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
© The Author(s). 2016
Received: 2 July 2016
Accepted: 24 November 2016
Published: 1 December 2016
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.
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.
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.
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.
KeywordsLevosimendan 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 OR-1896 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 short-term 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.
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 surgical intervention.
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) respectively.
The primary endpoint of the trial was postoperative 30-days survival. Long-term survival functions were 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 t-test 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).
Unmatched study population
Matched study population
n = 288 (100%)
n = 84 (29.17%)
n = 204 (70.83%)
n = 82 (33%)
n = 164 (67%)
Age [years]|; mean ± SD
69 ± 11
68 ± 11
70 ± 11
67 ± 11
68 ± 10
Sex [females] n (%)
Body mass index [kg/m2] mean ± SD
27 ± 7.0
27 ± 5.6
27 ± 7.5
27 ± 5.7
27 ± 8.2
Preoperative LVEF [%];mean ± SD
26 ± 7.3
26 ± 7.0
25 ± 8.0
26 ± 10
27 ± 11
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 (%)
Preoperative cardiopulmonary resuscitation; n (%)
Preoperative invasive ventilation; n (%)
Preoperative use of inotropes and vasoactive drugs; n (%)
EuroSCORE II [%]; mean ± SD
• Isolated CABG group
• Valve/aortic surgery group
• Combi group
17.3 ± 16.4
14.3 ± 13.4
17.9 ± 19.8
21.4 ± 17.4
19.2 ± 16.4
17.8 ± 17.7
11.7 ± 10.2
23.0 ± 16.2
16.5 ± 16.4
12.9 ± 11.7
20.1 ± 21.8
20.4 ± 18.2
19.0 ± 16.6
15.8 ± 12.1
13.7 ± 10.0
20.1 ± 13.4
17.1 ± 17.3
12.6 ± 11.3
20.9 ± 22.8
21.4 ± 18.9
Type of Surgery; n (%)
• Isolated CABG
• Valve Surgery or Surgery on Thoracic aorta
• Combination procedures
Systolic blood pressure at induction of anaesthesia [mmHg]; median (IQR)
Diastolic blood pressure at induction of anaesthesia [mmHg]; median (IQR)
Extracorporeal circulation time [min.]; median (IQR)
114 ± 34
111 ± 26
Cardioplegic arrest time [min.]; median (IQR)
73 ± 30
72 ± 24
Postoperative medical and mechanical circulatory support
Matched study population
n = 82
n = 164
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 (%)
Postoperative GFR [ml/min.]; mean (95%-CI)
Postoperative GFR/preoperative GFR [ml/min.]; mean (95%-CI)
Acute kidney injury; n (%)
• AKIN I
• AKIN II
• AKIN III
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)
Length of stay
Postoperative LOS ICU [h]; median (IQR)
Postoperative LOS total [d]; median (IQR)
Additional mechanical circulatory provided by intraoperative or postoperative initiation of intra-aortic balloon pump (IABP) was more frequently applied in the LS-group (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).
Linear modeling for preoperative predictors influencing survival 30 days postoperatively, postoperative atrial fibrillation and postoperative acute kidney injury
Postoperative AF within 24h
Postoperative acute kidney injury
Aortic cross clamp time (log)
EuroSCORE II (log)
Preoperative admission to ICU
Preoperative CRP (log)
Preoperative white blood cell count (log)
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).
30-days survival; n (%)
n = 82
n = 155
All patients n = 237
Subgroup: procedural categories
Isolated valve surgery / ascending aortic surgery
Subgroup analysis: renal impairment
GFR 51–85 ml/min.
GFR < 51ml/min.
Subgroup analysis: preoperative LVEF
Subgroup analysis: EuroSCORE II
EuroSCORE II <15
EuroSCORE II 15–17
EuroSCORE II 18–20
EuroSCORE II 21–23
EuroSCORE II >23
Subgroup analysis: Recent myocardial infarction
No recent myocardial infarction
Recent myocardial infarction
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 >23. These findings suggest differential effects of LS depending on procedure-related factors as well as on patient-related factors. However, the size and design of our study disables any final conclusion upon the significance of these aspects.
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 short-term-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 further studies.
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 impairment.
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 steady-state 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 properly.
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 justified.
Coronary artery bypass grafting surgery
Extracorporeal life support
Glomerular filtration rate
Intensive care unit
Left-ventricular ejection fraction
The authors thank Irina Oswald for excellent assistance during long-term follow-up.
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-Röntgen-Foundation 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, the Von-Behring-Röntgen-Foundation.
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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