Impact of prophylactic administration of Levosimendan on short-term and long-term outcome in high-risk patients with severely reduced left-ventricular ejection fraction undergoing cardiac surgery – a retrospective analysis
Grieshaber et al. Journal of Cardiothoracic Surgery
Impact of prophylactic administration of Levosimendan on short-term and long- term outcome in high-risk patients with severely reduced left-ventricular ejection fraction undergoing cardiac surgery - a retrospective analysis
Philippe Grieshaber 0
Stella Lipp 0
Andreas Arnold 2
Gerold Görlach 0
Matthias Wollbrück 1
Peter Roth 0
Bernd Niemann 0
Jochen Wilhelm 3
Andreas Böning 0
0 Department of Adult and Pediatric Cardiovascular Surgery, University Hospital Giessen , Rudolf-Buchheim-Str. 7, DE-35392 Giessen , Germany
1 Department of Anaesthesiology and Intensive Care Medicine, University Hospital Giessen , Giessen , Germany
2 Department of Neurology, University Hospital Giessen , Giessen , Germany
3 Department of Internal Medicine, German Center for Lung Research, Justus Liebig University , Giessen , Germany
Background: Patients with severely reduced left-ventricular ejection fraction carry a high risk of morbidity and mortality after cardiac surgery. Levosimendan can be used prophylactically in these patients having shown positive effects on short-term outcome. However, effects on long-term outcome and patient subgroups benefiting the most are unknown. We aim to address these topics with real-life data from our clinical practice. Methods: Two hundred eigthy eight patients with preoperative LVEF ≤ 35% underwent cardiac surgery with cardiopulmonary bypass between 2009 and 2013. Thereof, 246 were included in the matched analysis. Eigthy two patients received 12.5mg Levosimendan starting at induction of anesthesia. Outcomes of patients undergoing coronary artery bypass grafting surgery (n = 103), isolated valve surgery/ascending aortic surgery (n = 45) and those undergoing combination procedures (n = 98) were analyzed separately. Additionally, multivariate regression analysis was conducted in order to identify predictors of short-term outcome parameters for different subgroups of patients. Results: Thirty days mortality rates of 16% in the Levosimendan group and 21% in the control group (OR 0.7; 95%CI 0.36-1.5; p = 0.37) were observed. Levosimendan showed a positive effect on postoperative renal function. A higher rate of new-onset atrial fibrillation (OR 4.0; 95%-CI 2.2-7-2; p < 0.0001) was observed in the Levosimendan group. Follow-up until three years postoperatively showed no differences in long-term survival between the groups. Conclusion: Prophylactic administration of Levosimendan did not affect overall short- and long-term outcomes. The value of prophylactic use of Levosimendan remains questionable and more data is needed to confirm subgroups that might benefit most.
Levosimendan; Cardiac surgery; Low cardiac output syndrome; High-risk patients
Levosimendan (LS) improves myocardial contractility
without increasing myocardial oxygen demand by
increasing calcium-sensitivity of the myocardial contractile
units through binding to troponin C . Furthermore, it
induces systemic vascular and coronary artery dilation
through activation of adenosine triphosphate
(ATP)dependent potassium channels in the vascular smooth
muscle cells . The effect of LS and its metabolite
OR1896 are reported to last up to seven days . LS effects
have been thoroughly investigated in the treatment for
acutely decompensated chronic heart failure, showing
positive results when compared to either dobutamine
(RUSSLAN study) or placebo (LIDO study) [3, 4].
However, the REVIVE I and II studies showed adverse effects
on those patients treated with LS .
Patients with preoperatively severely reduced
ventricular contractility undergoing cardiac surgery with
cardiopulmonary bypass (CPB) carry a substantial risk of
postoperative low cardiac output syndrome with its
consequences (organ malperfusion, shock, multi-organ
failure). The advantageous properties of LS make it a
promising therapeutic or even prophylactic option for
prevention of these complications.
A number of small-sized prospective randomized trials
have shown positive effects of prophylactic LS
administration on postoperative cardiac performance [6, 7],
renal function [8, 9], inflammation , demand on
other inotropic drugs  as well as on short-term
survival [12, 13]. However, the transferability of these
excellent results to real-life practice has been questioned and,
despite LS being one of the best-investigated drugs in
cardiovascular medicine in the recent years, its
prophylactic use in cardiac surgery has not become a widely
established therapeutic concept. Furthermore, the
potential durability of the LS effect resulting in improved
long-term survival has not been shown so far [14, 15]. In
order to give an update from the clinical routine and to
generate hypotheses for further studies, we investigated,
if the effect of prophylactic LS administration on
shortterm outcome can be confirmed in patients with
preoperative LVEF ≤35% undergoing cardiac surgery
outside the controlled setting of prospective trials.
Furthermore we aimed to describe for the first time the
effect of prophylactic LS on long-term survival in these
patients. Also, dependence of the LS effect on
complexity of the surgical procedure was investigated.
The present study was a retrospective single-center
study. It aimed to describe the effect of prophylactic LS
administration in patients with preoperative LVEF ≤35%
undergoing cardiac surgery with the use of CPB.
The ethical committee of the Faculty of Medicine at
Justus Liebig University Giessen, Germany approved the
study. The trial was designed and conducted in
accordance to the Declaration of Helsinki.
Patients with preoperative LVEF ≤ 35% who underwent
cardiac surgical procedures with CPB at our institution
between 01/2009 and 12/2013 where identified from
institutional patient records and data issued to the
nationwide quality assurance program. Clinical records of
these patients were reviewed and long-term survival was
determined by obtaining the patients’ excerpts from the
German federal residents’ registry. In order to correct
for relevant differences in baseline characteristics, a
1:2propensity score matching of LS group and control
group was conducted (Fig. 1).
Administration of LS
Patients received 12.5 mg LS via continuous intravenous
infusion over 24 h starting at the induction of anesthesia.
We did not apply an initial bolus. The treating surgeon
and the anesthesiologist decided whether to administer
prophylactic LS on an individual basis. Besides the LVEF,
determined using the biplane Simpson method, criteria
for LS use included preoperative state of cardiac
compensation (clinical features evaluated during the
preoperative visit: presence of dyspnea at rest, orthopnea,
edema), hemodynamic reaction to induction of
anesthesia (decrease of systolic blood pressure by
>30mmHg without immediate stabilization after
administration of inotropes, vasopressors or volume
resuscitation) as well as complexity and estimated duration of the
Perioperatively, medical circulatory support and
hemodynamic monitoring was managed at the discretion
of the treating intensive care physicians according to the
relevant guidelines .
Outcomes were compared between patients who
received prophylactic LS and patients who did not. In
order to clarify if the effect of prophylactic LS might be
different depending on the complexity of surgery,
outcomes were further analyzed separately for patients who
underwent isolated coronary artery bypass grafting
surgery (CABG group), isolated valve or aortic surgery
(valve group) or combination procedures (combi group)
The primary endpoint of the trial was postoperative
30-days survival. Long-term survival functions were
Fig. 1 Patient inclusion flow chart. From 3.951 patients operated on in the inclusion period, 288 presented with preoperative LVEF ≤35%. Of
these, 84 patients received prophylactic LS and 204 did not. After propensity score matching, 246 patients remained in the analysis with 82
patients in the LS group and 164 patients in the control group. Abbreviations: CABG: Coronary artery bypass grafting surgery, LS: Levosimendan,
LVEF: Left-ventricular ejection fraction
determined and compared using Kaplan-Meier
estimation. Secondary endpoints included postoperative need
for medical and mechanical circulatory support, renal
function, new-onset atrial fibrillation as well as lengths
of intensive care unit (ICU) stay and hospital admission.
In this retrospective study, a descriptive statistical
analysis was performed using SPSS Version 22 (IBM,
Armonk, USA), GraphPad Prism version 6 software
(GraphPad Software, Inc., La Jolla, CA, USA) and R
version 3.1.2. Patient characteristics were compared using
Fisher’s exact test or Student’s t-test as appropriate. In
order to correct for potential confounding baseline
parameters between the LS group and the control group,
propensity score matching of the groups was performed.
Covariates included in the matching were age, gender,
BMI, preoperative LVEF, pulmonary hypertension
(categorized into no, moderate, severe), EuroSCORE II,
preoperative chronic kidney injury (categorized into no,
stadium 1, stadium 2, stadium 3 and stadium 4) and
weight of the intervention (categorized in isolated
CABG, isolated aortic/valve surgery, combination
procedure). Hereafter, nearest neighbor matching in a 1:2
(LS : Control) fashion was performed. The maximum
caliper between matched participants was set at 0.2.
Group comparison for postoperative outcome
parameters was performed by Fisher’s exact test or Student’s
ttest between LS group and control group. Long-term
survival functions were determined using Kaplan-Meier
estimation and compared using the log rank test.
The effect of LS administration on the clinical
outcome parameters ‘30-days survival’, ‘postoperative acute
kidney injury (as defined by the AKIN-Criteria )’ and
‘postoperative new-onset atrial fibrillation within 24h
post-surgery’ was additionally estimated by multivariate
regression using generalized linear models. Survival data
was fitted using Cox-proportional hazard models. Some
metric predictors were log-transformed to linearize their
relationship with the response (see Additional file 1 for
detailed model formulations and coefficient tables).
Of all patients who underwent cardiac surgical
procedures with CPB at our institution between 01/2009 and
12/2013, 288 patients presented with preoperative LVEF
< 35%. Thereof, 84 patients received LS prophylactically,
204 did not receive LS. Before propensity score
matching, differences in preoperative renal function, previously
known pulmonary hypertension and prevalence of
recent acute myocardial infarction between the groups
were observed. In the matched study population (n =
246; LS: n = 82; Control n = 164), these differences were
eliminated and patients’ baseline characteristics were
balanced between the groups (Table 1; Additional file 2).
Unmatched study population
All patients LS + LS
n = 288 (100%) n = 84 (29.17%) n = 204 (70.83%)
Matched study population
Table 1 Baseline characteristics
Age [years]|; mean ± SD
Sex [females] n (%)
Body mass index [kg/m2] mean ± SD
Preoperative LVEF [%];mean ± SD
Preoperative renal impairment; n (%)
Stage 2 (GFR 85-120ml/min.)
Stage 3 (GFR 51-85ml/min.)
Stage 4 (GFR <51ml/min.)
Stage 5 (Dialysis)
Preoperative atrial fibrillation; n (%)
resuscitation; n (%)
Preoperative invasive ventilation; n (%)
EuroSCORE II [%]; mean ± SD
Isolated CABG group
Valve/aortic surgery group
Systolic blood pressure at induction of
anaesthesia [mmHg]; median (IQR)
Diastolic blood pressure at induction of 69 (60–82)
anaesthesia [mmHg]; median (IQR)
Extracorporeal circulation time [min.];
Cardioplegic arrest time [min.];
Demographics and intraoperative data of the study population before (left) and after propensity score matching (right). The unmatched population shows
significant differences between LS and control group with more severe chronic renal impairment and a more complex procedural profile in the LS group. After
matching, the groups are well balanced.
Abbreviations: CABG coronary artery bypass grafting surgery, GFR Glomerular filtration rate, LS Levosimendan, LVEF Left-ventricular ejection fraction
The procedural profiles showed a tendency towards more
complex procedures in the LS group compared to the
control group with 39% vs. 43% isolated CABG
procedures and 46% vs. 37% combination procedures (p = 0.16).
Isolated valve surgery and surgery on the thoracic aorta
were evenly distributed between the groups (Table 1).
Altogether, patients in both groups represented a
highrisk patient population with EuroSCORE II values of
19.0% in the LS group and 17.1% in the control group
(p = 0.41) (details of the EuroSCORE II – relevant
parameters: Additional file 2). Of note, CABG patients in
the LS group had higher EuroSCORE II compared to
the control group (15.8% vs.12.6%; p = 0.56) and valve
group patients who received LS had lower EuroSCORE
II values compared to the control group (13.7% vs. 20.9%;
p = 0.37). Blood pressure at induction of anesthesia as well
as duration of CPB and cardioplegic arrest were similar in
both groups (Table 1).
Postoperative medical and mechanical circulatory support
The proportions of patients requiring postoperative
medical support with epinephrine, norepinephrine, milrinone
and dobutamine as well as the duration of application of
these agents in these patients is shown in Table 2. Overall,
83% of LS patients compared with 68% of the control
group patients required epinephrine (p < 0.001). Duration
115 (101–123) 119 (103–126) 0.74
Table 2 In-hospital outcomes
Medical circulatory support
Epinephrine required; n (%)
Duration Epinephrine [h]; median (IQR)
Nordrenaline required; n (%)
Duration Nordrenaline [h]; median (IQR)
Dobutamine required; n (%)
Duration Dobutamine [h]; median (IQR)
Milrinone required; n (%)
Duration Milrinone [h]; median (IQR)
Mechanical circulatory support
IABP insertion; n (%)
Duration IABP support [h]; median (IQR)
ECLS implantation; n (%)
Acute kidney injury; n (%)
Length of stay
New onset chronic dialysis; n (%)
AF within 24h post-OP; n (%)
CK until POD4 [U/l]; mean (95%-CI)
CKMB until POD4 [U/l]; mean (95%-CI)
Postoperative LOS ICU [h]; median (IQR)
Postoperative LOS total [d]; median (IQR)
Postoperative GFR [ml/min.]; mean (95%-CI)
Postoperative GFR/preoperative GFR [ml/min.]; mean (95%-CI)
Comparison between patients who received prophylactic LS and patients who did not. Patients in the LS group show increased need for medical and mechanical
circulatory support (IABP) as well as an increased rate of postoperative atrial fibrillation, resulting in a prolonged demand for intensive care
Abbreviations: AF Atrial fibrillation, AKIN Acute kidney injury network, CK Creatinkinase, CKMB Creatinkinase, isoform MB, CRP C-reactive protein, ECLS Extracorporeal
life support, IABP Intra-aortic balloon pump, LOS Length of stay, LS Levosimendan, POD post-operative day, WBC White blood cell count
of norepinephrine support was longer in the LS group
compared to the control group (median: 35h vs. 20h; p =
0.005). Otherwise, prevalence and duration of additional
medical circulatory support did not differ between the
Additional mechanical circulatory provided by
intraoperative or postoperative initiation of intra-aortic balloon
pump (IABP) was more frequently applied in the
LSgroup (21%) compared to the control group (6.1%; p =
0.0015). Postoperative ECLS (extracorporeal life support)
implantation was necessary more often in the LS-group
(6/82; 7.3%) compared to the control group without
statistical significance (6/164; 3.7%; p = 0.40).
In the matched study population, preoperative renal
function shows no significant differences between LS
group and control group. However, a tendency towards
more severely impaired renal function in the LS group is
present (Table 1). In the postoperative course,
glomerular filtration rates (GFR) showed an initial postoperative
decline in both groups with a recovery within four days
postoperatively (data not shown). Mean postoperative
GFR and the ratio of postoperative GFR to preoperative
GFR did not differ between LS-group and control group
patients (Table 2). Multivariate regression analysis
revealed a reductive effect of LS on the incidence of acute
kidney injury (coefficient -1.37; p < 0.001). Interestingly,
also preoperative IABP implantation had a comparable
significant renoprotective effect (coefficient -1.69; p = 0.013)
while aortic cross clamping time had an incremental effect
on acute kidney injury (coefficient 1.45; p = 0.024) (Table 4).
We observed an overall increased incidence of atrial
fibrillation within 24h postoperatively in patients receiving
prophylactic LS (62/82; 76%) compared to control group
patients (72/164; 44%; p < 0.0001; OR 4.0; 95%-CI 2.2–7-2)
(Table 2). This effect persisted in the differentiated
comparison for CABG patients (OR 6.5; 95%-CI 1.8–21) and
combination procedure patients (OR 2.5; 95%-CI 1.0–3.8).
Linear regression confirmed prophylactic LS to be a
predictor of postoperative AF (coefficient 0.86; p = 0.038). Also
preoperative IABP insertion and aortic cross clamping time
increased the risk of postoperative AF (Table 3).
Patients in the LS group needed longer postoperative
intensive care (median 150h; IQR 71-200h) compared
to control group patients (median 139h; IQR 67-168h;
p = 0.047) (Table 2). Postoperative length of hospital
admission was 11 days (IQR 7–13 days), with no
difference between LS group and control group.
Overall 30-days survival was reduced due to the patients’
high preoperative risk profile and a trend towards a
higher survival rate in patients receiving prophylactic LS
(69/82; 84%) compared to the control group (123/155;
79%; p = 0.40) was observed. Multivariate regression
confirmed a tendency towards positive influence of LS on
30-days survival (coefficient 0.99; p = 0.12) while
postoperative IABP implantation (coefficient -2.36; p = 0.022)
and EuroSCORE II (coefficient -1.12; =0.0012) were
significant predictors of reduced 30-days survival. All other
investigated possible predictors did not influence 30-days
survival (Table 3).
Different subgroup analyses for 30-days survival were
conducted depending on (1) Procedural categories, (2)
Stages of renal impairment, (3) Preoperative LVEF, (4)
Categories of preoperative risk estimation using
EuroSCORE II and (5) Concomitance of recent myocardial
infarction. Here, tendencies towards pronounced
beneficial effects of LS were observed for patients undergoing
isolated valve/aortic surgery (30-days survival LS group:
92% vs. control group: 70%; p = 0.24), for patients with
moderate chronic kidney injury/GFR 51–85ml/min.
(30-days survival LS group: 85% vs. control group: 66%;
p = 0.19), for patients with LVEF <25% (30-days survival
LS group: 81% vs. control group: 71%; p = 0.34), patients
who had no recent myocardial infarction (30-days survival
Table 3 Linear modeling for preoperative predictors influencing survival 30 days postoperatively, postoperative atrial fibrillation and
postoperative acute kidney injury
30-days survival Postoperative AF within 24h Postoperative acute kidney injury
Coefficient Standard error p-Value Coefficient Standard error p-Value Coefficient Standard error p-Value
0.99 0.64 0.12 0.86 0.42 0.038 -1.37 0.53 0.0094
Aortic cross clamp time (log)
EuroSCORE II (log)
Preoperative admission to ICU -0.34
Preoperative CRP (log)
Multivariate regression analysis using generalized linear models was performed for the responses’30-days survival’, ‘postoperative new onset AF’ and ‘postoperative
acute kidney injury’. LS has no significant effect on 30-days survival but contributes significantly to postoperative AF and significantly reduces postoperative acute
Abbreviations: AF: Atrial fibrillation, BMI Body-mass index, CRP C-reactive protein, IABP Intra-aortic balloon pump, ICU Intensive care unit, LS Levosimendan,
LS group: 91% vs. control group: 83%; p = 0.22) and
patients with EuroSCORE II > 23 (30-days survival LS group:
70% vs. control group: 51%; p = 0.19) (Table 4).
Median follow-up time was 610 days (IQR 130–1192
days). Follow up was complete for 238/246 (97%) patients.
Kaplan-Meier estimation was (1) applied for all patients
and (2) differentiated into the categories of surgical
procedures (Fig. 2). Survival curves showed an initial decline in
survival for both groups, representing the immediate
postoperative period. Subsequently, a slower decline was
observed in both groups. Overall survival was 76% (LS) and
79% (control) at one year, 73% (LS) and 76% (control) at
two years and 68% (LS) and 71% (control) at three years
postoperatively. In isolated CABG, LS patients tended to
reduced long-term survival compared with the control
group (Fig. 2b), contrarily to valve-group patients whose
long-term survival exceeded the control group’s survival
We present real-world data from a high-risk patient
collective undergoing cardiac surgery with CPB. LS
application had no significant effect on overall 30-days survival
which is on one hand contradictory to previous studies
showing positive effects of prophylactic LS on short-term
survival [11, 12]. On the other hand, recent meta-analysis
of the available data revealed conflicting results on whether
or not LS reduces mortality [18, 19]. A differentiated
analysis of our patient subgroups showed tendencies towards
positive effects of LS on 30-days survival in patients
undergoing valve/aortic or combination procedures, patients
with moderate chronic renal impairment, patients who had
no recent myocardial infarction, patients with LVEF <25%
and patients with EuroSCORE II risk estimation scores
Table 4 30-days survival
All patients n = 237
Subgroup: procedural categories
Isolated valve surgery / ascending aortic surgery
Subgroup analysis: renal impairment
GFR 51–85 ml/min.
EuroSCORE II <15
EuroSCORE II 15–17
EuroSCORE II 18–20
EuroSCORE II 21–23
EuroSCORE II >23
Subgroup analysis: preoperative LVEF
Subgroup analysis: EuroSCORE II
Subgroup analysis: Recent myocardial infarction
No recent myocardial infarction
Recent myocardial infarction
30-days survival data were available for 237/246 patients (96%). Overall, 30-days survival did not differ between patients who received prophylactic LS and patients who
did not. In the subgroup analyses depending on procedural categories, renal impairment, preoperative LVEF, EuroSCORE II and recent myocardial infarction, no significant
differences between LS group and control group were observed
Abbreviations: CABG Coronary artery bypass grafting surgery, GFR Glomerular filtration rate, LS Levosimendan, LVEF Left-ventricular ejection fraction
Fig. 2 Kaplan-Meier estimation for long-term survival. Vertical lines at one, two and three years postoperatively. a. Overall survival. After an initial
decline, survival remains stable after one two and three years in both groups. Survival curves do not differ. b. After isolated CABG, patients who
received LS showed lower survival without statistical significance. c. After isolated valve or aortic surgery, LS patients show stable survival compared to
reduced survival in the control group without statistical significance. D. After combination procedures, survival curves between the groups do
not differ. Abbreviations: CABG: Coronary artery bypass grafting surgery, LS: Levosimendan
>23. These findings suggest differential effects of LS
depending on procedure-related factors as well as on
patientrelated factors. However, the size and design of our study
disables any final conclusion upon the significance of these
LS reduced the incidence of postoperative acute renal
failure significantly. This result is consistent with
previous studies showing renoprotective properties of LS in
cardiac surgical patients [8, 14].
Surprisingly, LS patients showed an excessively high
rate of atrial fibrillation within 24h postoperatively
compared to the control group (85% vs. 46%). As LS does not
increase intracellular calcium levels, it has been postulated
that LS might be advantageous compared to traditional
inotropes concerning the pro-arrhythmic effects. However,
our result is consistent with the SURVIVE I and II trials,
which also showed higher rates of arrhythmias in
ADHF-patients treated with LS .
Postoperative need for medical circulatory support was
increased in the LS group, resulting in a prolonged need
for intensive care. According to the lack of positive
shortterm-effects of LS, long-term survival up to three years
postoperatively was not improved. Our observations are
consistent with a previous study by Lahtinen et al. that
compared prophylactic LS with placebo and reported
similar survival in both groups 6 months postoperatively .
In summary, this study showed no or at least
substantially weaker effects of prophylactic LS compared to
previous reports. It is well arguable, how retrospective data
should be weighed compared to methodically superior
prospective data: Prospective randomized-controlled
studies are the gold standard for evaluation of clinical effects
of single interventions. However, this controlled setting
differs substantially from the clinical routine setting. This
might, among others, result in compliance bias and
contamination bias with consecutively reduced external
validity [21–24]. Thus, retrospective data, reflecting
real-life practice, could give important additional
information in order to classify the value of an intervention
in the daily routine and to generate hypotheses for
Some aspects could be explanatory for a reduced
overall LS-effect in the routine setting: First, the effect of LS
might have been underutilized by our therapeutic regime.
We did not apply an initial loading dose prior to
continuous infusion over 24h: A current expert opinion paper
states that an initial bolus at induction of anesthesia is a
feasible option without emphasizing explicit positive
effects of loading dose administration . Contrarily,
application of a LS bolus carries the risk of acute vasodilation
and hemodynamic destabilization and has been shown to
increase mortality in different clinical settings .
Therefore, LS bolus administration has not been practiced in
our clinical routine. As we did not adjust LS dosing for
renal impairment, overdosing and increased side effects
might have resulted in some patients with severe renal
Second, the timing of LS administration appears to be
critical: In our practice, LS was started after induction of
anesthesia, when LVEF was determined using
transoesophageal echocardiography. Without initial bolus, a
steadystate is achieved after 4h . As median operation time
in our study population was 157 min., the full effect of LS
might not have been reached at the critical time points,
namely weaning from cardiopulmonary bypass and
immediate postoperative phase.
Third, patient selection might have been too
restrictive. We only administered prophylactic LS to patients
with severely reduced LVEF. It might be argued that
these patients’ precondition impedes positively influencing
their postoperative outcome. However, we even observed
a trend towards more pronounced survival benefit 30 days
postoperatively in patients with preoperative LVEF < 25%.
This observation is consistent with a meta-analysis of
randomized controlled trials on prophylactic LS in cardiac
surgery patients by Harrison et al. suggesting that patients
with preoperatively severely reduced LVEF benefit in a
greater extent from prophylactic LS compared to patients
with preoperatively normal LVEF .
On the other hand, methodical limitations of this
study could have biased the results:
First, this is a retrospective analysis with all its limitations.
In most of the patients, no continuous cardiac-output
monitoring was applied. Consecutively, medical circulatory
support management was mainly based on individual decisions
by the treating physicians. This might have contributed to
suboptimal management of inotropes and vasopressors.
The study included a total of 288 patients, a relatively small
number of patients, with only 84 patients receiving
prophylactic LS. This study population might have been too small
to show possibly significant effects of prophylactic LS
A major limitation of this study is, that the criteria for
administration of LS were loose and decision individually
taken by the treating surgeon and anesthesiologist during
induction of anesthesia, which might have led to sampling
bias with sicker patients in the LS group. However, after
propensity score matching, risk estimation using
EuroSCORE II and other baseline characteristics showed no
relevant difference between the groups. Nevertheless,
unknown confounders could still have biased the results.
Prophylactic LS application in high-risk patients with
preoperative LVEF ≤35% undergoing cardiac surgery had
no relevant positive effect on short- and long- term survival.
Although LS application was associated with improved
postoperative renal function, the occurrence of postoperative
atrial fibrillation was even increased compared to patients
who did not receive any preoperative preconditioning.
Optimal utilization of potential LS effects and translation of
these effects into long-term benefit has not been achieved
yet as critical questions are still unanswered: It remains
unclear when and how to start prophylactic LS administration
and which patients undergoing which procedures benefit
most from this intervention. Furthermore, comparisons to
established preconditioning concepts (e.g., prophylactic
intra-aortic balloon counterpulsation) have to be
substantiated in future studies. Based on the results of this
study, a prospective trial with 462 patients per group
would be needed to generate definitive results. Until
then, reluctance to include prophylactic LS application,
a cost-intensive (3.725€ per standard dose (12.5mg) )
non-subsidized intervention, into clinical routine seems
Additional file 1: Generalized linear models Symbolic representation of
the linear models used to estimate the effect of prophylactic Levosimendan
and other predictors on 30-days survival, on postoperativ acute kidney injury
(AKIN I-III) and on postoperative new-onset atrial fibrillation respectively.
(DOCX 81 kb)
Additional file 2: EuroSCORE II-relevant baseline characteristics of the
unmatched and matched study populations Before matching, LS group
and control group significant differences with more frequent occurrence
of ‘acute myocardial infarction’ in the control group and more severe
pulmonary hypertension in the LS group. After matching, these significant
differences were eliminated. (DOCX 73 kb)
CABG: Coronary artery bypass grafting surgery; CI: Confidence interval;
CPB: Cardiopulmonary bypass; ECLS: Extracorporeal life support;
GFR: Glomerular filtration rate; ICU: Intensive care unit; IQR: Interquartile range;
LS: Levosimendan; LVEF: Left-ventricular ejection fraction; OR: Odds ratio
This is an investigator-initiated project without external funding. The authors
of this manuscript received external funding for other research projects from
the following sources: PG: The German Heart Foundation, the University
Hospital Giessen and Marburg Research Fund, the
Von-Behring-RöntgenFoundation SL: none AA: none MW: none PR: none BN: The German Heart
Foundation, the University Hospital Giessen and Marburg Research Fund,
the Von-Behring-Röntgen-Foundation JW: none AB: The German Heart
Foundation, the University Hospital Giessen and Marburg Research Fund,
Availability of data and material
All data generated or analysed during this study are included in this published
article and its supplementary information files.
PG initiated and led the study, coordinated data collection and analysis as well
as drafting oft he manuscript. SL and AA carried out data collection and data
anlysis and contributed in drafting the manuscript. PG, SL, AA, MW, PR, BN, AB,
JW drafted parts of the manuscript and all authors revised the manuscript
critically and approved the manuscript finally. JW contributed in data analysis
and carried out linear modeling analyses.
The authors of this manuscript have research support from The German
Heart Foundation, the University Hospital Giessen and Marburg Research
Fund, the Von-Behring-Röntgen-Foundation (PG, BN and AB). PG received a
travel grant (1000€) from Orion Pharma GmbH, Hamburg, Germany. AB received
a presentation honorarium from Orion Pharma GmbH, Hamburg, Germany. The
authors declare that there are no further conflicting financial or non-financial
interests. All authors confirm that they had full control of the design and the
methods of the study, the data analysis and the production of the written report.
Consent for publication
Ethics approval and consent to participate
The ethical committee of the Faculty of Medicine at Justus Liebig University
Giessen, Germany approved the study. The trial was designed and conducted
in accordance to the Declaration of Helsinki. Patients gave consent to collection
and analysis of their data for scientific purposes prior to operation.
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