoring
levosimendan.
When study drug infusion rate was
considered, a significant reduction in
mortality was found, either for studies
with low infusion rates (ⱕ0.1 ␮g/kg/min)
or in studies with infusion rate ⬎0.1 ␮g/
kg/min. A significant reduction in mortality was found in those administering or
not levosimendan bolus.
A subanalysis on sepsis with only two
studies included found no difference in
mortality between levosimendan and
control groups (see supplemental data
[Supplemental Digital Material 18, http://
links.lww.com/CCM/A342]).
LOS was reduced in the levosimendan
group (WMD ⫽ ⫺1.31 [⫺1.95; ⫺0.31], p
Crit Care Med 2012 Vol. 40, No. 2
Table 1. Description of the 45 studies included in the meta-analysis
First Author
Setting
Levosimendan Control
Patients
Patients
Control
Bolus Continuous
Dose Infusion Dose
␮g/kg
␮g/kg/min
Adamopoulos
(71)
Al-Shawaf (73)
Alhashemi (72)
Cardiology
23
46
Cardiac surgery
Septic shock
14
21
16
21
Dobutamine,
placebo
Milrinone
Dobutamine
Alvarez (75)
Alvarez (74)
Barisin (76)
Berger (77)
Cardiac surgery
Cardiac surgery
Cardiac surgery
Cardiology
15
25
21
39
15
25
10
36
Dobutamine
12
Dobutamine
12
Placebo
12–24
Prostaglandin E1
12
Cardiology
Cardiac surgery
Cardiac surgery
Cardiology
Cardiology
Cardiac surgery
Cardiology
Cardiology
Cardiology (primary
coronary
angioplasty)
García-González Cardiology (primary
(86)
coronary
angioplasty)
Husedzinovií
Cardiac surgery
(87)
Ikonomidis (88) Cardiology
Järvelä (89)
Cardiac surgery
Kleber (90)
Cardiology
29
15
40
30
20
30
30
103
16
31
15
20
32
20
30
15
100
16
Dobutamine
Milrinone
Milrinone
Dobutamine
Dobutamine
Placebo
Placebo
Dobutamine
Enoximone
6–12
6–12
12
24
12
0.1–0.2
0.1
0.1
0.1
0.1
0.2
0.1
0.1–0.2
0.1–0.2
11
11
Dobutamine
24
0.1
12
13
Placebo
12
21
12
18
21
12
10
Placebo
Placebo
Placebo
12
0.1–0.2
0.2
0.1–0.2
Lahtinen (91)
Leppikangas
(92)
Levin (95)
Levin (93)
Levin (94)
Levin (97)
Levin (96)
Cardiac surgery
Vascular surgery
103
10
104
11
Placebo
Placebo
24
24
0.2
0.2
Cardiac surgery
Cardiac surgery
Cardiac surgery
Cardiac surgery
Cardiology
69
36
39
127
40
68
35
38
126
40
Dobutamine
Dobutamine
Placebo
Dobutamine
Placebo
10
10
10
10
0.1
0.1
0.1
0.1
0.1
Lilleberg (98)
Mavrogeni (99)
Cardiology
Cardiology
11
25
11
25
Placebo
Nothing
12
6
0.1–0.2
0.1–0.2
Mebazaa (11)
Moiseyev (9)
Cardiology
Cardiology
664
402
663
102
Dobutamine
Placebo
12
6/12/
24/24
0.2
0.1–0.4
Morelli (100)
Nieminen (101)
Sepsis
Cardiology
15
95
15
56
Nijhawan (102)
Packer (23)
Packer (12)
Parissis (103)
Slawsky (104)
Trikas (105)
Tritapepe (107)
Tritapepe (106)
Tziakas (108)
Zairis (10)
Cardiac surgery
Cardiology
Cardiology
Cardiology
Cardiology
Cardiology
Cardiac surgery
Cardiac surgery
Cardiology
Cardiology
12
51
299
42
98
24
12
53
30
100
6
49
301
21
48
24
12
53
30
99
Zemljic (109)
Cardiology
20
20
Dobutamine
Dobutamine,
placebo,
ethanol
vehicle
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Dobutamine,
placebo
Nothing
Bergh (78)
De Hert (79)
De Hert (80)
Duygu (81)
Duygu (82)
Eriksson (83)
Flevari (84)
Follath (8)
Fuhrmann (85)
Crit Care Med 2012 Vol. 40, No. 2
Length of
Infusion
Follow-Up
6
0.1
24 hrs
4 mos
12
0.1–0.2
0.05–0.2
24 hrs
24 hrs
0.2
0.2
24 hrs
24 hrs
End of hospitalization
End of intensive care
unit stay
1 day
15 days
End of hospitalization
12 mos
12
3/6/
12/24/
36
18/26
12
12
6
6
24
24
6
16
12
0.1
Monthly 24 hrs
intermittent
infusion
24 hrs
19 ⫾ 4 hrs
22–23 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs
30 days
End of hospitalization
30 days
6 mos
30 days
30 days
3 mos
6 mos
30 days
12 mos
End of hospitalization
24 hrs
24 hrs
24 hrs, then
intermittent
infusion 6 hrs
every 2 wks
24 hrs
24 hrs
18 mos
1 yr
84 days
24 hrs
24 hrs
24 hrs
24 hrs
24 hrs every 2
months
intermittent
infusion
24 hrs
Monthly 24 hrs
intermittent
infusion
24 hrs
6 hrs
End of hospitalization
30 days
30 days
End of hospitalization
1 yr
End of hospitalization
5 yrs
14 days
6 mos
6 mos
6 mos
0.2
0.05–0.6
24 hrs
24 hrs
30 days
2–9 days
0.2–0.3
0.1–0.2
0.2
0.1
0.1–0.4
0.1–0.4
6 hrs
24 hrs
24 hrs
24 hrs
4–6 hrs
24 hrs
0.1
0.2
24 hrs
24 hrs
End of hospitalization
5 days
3 mos
End of hospitalization
30 days
30 days
End of hospitalization
30 days
End of hospitalization
6 mos
0.1
24 hrs
3 mos
637
Table 2. Methodologic quality summary: Review authors’ judgments about each methodologic quality item for each included study
Domain/Question
Adequate
Sequence
Generation?
Allocation
Concealment
Used?
Adamopoulos (71)
Al-Shawaf (73)
Alhashemi (72)a
Alvarez (75)
Alvarez (74)
Barisin (76)
Berger (77)
Bergh (78)
De Hert (79)
De Hert (80)
Duygu (81)
Duygu (82)
Eriksson (83)
Flevari (84)
Follath (8)
Fuhrmann (85)
García-González (86)
Husedzinovií (87)
Ikonomidis (88)
Järvelä (89)
Kleber (90)
Lahtinen (91)a
Leppikangas (92)
Levin (95)
Levin (93)a
Levin (94)a
Levin (97)a
Levin (96)a
Lilleberg (98)
Mavrogeni (99)
Mebazaa (11)
Moiseyev (9)
Morelli (100)
Nieminen (101)
Nijhawan (102)
Packer (23)a
Packer (12)a
Parissis (103)
Slawsky (104)
Trikas (105)
Tritapepe (106)
Tritapepe (107)
Tziakas (108)
Zairis (10)a
Zemljic (109)
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Yes
Unclear
No
Unclear
Yes
Yes
Unclear
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Unclear
Yes
Yes
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Yes
Unclear
Yes
Yes
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
a
Incomplete
Outcome
Data
Addressed?
Uniform and
Explicit
Outcome
Definitions?
Free From
Selective
Outcome
Reporting?
Free
From
Other
Bias?
Overall
Risk of
Bias?
No
No
No
No
No
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
No
Unclear
Unclear
Unclear
Unclear
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
No
Yes
Yes
Unclear
Yes
Yes
Yes
Yes
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Unclear
Unclear
Unclear
No
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Unclear
Unclear
Yes
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
Unclear
No
Unclear
Unclear
Unclear
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Unclear
Yes
Yes
Unclear
Unclear
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
No
Unclear
Unclear
Yes
Yes
Yes
Yes
Yes
Yes
Unclear
Yes
Moderate
Moderate
High
Moderate
Moderate
Low
Moderate
Low
Low
Low
Moderate
Low
Moderate
Moderate
Low
Moderate
High
Moderate
Moderate
Low
Low
Moderate
Low
Moderate
High
High
High
High
Moderate
Moderate
Low
Low
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Moderate
Low
Moderate
High
Moderate
Study published as abstract only.
for effect ⫽ .007, Q ⫽ 56.15, p for heterogeneity ⬍.0001, I2 ⫽ 71% with 17 studies included) (Fig. 3). The reduction in
LOS was not found in the cardiac surgery
setting (see supplemental data [Supplemental Digital Material 19, http://links.
lww.com/CCM/A342]) but was confirmed
in the cardiology setting (WMD ⫽ ⫺1.59
[⫺2.33; ⫺0 – 85], p for effect ⬍.0001,
Q ⫽ 15.52, p for heterogeneity ⫽ .03,
I2 ⫽ 54.9% with eight studies included;
see supplemental data [Supplemental
Digital Material 20, http://links.lww.com/
CCM/A342]), even when only studies with
placebo as comparator were considered
638
Blinding?
Concurrent
Therapies
Similar?
(WMD ⫽ ⫺2.05 [⫺2.70; ⫺1.40], p for
effect ⬍ .001, Q ⫽ 1.94, p for heterogeneity ⫽ .379, I2 ⫽ 0% with three studies
included; see supplemental data [Supplemental Digital Material 21, http://links.
lww.com/CCM/A342]).
Numerous other subanalyses of adverse events and complications rate were
conducted and are summarized in Table 4
and in Supplemental Digital Material
22–26 (http://links.lww.com/CCM/A342).
Visual inspection of funnel plots did
not identify a skewed or asymmetrical
shape for mortality (Fig. 4) or LOS (Fig.
5). Quantitative evaluation did not sug-
gest a presence of publication bias, as
measured by the Begg test (p ⫽ .512 for
mortality, p ⫽ .967 for LOS) and Peters
test (p ⫽ .135 for mortality, p ⫽ .849 for
LOS). Absence of bias was also confirmed
by trim and fill approach.
Sensitivity analyses confirmed the
overall results of our work for the overall
mortality results (see supplemental data
[Supplemental Digital Material 27, http://
links.lww.com/CCM/A342]). Indeed, sensitivity analyses performed by sequentially removing each study and
reanalyzing the remaining dataset (producing a new analysis for each study reCrit Care Med 2012 Vol. 40, No. 2
Study
ID
RR (95% CI)
%
Weight
Adamopoulos S 2006
Al−Shawaf E 2006
Alhashemi JA 2009
Alvarez J 2005
Alvarez J 2006
Barisin S 2004
Berger R 2007
Bergh CH 2010
De Hert SG 2007
De Hert SG 2008
Duygu H 2008
Duygu H 2008
Eriksson HI 2009
Flevari P 2006
Follath F 2002
Fuhrmann JT 2008
Garcia−Gonzalez MJ 2006
Husedzinovic I 2005
Ikonomidis I 2007
Jarvela K 2008
Kleber FX 2009
Lahtinen P 2009
Leppikangas H 2008
Levin R 2008
Levin R 2008
Levin R 2008
Levin R 2009
Levin R 2009
Lilleberg J 2007
Mavrogeni S 2007
Mebazaa A 2007
Moiseyev VS 2002
Morelli A 2005
Nieminem M 2000
Nijhawan N 1999
Packer M 2003
Packer M 2005
Parissis JT 2007
Slawsky MT 2000
Trikas A 2006
Tritapepe L 2006
Tritapepe L 2009
Tziakas DN 2005
Zairis MN 2004
Zemljic G 2007
Overall (I−squared = 15.4%, p = 0.191)
0.44 (0.10, 1.89)
1.14 (0.08, 16.63)
0.77 (0.44, 1.35)
2.00 (0.07, 55.24)
1.00 (0.07, 15.12)
0.48 (0.01, 22.31)
0.79 (0.29, 2.13)
2.14 (0.20, 22.34)
0.25 (0.01, 5.10)
0.13 (0.01, 1.05)
1.54 (0.77, 3.07)
0.50 (0.21, 1.20)
0.25 (0.01, 5.32)
1.50 (0.17, 13.23)
0.69 (0.46, 1.04)
0.50 (0.22, 1.14)
3.00 (0.37, 24.58)
1.08 (0.02, 50.43)
0.17 (0.01, 3.13)
3.00 (0.36, 24.92)
0.28 (0.01, 7.57)
1.01 (0.48, 2.14)
1.10 (0.37, 3.27)
0.35 (0.15, 0.83)
0.22 (0.05, 0.93)
0.12 (0.02, 0.93)
0.45 (0.21, 0.94)
0.32 (0.14, 0.71)
1.00 (0.02, 46.05)
0.25 (0.06, 1.06)
0.93 (0.78, 1.11)
0.72 (0.51, 1.01)
0.78 (0.39, 1.54)
0.59 (0.04, 9.24)
0.50 (0.01, 22.25)
0.77 (0.22, 2.70)
1.10 (0.84, 1.44)
0.50 (0.01, 24.33)
0.49 (0.10, 2.34)
0.33 (0.08, 1.42)
1.00 (0.02, 46.40)
1.00 (0.02, 49.47)
1.00 (0.02, 48.77)
0.51 (0.32, 0.81)
1.00 (0.02, 47.97)
0.80 (0.72, 0.89)
0.53
0.16
3.56
0.10
0.15
0.08
1.13
0.20
0.12
0.25
2.35
1.45
0.12
0.24
6.66
1.66
0.25
0.08
0.13
0.25
0.10
1.97
0.94
1.48
0.52
0.27
2.00
1.72
0.08
0.53
35.55
9.70
2.41
0.15
0.08
0.71
15.67
0.07
0.46
0.53
0.08
0.07
0.07
5.30
0.07
100.00
.00888
1
113
Figure 2. Forest plot for the risk of mortality. The use of levosimendan was associated with a significant reduction in mortality at the longest follow-up
available (507 of 2915 [17.4%] in the levosimendan group vs. 598 of 2565 [23.3%] in the control arm, risk ratio [RR]: 0.80 [0.72; 0.89], p for effect⬍ .001,
Q ⫽ 51.98, p for heterogeneity ⫽ .191, I2 ⫽ 15.4%, NNT ⫽ 17 with 5,480 patients and 45 studies included). CI, confidence interval.
moved), and by analyzing only data from
studies with low risk of bias did not determine major changes in direction or
magnitude of statistical findings, confirming for each analysis the pooled effect
(RR ⬍1 or WMD ⬍0) and the statistical
significance (p ⬍ .05).
Crit Care Med 2012 Vol. 40, No. 2
DISCUSSION
This is the most comprehensive metaanalysis yet performed on levosimendan,
and statistically the most robust. Survival
benefits of levosimendan were confirmed
in numerous subanalyses and sensitivity
analyses. The findings of the present
meta-analysis are more important if we
consider that we noted a reduction in
LOS in patients receiving levosimendan.
The central finding of our analysis is
that levosimendan reduced mortality in
both the overall population, and in the
subpopulations of cardiac surgery and
639
Table 3. Subanalyses on mortality
Subgroups of
Interest
Studies with the longest follow-up of
at least 30 days
Studies with the longest follow-up of
at least 90 days
Studies with the longest follow-up of
at least 180 days
Studies with surgical or percutaneous
revascularization
Studies with patients on mechanical
ventilation
Studies with mortality as primary
end point
Studies with more than 100 patients
Blinded studies
Studies with levosimendan infusion
ⱕ0.1 ␮g/kg/min
Levosimendan infusion ⬎0.1 ␮g/kg/min
Studies with Levosimendan bolus
Studies without levosimendan bolus
Studies with sepsis patients
Number Event Levosimendan
of Studies
Group
Event Control
Group
Risk Ratio (95%
Confidence Interval)
p
I2
Number Needed
to Treat
28
464 of 2255 (21%)
522 of 1981 (26%)
0.725 (0.597–0.879)
.001 34%
17 (16–18)
17
438 of 1880 (23%)
468 of 1683 (28%)
0.794 (0.641–0.983)
.034 42%
22 (21–23)
12
346 of 1457 (24%)
377 of 1252 (30%)
0.745 (0.570–0.974)
.032 52%
16 (15–17)
16
30 of 484 (6.7%)
.001
14 (13–15)
22
232 of 1380 (17%)
304 of 1343 (23%)
0.612 (0.457–0.820)
.001 26%
17 (16–18)
9
397 of 1726 (23%)
397 of 1421 (28%)
0.669 (0.507–0.882)
.004 66%
20 (19–22)
12
27
18
427 of 2164 (20%)
449 of 2273 (20%)
68 of 727 (9%)
459 of 1864 (25%)
474 of 1961 (24%)
120 of 650 (18%)
0.758 (0.620–0.927)
0.86 (0.77–0.97)
0.556 (0.396–0.782)
.007 40%
.011 1.0%
.001 26%
20 (19–22)
23 (21–24)
11 (10–12)
22
35
10
2
421 of 1990 (21%)
459 of 2579 (18%)
48 of 336 (14%)
17 of 36 (47%)
398 of 1628 (24%)
476 of 2186 (22%)
122 of 379 (32%)
22 of 36 (61%)
0.878 (0.779–0.990)
.033 0.0%
0.843 (0.752–0.945)
.003 5.3%
0.579 (0.437–0.768) ⬍.001 12%
0.77 (0.50–1.19)
.2
0.0%
59 of 448 (13.7%) 0.511 (0.342–0.764)
0.0%
30 (28–33)
25 (24–27)
5.6 (5.3–5.8)
Forest plots are presented as supplemental material (Supplemental Digital Material, http://links.lww.com/CCM/A342).
cardiology. Survival benefit from levosimendan was apparent in comparison with
conventional inotrope therapy (i.e., dobutamine), as reported in our own and
other, earlier meta-analyses. In addition,
and in important contrast to earlier estimates (14, 110), our new analysis of an
enlarged dataset revealed a survival benefit of levosimendan in trials vs. placebo.
In some of the included studies, cardiogenic shock was an exclusion criteria,
and this may be reflected by the low mortality rate reported in patients hospitalized for heart failure in our metaanalysis. On the other side, the cardiac
surgery population of our meta-analysis
was at high risk and presented a perioperative risk of mortality (5%–10%) that is
highly increased when compared to modern cardiac surgery (about 1%–3% as reported in literature [111]). Since the effect of levosimendan on mortality was
stronger in the cardiac surgery setting,
we suggest that the increased effects in
populations at higher risk of mortality
may reflect a specific action of levosimendan, which may be translated to other
critically ill populations.
Many of the studies included in our
analysis were individually statistically underpowered. However, as illustrated in
Figure 2, many of them (28 studies, 62%)
conformed to the trend for benefit identified in the aggregate estimate, while six
studies (13%) had neutral findings. We
regard this indication of broad consistency between numerous individual stud640
ies and the overall result as a noteworthy
feature of this exercise: it provides assurance that the net survival benefit attributable to levosimendan is not the product
of a single dominating trial (or a few
dominating trials) in a narrowly defined
patient population. All the secondary
analyses, including bias, influence, and
robustness analysis, confirmed the validity of our findings.
This demonstration of a survival benefit from levosimendan is in contrast to
investigations into the effects of conventional inotropes, in which demonstrations of improvement in hemodynamic
indices has not been accompanied by survival benefits (1–5). Bayram et al (1) concluded that short-term use of these
agents was associated with increased
postdischarge mortality, particularly in
patients with ischemic heart disease,
while Thackray et al (2) reported that,
compared to placebo, intravenous administration of adrenergic inotrope agents
tended to increase mortality (odds ratio
1.50, 95% confidence interval 1.51–3.92),
albeit this did not reach significance. Levosimendan is in fact the first inotropic
agent to establish a positive impact on
patient survival time for any inotropic
agent in comparison with placebo. Previous positive findings in comparisons vs.
active controls have all favored levosimendan over agents such as dobutamine:
our new inspection of the data affirm that
finding.
It is also interesting to note that large,
head-to-head comparisons of other inotropic agents were recently performed
and no difference was noted. Annane et al
(112) suggested that there is no evidence
for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock, while De Backer et
al (113) found that there was no significant difference in the rate of death between patients with shock who were
treated with dopamine as the first-line
vasopressor agent and those who were
treated with norepinephrine. However,
dopamine treatment was associated with
a significantly higher rate of cardiac adverse events together with a borderline p
value (.07) for increased intensive care
unit mortality in dopamine-treated patients when compared to norepinephrine,
suggesting a detrimental effect of highdose dopamine.
Data from 17 of the studies we identified revealed that levosimendan was associated with a reduced LOS. This finding
was replicated in a subset of nine studies
in the cardiology setting. This finding is
compatible with the work of Ribeiro et al
(110). The absence of evidence for any
similar reduction in LOS in the cardiac
surgery setting may be a paradoxical effect of the survival benefit seen with levosimendan: the greater proportion of levosimendan-treated survivors leads to an
increase in average LOS vis-à-vis controltreated patients who do not survive.
Crit Care Med 2012 Vol. 40, No. 2
%
Study
ID
WMD (95% CI)
Weight
Barisin S 2004
−0.80 (−4.67, 3.07)
3.26
Bergh CH 2010
−1.40 (−9.00, 6.20)
1.07
De Hert SG 2007
−3.00 (−7.32, 1.32)
2.77
De Hert SG 2008
−6.00 (−11.06, −0.94)
2.16
Duygu H 2008
0.00 (−1.10, 1.10)
9.72
Duygu H 2008
−2.00 (−2.62, −1.38)
11.02
Eriksson HI 2009
0.10 (−3.53, 3.73)
3.58
Follath F 2002
0.80 (−2.59, 4.19)
3.93
Husedzinovic I 2005
−1.20 (−5.64, 3.24)
2.66
Jarvela K 2008
1.60 (−0.32, 3.52)
7.15
Leppikangas H 2008
−3.00 (−8.49, 2.49)
1.89
Mebazaa A 2007
−2.50 (−5.51, 0.51)
4.56
Packer M 2005
−1.60 (−2.56, −0.64)
10.14
Parissis JT 2007
−2.60 (−3.63, −1.57)
9.91
Trikas A 2006
−2.00 (−3.71, −0.29)
7.78
Tritapepe L 2006
−1.50 (−3.10, 0.10)
8.14
Tritapepe L 2009
0.90 (−0.01, 1.81)
10.27
Overall (I−squared = 71.0%, p = 0.000)
−1.13 (−1.95, −0.31)
100.00
NOTE: Weights are from random effects analysis
−11.1
0
11.1
Figure 3. Forest plot for the length of hospital stay. Length of hospital stay was reduced in the levosimendan group (weighted mean difference [WMD]
⫺1.31 [⫺1.95; ⫺0.31], p for effect ⫽ .007, Q ⫽ 56.15, p for heterogeneity ⬍ .0001, I2 ⫽ 71% with 17 studies included). CI, confidence interval.
Table 4. Adverse events
Outcome of Interest
Myocardial infarction
Ventricular arrhythmias
Supraventricular arrhythmias
Hypotension
Composite end point of hypotension
and/or norepinephrine use
Number of
Studies
Event
Levosimendan
Event
Control
Risk Ratio
(95% Confidence Interval)
p
I2
23
9
19
22
25
28 of 1161 (2.4%)
157 of 1344 (12%)
239 of 1958 (12%)
330 of 1532 (22%)
388 of 1599 (24%)
32 of 726 (4.4%)
152 of 1292 (12%)
203 of 1619 (13%)
211 of 1090 (19%)
268 of 1157 (23%)
0.804 (0.512–1.261)
0.885 (0.611–1.281)
0.997 (0.776–1.280)
1.389 (0.996–1.936)
1.219 (0.954–0.558)
.3
.5
.9
.053
.11
0.0%
43%
37%
48%
61%
Forest plots are presented in Supplemental Digital Material, http://links.lww.com/CCM/A342).
Levosimendan is currently used in ⬎50
countries and is listed in the European Society of Cardiology guidelines for treatment
of acute heart failure (114). However, to the
best of our knowledge, the Federal Drug
Administration has not yet approved it for
use in the United States.
Detailed explanation of the beneficial
effects of levosimendan is beyond the
Crit Care Med 2012 Vol. 40, No. 2
scope of a meta-analysis, but various aspects of the pharmacology of the drug
may be relevant. Levosimendan is primarily a calcium sensitizer. It displays
calcium-dependent binding to troponin
C, with higher affinity at high calcium
concentrations and lower affinity at low
calcium concentrations. By stabilizing
the calcium-troponin C complex, levosi-
mendan prolongs the actin-myosin crossbridge association rate. This mechanism
differentiates levosimendan from classic
inotropes and is regarded as the basis of
the drug’s ability to improve myocardial
efficiency without increasing myocardial
oxygen demand (115). The beneficial
effects of levosimendan may also be related to a vasodilatory effect mediated
641
tal discharge (WMD ⫽ ⫺1.38 days
[⫺2.78, 0.03], p ⫽ .05) in patients (n ⫽
74) receiving levosimendan (117). Another meta-analysis of randomized controlled trials (118) already suggested a
beneficial effect of levosimendan on survival, but the analysis was limited to the
specific setting of cardiac surgery.
s.e. ln(RR)
1
.5
0
Funnel plot with pseudo 95% confidence limits
2
1.5
Limitations of the Study
−4
−2
0
ln(RR)
2
4
Figure 4. Funnel plot for the risk of mortality. RR, risk ratio; s.e., standard error.
4
3
s.e.WMD
2
1
0
Funnel plot with pseudo 95% confidence limits
−10
−5
0
WMD
5
10
Figure 5. Funnel plot for the length of hospital stay. WMD, weighted mean difference; s.e., standard
error.
by an adenosine triphosphate-sensitive
potassium-channel opening effect, which
may reduce ventricular afterloading (115,
116).
The beneficial effect of levosimendan
on mortality seems to be more pronounced when the drug is administered
at an infusion rate ⱕ.01 ␮g/kg/min, even
if only a trend was noted toward an increased survival in this group. This hypothesis is strengthened by the signifi642
cant increase in the rate of hypotension
that was evidenced only in the subgroups
of patients receiving an infusion rate
⬎.01 ␮g/kg/min or a bolus dose.
A recent meta-analysis of five randomized trials (139 patients) undergoing cardiac surgery was powered sufficiently to
demonstrate a significant reduction in
postoperative peak release of cardiac troponin (WMD ⫽ 2.5 ng/dL [⫺3.86,
⫺1.14], p ⫽ .0003) and in time to hospi-
Although this is the most comprehensive dataset so far assembled from clinical
trials of levosimendan, the range of critical illness situations is largely restricted
to cardiological settings. The dataset for
sepsis is too small to draw conclusions
about the relative or absolute merits of
levosimendan vs. conventional inotropes
in this setting. Our analysis included only
two trials in interventional cardiology
and does not explicitly address the situation of preemptive hemodynamic intervention to improve postoperative outcomes in moderate or high-risk surgical
cases (119). Our conclusions about the
relative superiority of levosimendan over
conventional inotropes cannot be assumed to extend to that situation. We
have reported previously (13) that the
significant reduction in mortality and
rate of myocardial infarction associated
with levosimendan is achieved at the expense of a significant increase in the rate
of hypotension (p ⫽ .02 vs. controls).
This is a recognized feature of levosimendan and should be part of any risk-benefit
calculation. Nonetheless, the present
meta-analysis did not confirm a significant effect of the drug on hypotension.
LOS was not corrected for mortality in
most of the included studies, so in our
results, LOS is not corrected for mortality. This may underestimate the real effect of levosimendan on LOS and its real
impact on costs. Whereas a network
meta-analysis including all available cardiac inotropes could have been envisioned, it was beyond the scope of our
work. Finally, no formal test of agreement between reviewers was performed,
since all divergences were solved with
consensus as soon as evident.
CONCLUSIONS
This meta-analysis suggests that the
use of levosimendan in lieu of usual therapies is associated with a significant reduction in mortality. Additional large,
multicenter, randomized trials (120)
powered to clinically relevant end points,
Crit Care Med 2012 Vol. 40, No. 2
including mortality, will be needed to
confirm these deductions about the clinical advantages of levosimendan over
conventional inotropes.
9.
ACKNOWLEDGMENTS
We thank A. Mizzi, P. Prati, V. Ajello,
G. Bruno, C. Gerli, V. De Santis, L. Corno,
L. Tritapepe, G. Marino, and M. Zambon
for their contribution on data extraction,
sharing their expertise, and their valuable
comments on the report. Their substantial assistance and support greatly favored
the preparation of this paper. We also
thank the primary and contact authors
of the included studies who kindly provided
additional details for this review.
10.
11.
REFERENCES
12.
1. Bayram M, De Luca L, Massie MB, et al:
Reassessment of dobutamine, dopamine,
and milrinone in the management of acute
heart failure syndromes. Am J Cardiol 2005;
96:47G–58G
2. Thackray S, Easthaugh J, Freemantle N, et
al: The effectiveness and relative effectiveness of intravenous inotropic drugs acting
through the adrenergic pathway in patients
with heart failure-a meta-regression analysis. Eur J Heart Fail 2002; 4:515–529
3. Metra M, Eichhorn E, Abraham WT, et al:
Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced
heart failure: The randomized, doubleblind, placebo-controlled, parallel group
ESSENTIAL trials. Eur Heart J 2009; 30:
3015–3026
4. Abraham WT, Adams KF, Fonarow GC, et al:
In-hospital mortality in patients with acute
decompensated heart failure requiring intravenous vasoactive medications: An analysis from the Acute Decompensated Heart
Failure National Registry (ADHERE). J Am
Coll Cardiol 2005; 46:57– 64
5. Mebazaa A, Parissis J, Porcher R, et al:
Short-term survival by treatment among
patients hospitalized with acute heart failure: The global ALARM-HF registry using
propensity scoring methods. Intensive Care
Med 2011; 37:290 –301
6. Despas F, Trouillet C, Franchitto N, et al:
Levosimedan improves hemodynamics
functions without sympathetic activation in
severe heart failure patients: Direct evidence from sympathetic neural recording.
Acute Card Care 2010; 12:25–30
7. Papp Z, Csapó K, Pollesello P, et al: Pharmacological mechanisms contributing to
the clinical efficacy of levosimendan. Cardiovasc Drug Rev 2005; 23:71–98
8. Follath F, Cleland JG, Just H, et al: Efficacy
and safety of intravenous levosimendan
compared with dobutamine in severe low-
Crit Care Med 2012 Vol. 40, No. 2
13.
14.
15.
16.
17.
18.
19.
20.
output heart failure (the LIDO study): A
randomised double-blind trial. Lancet 2002;
360:196 –202
Moiseyev VS, Põder P, Andrejevs N, et al:
Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left
ventricular failure due to an acute myocardial infarction. A randomized, placebocontrolled, double-blind study (RUSSLAN).
Eur Heart J 2002; 23:1422–1432
Zairis MN, Apostolatos C, Anastasiadis P, et
al: The effect of a calcium sensitizer or an
inotrope or none in chronic low output
decompensated heart failure: Results from
the calcium sensitizer or inotrope or none
in low output heart failure study (CASINO).
J Am Coll Cardiol 2004; 43:A206 –A207
Mebazaa A, Nieminen MS, Packer M, et al:
Levosimendan vs dobutamine for patients
with acute decompensated heart failure:
The SURVIVE Randomized Trial. JAMA
2007; 297:1883–1891
Packer M, Revive II Trial Investigators: REVIVE II: Multicenter placebo-controlled
trial of levosimendan on clinical status in
acutely decompensated heart failure. Circulation 2005; 112:3363
Landoni G, Mizzi A, Biondi-Zoccai G, et al:
Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies. Minerva Anestesiol 2010; 76:276 –286
Delaney A, Bradford C, McCaffrey J, et al:
Levosimendan for the treatment of acute
severe heart failure: A meta-analysis of randomised controlled trials. Int J Cardiol
2010; 138:281–289
Mebazaa A, Nieminen MS, Filippatos GS, et
al: Levosimendan vs. dobutamine: Outcomes for acute heart failure patients on
beta-blockers in SURVIVE. Eur J Heart Fail
2009; 11:304 –311
Cohen-Solal A, Logeart D, Huang B, et al:
Lowered B-type natriuretic peptide in response to levosimendan or dobutamine
treatment is associated with improved survival in patients with severe acutely decompensated heart failure. J Am Coll Cardiol
2009; 53:2343–2348
Cleland JG, Freemantle N, Coletta AP, et al:
Clinical trials update from the American
Heart Association: REPAIR-AMI, ASTAMI,
JELIS, MEGA, REVIVE-II, SURVIVE, and
PROACTIVE. Eur J Heart Fail 2006;
8:105–110
Gheorghiade M, Pang PS: Are BNP changes
during hospitalization for heart failure a
reliable surrogate for predicting the effects
of therapies on post-discharge mortality?
J Am Coll Cardiol 2009; 53:2349 –2352
Nieminen MS: Levosimendan compared
with dobutamine in low output patients.
Minerva Anestesiol 2003; 69:258 –263
Cleland JG, Takala A, Apajasalo M, et al:
Intravenous levosimendan treatment is
cost-effective compared with dobutamine in
severe low-output heart failure: An analysis
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
based on the international LIDO trial. Eur
J Heart Fail 2003; 5:101–108
Cleland JG, Ghosh J, Freemantle N, et al:
Clinical trials update and cumulative metaanalyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids
and cardiac resynchronisation therapy in
heart failure. Eur J Heart Fail 2004;
6:501–508
Coletta AP, Cleland JG, Freemantle N, et al:
Clinical trials update from the European
Society of Cardiology Heart Failure meeting: SHAPE, BRING-UP 2 VAS, COLA II,
FOSIDIAL, BETACAR, CASINO and metaanalysis of cardiac resynchronisation therapy. Eur J Heart Fail 2004; 6:673– 676
Packer M, Colucci WS, Fisher L, et al: Development of a comprehensive new end
point for the evaluation of new treatments
for acute decompensated heart failure (results with levosimendan in the REVIVE-1
study). Abstr. J Card Fail 2003; 9:S61
Kota B, Prasad AS, Economides C, et al:
Levosimendan and calcium sensitization of
the contractile proteins in cardiac muscle:
Impact on heart failure. J Cardiovasc Pharmacol Ther 2008; 13:269 –278
de Lissovoy G, Fraeman K, Teerlink JR, et
al: Hospital costs for treatment of acute
heart failure: Economic analysis of the REVIVE II study. Eur J Health Econ 2010;
11:185–193
Biondi-Zoccai GG, Agostoni P, Abbate A, et
al: A simple hint to improve Robinson and
Dickersin’s highly sensitive PubMed search
strategy for controlled clinical trials. Int J
Epidemiol 2005; 34:224 –225; author reply
225
Higgins JPT, Green S: Cochrane handbook
for systematic reviews of interventions (v
5.0.2). Available at: http://www.cochranehandbook.org. Accessed January 4, 2011
Peters JL, Sutton AJ, Jones DR, et al: Comparison of two methods to detect publication bias in meta-analysis. JAMA 2006; 295:
676 – 680
Dear KBG, Begg CB: An approach for assessing publication bias prior to performing
a meta-analysis. Statistical Science 1992;
7:237–245
Duval S, Tweedie R: Trim and fill: A simple
funnel-plot-based method of testing and adjusting for publication bias in metaanalysis. Biometrics 2000; 56:455– 463
Review manager (RevMan) [computer program] version 5.0. Copenhagen: The Nordic
Cochrane Centre, the Cochrane Collaboration, 2008. Available at: http://ims.cochrane.
org/revman. Accessed January 4, 2011
Liberati A, Altman DG, Tetzlaff J, et al: The
PRISMA statement for reporting systematic
reviews and meta-analyses of studies that
evaluate healthcare interventions: Explanation and elaboration. BMJ 2009; 339:b2700
Akselrod B, Trekova N, Tolstova I, et al:
Preoperative levosimendan administration:
What is the vascular payment during anaes-
643
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
644
thesia? J Cardiothorac Vasc Anesth 2010;
24:S18
Avgeropoulou C, Andreadou I, MarkantonisKyroudis S, et al: The Ca2⫹-sensitizer levosimendan improves oxidative damage,
BNP and pro-inflammatory cytokine levels
in patients with advanced decompensated
heart failure in comparison to dobutamine.
Eur J Heart Fail 2005; 7:882– 887
Chamos C, Daidou T, Delis E, et al: The
effects of levosimendan compared with milrinone in cardiac surgery patients. J Cardiothorac Vasc Anesth 2009; 23:S19
De Luca L, Proietti P, Celotto A, et al: Levosimendan improves hemodynamics and
coronary flow reserve after percutaneous
coronary intervention in patients with
acute myocardial infarction and left ventricular dysfunction. Am Heart J 2005; 150:
563–568
De Luca L, Sardella G, Proietti P, et al:
Effects of levosimendan on left ventricular
diastolic function after primary angioplasty
for acute anterior myocardial infarction: A
Doppler echocardiographic study. J Am Soc
Echocardiogr 2006; 19:172–177
Duman D, Palit F, Simsek E, et al: Effects of
levosimendan versus dobutamine on left
atrial function in decompensated heart failure. Can J Cardiol 2009; 25:e353– e356
Duygu H, Nalbantgil S, Zoghi M, et al: Comparison of ischemic side effects of levosimendan and dobutamine with integrated
backscatter analysis. Clin Cardiol 2009; 32:
187–192
Harjola VP, Oikarinen L, Toivonen L, et al:
The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with
NYHA Classes II-III heart failure. Int J Clin
Pharmacol Ther 2008; 46:389 –399
Jörgensen K, Bech-Hanssen O, Houltz E, et
al: Effects of levosimendan on left ventricular relaxation and early filling at maintained preload and afterload conditions after aortic valve replacement for aortic
stenosis. Circulation 2008; 117:1075–1081
Kasikcioglu HA, Uyarel H, Tartan Z, et al:
Do calcium sensitizers affect right ventricular functions in patients with chronic
heart failure? Int J Cardiol 2007; 118:
246 –248
Knez I, Schweiger S, Ovcina I, et al: Effects
of Ca2⫹ sensitiser levosimendan on flow in
internal thoracic and radial arteries in patients undergoing CABG–preliminary results. Abstr. Eur Heart J 2005; 26:527
Kurt IH, Yavuzer K, Batur MK: Short-term
effect of levosimendan on free light chain
kappa and lambda levels in patients with
decompensated chronic heart failure. Heart
Vessels 2010; 25:392–399
Lilleberg J, Nieminen MS, Akkila J, et al:
Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary
blood flow and myocardial substrate utilization early after coronary artery bypass
grafting. Eur Heart J 1998; 19:660 – 668
46. Moertl D, Berger R, Huelsmann M, et al:
Short-term effects of levosimendan and
prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels
in patients with decompensated chronic
heart failure. Eur J Heart Fail 2005;
7:1156 –1163
47. Parissis JT, Adamopoulos S, Antoniades C,
et al: Effects of levosimendan on circulating
pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 2004; 93:1309 –1312
48. 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; 92:1768 –1772
49. Parissis JT, Andreadou I, Markantonis SL, et
al: Effects of Levosimendan on circulating
markers of oxidative and nitrosative stress
in patients with advanced heart failure. Atherosclerosis 2007; 195:e210 – e215
50. Parissis JT, Karavidas A, Bistola V, et al:
Effects of levosimendan on flow-mediated
vasodilation and soluble adhesion molecules in patients with advanced chronic
heart failure. Atherosclerosis 2008; 197:
278 –282
51. Parissis JT, Panou F, Farmakis D, et al:
Effects of levosimendan on markers of left
ventricular diastolic function and neurohormonal activation in patients with advanced heart failure. Am J Cardiol 2005;
96:423– 426
52. Sonntag S, Sundberg S, Lehtonen LA, et al:
The calcium sensitizer levosimendan improves the function of stunned myocardium
after percutaneous transluminal coronary
angioplasty in acute myocardial ischemia.
J Am Coll Cardiol 2004; 43:2177–2182
53. Yilmaz MB, Karadas F, Erdem A, et al: Improvement in Doppler alternans in patients
with severe heart failure: Levosimendan
versus dobutamin. Int J Cardiol 2008; 125:
104 –106
54. Yilmaz MB, Yalta K, Yontar C, et al: Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine.
Cardiovasc Drugs Ther 2007; 21:431– 435
55. Wang L, Cui L, Wei JP, et al: [Efficacy and
safety of intravenous levosimendan compared with dobutamine in decompensated
heart failure]. Zhonghua Xin Xue Guan
Bing Za Zhi 2010; 38:527–530
56. Yilmaz MB, Yontar C, Erdem A, et al: Comparative effects of levosimendan and dobutamine on right ventricular function in patients with biventricular heart failure.
Heart Vessels 2009; 24:16 –21
57. Nieminen MS, Cleland JG, Eha J, et al: Oral
levosimendan in patients with severe
chronic heart failure –the PERSIST study.
Eur J Heart Fail 2008; 10:1246 –1254
58. Põder P, Eha J, Sundberg S, et al: Pharma-
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
codynamics and pharmacokinetics of oral
levosimendan and its metabolites in patients with severe congestive heart failure:
A dosing interval study. J Clin Pharmacol
2004; 44:1143–1150
Branzi G, Malfatto G, Villani A, et al: Acute
effects of levosimendan on mitral regurgitation and diastolic function in patients
with advanced chronic heart failure. J Cardiovasc Med (Hagerstown) 2010; 11:
662– 668
Lehmann A, Kiessling AH, Isgro F, et al:
Levosimendan in patients with acute myocardial ischaemia undergoing emergency
surgical revascularization. Eur J Anaesthesiol 2008; 25:224 –229
Nanas JN, Papazoglou P, Tsagalou EP, et al:
Efficacy and safety of intermittent, longterm, concomitant dobutamine and levosimendan infusions in severe heart failure
refractory to dobutamine alone. Am J Cardiol 2005; 95:768 –771
Liu T, Li G, Xu G: Levosimendan may prevent postoperative atrial fibrillation
through anti-inflammatory and antioxidant
modulation. J Cardiothorac Vasc Anesth
2009; 23:757–758
Tasouli A, Papadopoulos K, Antoniou T, et
al: Efficacy and safety of perioperative infusion of levosimendan in patients with compromised cardiac function undergoing
open-heart surgery: Importance of early
use. Eur J Cardiothorac Surg 2007; 32:
629 – 633
Dominguez-Rodriguez A, Samimi-Fard S,
Garcia-Gonzalez MJ, et al: Effects of levosimendan versus dobutamine on left ventricular diastolic function in patients with cardiogenic shock after primary angioplasty.
Int J Cardiol 2008; 128:214 –217
Duygu H, Nalbantgil S, Ozerkan F, et al:
Effects of levosimendan on left atrial functions in patients with ischemic heart failure. Clin Cardiol 2008; 31:607– 613
Duygu H, Ozerkan F, Zoghi M, et al: Effect
of levosimendan on right ventricular systolic and diastolic functions in patients with
ischaemic heart failure. Int J Clin Pract
2008; 62:228 –233
Kivikko M, Lehtonen L, Colucci WS: Sustained hemodynamic effects of intravenous
levosimendan. Circulation 2003; 107:81– 86
Samimi-Fard S, Garcia-Gonzalez MJ, Dominguez-Rodriguez A, et al: Effects of levosimendan versus dobutamine on long-term
survival of patients with cardiogenic shock
after primary coronary angioplasty. Int
J Cardiol 2008; 127:284 –287
Levin RL, Degrange M, Porcile R, et al: The
preoperative utilization of levosimendan
(preoperative optimization) reduced mortality and low output syndrome after cardiac surgery in patients with low ejection
fraction (EF⬍25%). Circulation 2007;
116:82
Momeni M, Rubay J, Matta A, et al: Levosimendan in congenital cardiac surgery: A
randomized, double-blind clinical trial.
Crit Care Med 2012 Vol. 40, No. 2
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
J Cardiothorac Vasc Anesth 2011; 25:
419 – 424
Adamopoulos S, Parissis JT, Iliodromitis
EK, et al: Effects of levosimendan versus
dobutamine on inflammatory and apoptotic
pathways in acutely decompensated chronic
heart failure. Am J Cardiol 2006; 98:
102–106
Alhashemi JA, Alotaibi QA, Abdullah GM, et
al: Levosimendan vs dobutamine in septic
shock. J Crit Care 2009; 24:e14 – e15
Al-Shawaf E, Ayed A, Vislocky I, et al: Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery.
J Cardiothorac Vasc Anesth 2006; 20:
353–357
Alvarez J, Bouzada M, Fernández AL, et al:
[Hemodynamic effects of levosimendan
compared with dobutamine in patients with
low cardiac output after cardiac surgery].
Rev Esp Cardiol 2006; 59:338 –345
Alvarez J, Taboada M, Rodríguez J, et al:
[Hemodynamic effects of levosimendan following cardiac surgery]. Rev Esp Anestesiol
Reanim 2005; 52:389 –394
Barisin S, Husedzinovic I, Sonicki Z, et al:
Levosimendan in off-pump coronary artery
bypass: A four-times masked controlled
study. J Cardiovasc Pharmacol 2004; 44:
703–708
Berger R, Moertl D, Huelsmann M, et al:
Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with
refractory, advanced chronic heart failure.
Eur J Heart Fail 2007; 9:202–208
Bergh CH, Andersson B, Dahlström U, et al:
Intravenous levosimendan vs. dobutamine
in acute decompensated heart failure patients on beta-blockers. Eur J Heart Fail
2010; 12:404 – 410
De Hert SG, Lorsomradee S, Cromheecke S,
et al: The effects of levosimendan in cardiac
surgery patients with poor left ventricular
function. Anesth Analg 2007; 104:766 –773
De Hert SG, Lorsomradee S, vanden Eede
H, et al: A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with
myocardial dysfunction. J Cardiothorac
Vasc Anesth 2008; 22:699 –705
Duygu H, Ozerkan F, Nalbantgil S, et al:
Effect of levosimendan on E/E’ ratio in patients with ischemic heart failure. Int J Cardiol 2008; 123:201–203
Duygu H, Turk U, Ozdogan O, et al: Levosimendan versus dobutamine in heart failure patients treated chronically with carvedilol. Cardiovasc Ther 2008; 26:182–188
Eriksson HI, Jalonen JR, Heikkinen LO, et
al: Levosimendan facilitates weaning from
cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with
impaired left ventricular function. Ann
Thorac Surg 2009; 87:448 – 454
Flevari P, Parissis JT, Leftheriotis D, et al:
Effect of levosimendan on ventricular arrhythmias and prognostic autonomic in-
Crit Care Med 2012 Vol. 40, No. 2
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
dexes in patients with decompensated advanced heart failure secondary to ischemic
or dilated cardiomyopathy. Am J Cardiol
2006; 98:1641–1645
Fuhrmann JT, Schmeisser A, Schulze MR,
et al: Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit
Care Med 2008; 36:2257–2266
García-González MJ, Domínguez-Rodríguez
A, Ferrer-Hita JJ, et al: Cardiogenic shock
after primary percutaneous coronary intervention: Effects of levosimendan compared
with dobutamine on haemodynamics. Eur
J Heart Fail 2006; 8:723–728
Husedzinoviæ I, Barisin S, Bradiæ N, et al:
Levosimendan as a new strategy during offpump coronary artery bypass grafting: Double-blind randomized placebo-controlled
trial. Croat Med J 2005; 46:950 –956
Ikonomidis I, Parissis JT, Paraskevaidis I, et
al: Effects of levosimendan on coronary artery flow and cardiac performance in patients with advanced heart failure. Eur
J Heart Fail 2007; 9:1172–1177
Järvelä K, Maaranen P, Sisto T, et al: Levosimendan in aortic valve surgery: Cardiac
performance and recovery. J Cardiothorac
Vasc Anesth 2008; 22:693– 698
Kleber FX, Bollmann T, Borst MM, et al:
Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in
patients with pulmonary hypertension: Results of a pilot study. J Clin Pharmacol
2009; 49:109 –115
Lahtinen P, Pitkänen O, Pölönen P, et al:
Levosimendan reduces heart failure after
high risk cardiac surgery–a prospective,
randomized, placebo-controlled trial. Eur
Heart J 2009; 30:596
Leppikangas H, Tenhunen JJ, Lindgren L,
et al: Effects of levosimendan on indocyanine green plasma disappearance rate and
the gastric mucosal-arterial pCO2 gradient
in abdominal aortic aneurysm surgery. Acta
Anaesthesiol Scand 2008; 52:785–792
Levin RL, Degrange MA, Del-Mazo C, et al:
Superiority of levosimendan over dobutamine
in low cardiac output syndrome after aortic
valve replacement. Circulation 2008; 118:
E231
Levin RL, Degrange MA, Porcile R, et al:
Preoperative use of calcium sensitizer levosimendan reduces mortality and low cardiac
output syndrome in patients with aortic stenosis and left ventricular dysfunction. Circulation 2008; 118:E217
Levin RL, Degrange MA, Porcile R, et al:
[The calcium sensitizer levosimendan gives
superior results to dobutamine in postoperative low cardiac output syndrome]. Rev
Esp Cardiol 2008; 61:471– 479
Levin R, Porcile RT, Degrange M: The intermittent infusion of levosimendan reduces mortality and readmissions in patients with advanced heart failure.
Circulation 2009; 120:s865
Levin R, Porcile R, Salvagio F, et al: Levosi-
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
mendan reduces mortality in postoperative
low cardiac output syndrome after coronary
surgery. Circulation 2009; 120:S987–S988
Lilleberg J, Laine M, Palkama T, et al: Duration of the haemodynamic action of a
24-h infusion of levosimendan in patients
with congestive heart failure. Eur J Heart
Fail 2007; 9:75– 82
Mavrogeni S, Giamouzis G, Papadopoulou
E, et al: A 6-month follow-up of intermittent levosimendan administration effect on
systolic function, specific activity questionnaire, and arrhythmia in advanced heart
failure. J Card Fail 2007; 13:556 –559
Morelli A, De Castro S, Teboul JL, et al: Effects
of levosimendan on systemic and regional hemodynamics in septic myocardial depression.
Intensive Care Med 2005; 31:638 – 644
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; 36:1903–1912
Nijhawan N, Nicolosi AC, Montgomery MW,
et al: Levosimendan enhances cardiac performance after cardiopulmonary bypass: A prospective, randomized placebo-controlled trial.
J Cardiovasc Pharmacol 1999; 34:219 –228
Parissis JT, Papadopoulos C, Nikolaou M, et
al: Effects of levosimendan on quality of life
and emotional stress in advanced heart failure
patients. Cardiovasc Drugs Ther 2007; 21:
263–268
Slawsky MT, Colucci WS, Gottlieb SS, et al:
Acute hemodynamic and clinical effects of
levosimendan in patients with severe heart
failure. Study Investigators. Circulation
2000; 102:2222–2227
Trikas A, Antoniades C, Latsios G, et al:
Long-term effects of levosimendan infusion
on inflammatory processes and sFas in patients with severe heart failure. Eur J Heart
Fail 2006; 8:804 – 809
Tritapepe L, De Santis V, Vitale D, et al:
Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth
2009; 102:198 –204
Tritapepe L, De Santis V, Vitale D, et al:
Preconditioning effects of levosimendan in
coronary artery bypass grafting–a pilot
study. Br J Anaesth 2006; 96:694 –700
Tziakas DN, Chalikias GK, Hatzinikolaou
HI, et al: Levosimendan use reduces matrix
metalloproteinase-2 in patients with decompensated heart failure. Cardiovasc
Drugs Ther 2005; 19:399 – 402
Zemljic G, Bunc M, Yazdanbakhsh AP, et al:
Levosimendan improves renal function in
patients with advanced chronic heart failure
awaiting cardiac transplantation. J Card
Fail 2007; 13:417– 421
Ribeiro RA, Rohde LE, Polanczyk CA: Levosimendan in acute decompensated heart
failure: Systematic review and metaanalysis. Arq Bras Cardiol 2010; 95:
230 –237
Bonaros N, Vill D, Wiedemann D, et al:
645
112.
113.
114.
115.
646
Major risk stratification models do not predict perioperative outcome after coronary
artery bypass grafting in patients with previous percutaneous intervention. Eur J Cardiothorac Surg 2011; 39:e164 – e169
Annane D, Vignon P, Renault A, et al: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: A
randomised trial. Lancet 2007; 370:676 – 684
De Backer D, Biston P, Devriendt J, et al:
Comparison of dopamine and norepinephrine in the treatment of shock. N Engl
J Med 2010; 362:779 –789
Dickstein K, Cohen-Solal A, Filippatos G, et
al: ESC guidelines for the diagnosis and
treatment of acute and chronic heart failure
2008: The Task Force for the diagnosis and
treatment of acute and chronic heart failure
2008 of the European Society of Cardiology.
Developed in collaboration with the Heart
Failure Association of the ESC (HFA) and
endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart
Fail 2008; 10:933–989
Follath F: Newer treatments for decompen-
116.
117.
118.
119.
120.
sated heart failure: Focus on levosimendan.
Drug Des Devel Ther 2009; 3:73–78
Tavares M, Rezlan E, Vostroknoutova I, et
al: New pharmacologic therapies for acute
heart failure. Crit Care Med 2008; 36:
S112–S120
Zangrillo A, Biondi-Zoccai G, Mizzi A, et al:
Levosimendan reduces cardiac troponin release after cardiac surgery: A meta-analysis
of randomized controlled studies. J Cardiothorac Vasc Anesth 2009; 23:474 – 478
Landoni G, Mizzi A, Biondi-Zoccai G, et al:
Reducing mortality in cardiac surgery with
levosimendan: A meta-analysis of randomized controlled trials. J Cardiothorac Vasc
Anesth 2010; 24:51–57
Hamilton MA, Cecconi M, Rhodes A: A systematic review and meta-analysis on the use
of preemptive hemodynamic intervention
to improve postoperative outcomes in moderate and high-risk surgical patients.
Anesth Analg 2011; 112:1392–1402
Levosimendan in High Risk Patients Undergoing Cardiac Surgery (HSR-LEVO).
ClinicalTrials.gov Identifier NCT00994825.
Available at: http://www.clinicaltrials.gov. Accessed January 5, 2011
APPENDIX
Search strategy for PubMed, developed according to Biondi-Zoccai et al (26): (levosimendan OR simdax) AND (randomized controlled
trial[pt] OR controlled clinical trial[pt] OR randomized
controlled
trials[mh]
OR
random allocation[mh] OR double-blind
method[mh] OR single-blind method[mh]
OR clinical trial[pt] OR clinical trials[mh] OR
(clinical trial[tw] OR ((singl*[tw] OR doubl*[tw]
OR trebl*[tw] OR tripl*[tw]) AND (mask*[tw]
OR blind[tw])) OR (latin square[tw]) OR placebos[mh] OR placebo*[tw] OR random*[tw] OR
research design[mh:noexp] OR comparative
study[tw] OR follow-up studies[mh] OR prospective studies[mh] OR crossover studies[mh] OR
control[tw] OR controls[tw] OR controlled[tw]
OR prospectiv*[tw] OR volunteer*[tw]) NOT
(animal[mh] NOT human[mh]) NOT (comment[pt] OR editorial[pt] OR meta-analysis[pt]
OR practice-guideline[pt] OR review[pt])).
Crit Care Med 2012 Vol. 40, No. 2