Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials

Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a... Abstract It is currently unknown whether levosimendan can improve clinical outcomes in patients undergoing cardiac surgery. This meta-analysis aimed to assess the effect of levosimendan on mortality and the duration of intensive care unit (ICU) and hospital stay in adult patients undergoing cardiac surgery. A comprehensive search for eligible articles was conducted in PubMed, OVID and Cochrane databases of clinical trials and the Web of Science from database inception to August 2017. Stata/SE 11.0 was used to calculate the pooled odds ratio for postoperative mortality and the pooled standardized mean difference (SMD) for the duration of ICU stay and hospital stay. A total of 30 randomized controlled trials were included in the final analysis; the pooled results indicated that perioperative administration of levosimendan was associated with a reduction in postoperative mortality [5.8% vs 8.5%; odds ratio 0.66, 95% confidence interval 0.50–0.86, P = 0.002; I2 = 17.1%; 25 trials; 3239 patients] and length of ICU stay (SMD −0.32, 95% CI −0.58 to 0.06, P = 0.017; I2 = 88.0%; 23 trials; 2536 patients) compared with the control group but not in length of hospital stay (SMD −0.41, 95% CI −0.89 to 0.07, P = 0.094; I2 = 95.9%; 18 trials; 2047 patients). A subanalysis was conducted for trials published after 2015, and it suggested that levosimendan could not reduce the postoperative mortality (odds ratio = 0.91, 95% CI 0.63–1.31, P = 0.626; I2 = 0.9%), length of ICU stay (SMD −0.03, 95% CI −0.32 to 0.27, P = 0.850; I2 = 81.2%) or length of hospital stay (SMD 0.06, 95%CI −0.43 to 0.54, P = 0.821; I2 = 91.3%). To summarize, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. Levosimendan, Cardiac surgery, Meta-analysis, Outcomes, Mortality INTRODUCTION Patients undergoing cardiac surgery are at high risk of cardiac dysfunction, and those events that occur in the perioperative period are associated with higher mortality and worse clinical outcomes [1, 2]. Therefore, perioperative administration of positive inotropic drugs is necessary for those patients at high risk of cardiac dysfunction. Conventional inotropic agents, such as dobutamine and milrinone, can significantly improve cardiac function and, unfortunately, are always accompanied by increased myocardial oxygen consumption and malignant arrhythmia events. Levosimendan, a calcium-sensitized positive inotropic drug, can strengthen the stabilization of calcium-induced conformational changes in tropomyosin by enhancing the calcium sensitivity of troponin C [3] without increasing the intracellular calcium concentrations; thus, levosimendan can improve myocardial contraction without affecting the diastolic function and increasing myocardial oxygen consumption [4]. Over the past decade, more than 30 studies have focused on the effect of levosimendan on cardiac performance and clinical outcomes in patients undergoing cardiac surgery. Unfortunately, most of them have not found a beneficial effect on mortality, though a few studies demonstrated that levosimendan could reduce mortality in patients undergoing cardiac surgery [5–7]. While all previous meta-analyses [8–10] concluded that perioperative administration of levosimendan was associated with a significant reduction in mortality, most trials conducted in the recent 3 years, 3 multicentre randomized controlled trials in particular [11–13], failed to identify any improvement in the survival rate after the use of levosimendan. These conflicting results should be accounted for to inform clinical decision-making and policies. Hence, we conducted this meta-analysis to pool data from all related trials, especially from trials published in the most recent 3 years, to reassess the effect of levosimendan on clinical outcomes in patients undergoing cardiac surgery. METHODS Search strategy PubMed, OVID, the Cochrane Database of Clinical Trials and the Web of Science were systematically searched for randomized controlled trials of perioperative administration of levosimendan in adult patients undergoing cardiac surgery from database inception to August 2017 by 3 authors (L.S., Y.W and X.G.). A general search was conducted to avoid missing relevant literature. The medical subject headings (MeSH) term ‘cardiac surgical procedures’ combined with the term ‘levosimendan’ was systematically searched in the different databases, and the detailed search strategy is shown in the Supplementary Appendix. There was no language restriction in this meta-analysis, and all other language articles that provided English abstracts were included and translated into English for further screening. Study selection All relevant articles were initially reviewed for title and abstract by 3 authors (P.L., Y.Z. and C.H.) independently using a questionnaire, and any disagreements were resolved by discussion and consensus. Then, eligible articles were included in a full-text review, and we contacted the authors by email for the full text when the full text was unavailable online. The inclusion criteria included prospective randomized controlled trials, adult patients (≥18 years) undergoing cardiac surgery and perioperative administration of levosimendan with no restriction on dose or time of administration. The primary end-point in this meta-analysis was postoperative mortality, including 30-day mortality, 28-day mortality, intensive care unit (ICU) mortality, in-hospital mortality and 60-day mortality. The secondary end-points were duration of ICU stay and hospital stay. An article assessing at least one of the above indicators was included in this study. The exclusion criteria included non-human experimental studies, non-intravenous application of levosimendan, heart transplantation, percutaneous coronary intervention and lack of data on end-points. Moreover, duplicate published studies were also excluded, and the most recent updated data were included in the final analysis. Data extraction and quality assessment Data were extracted by 2 authors (Z.X. and X.Z.) with a custom-made form, which included the name of the first author, publication year, number of subjects, sample size, control intervention, starting time of levosimendan administration, dose of levosimendan, duration of follow-up, type of cardiac surgery, preoperative left ventricular ejection infraction (LVEF), duration of ICU stay and hospital stay. The primary end-point was postoperative mortality, including 30-day mortality, 28-day mortality, ICU mortality and in-hospital mortality. In studies in which both in-hospital mortality and 30-day/28-day mortality were reported, the longer follow-up mortality was included for analysis. The secondary end-points were duration of ICU stay and duration of hospital stay. If necessary, the authors were contacted to provide the missing data on primary outcomes, and we removed those studies for which the authors could not provide the missing data for this meta-analysis. Internal validity and risk of bias were assessed independently by 2 reviewers (X.Z. and Z.X.) according to the Cochrane Collection methods [14] with standardized criteria, and 6 domains were assessed, including adequate sequence generation, allocation concealment, blinding, incomplete outcome data, free of selective reporting and free of other bias. We defined in advance that studies with a high or unclear risk of bias in no more than 2 domains would be considered to be of high quality. Statistical analysis All statistical tests were performed using Stata/SE 11.0 (StataCorp, College Station, TX, USA). A pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated to assess the effect of levosimendan on mortality with the Peto method because death was a rare event in our included studies. Data on duration of ICU stay and hospital stay were pooled by using the standardized mean difference (SMD) with the inverse variance method due to the differences in time units of ICU stay. For continuous data reported as median with range, mean and standard deviation (SD) were estimated using the method of Hozo et al. [15]. If only the interquartile range (IQR) was available, then SD was estimated with the formula proposed by the Cochrane handbook: SD = IQR/1.35 [16]. Heterogeneity between studies was assessed by I2 with the corresponding χ2 test. The fixed-effect method was used in cases of low or moderate statistical inconsistency (I2 < 50%), and the random-effect method was used in cases of high statistical inconsistency (I2 ≥ 50%) to calculate the pooled SMD. Meta-regression was performed to detect the following factors: publication year, sample size, interventions in the control group, preoperative LVEF, whether levosimendan was administered with a loading dose and the starting time of administration, and whether this had an influence on the effect of levosimendan on perioperative mortality. We predefined low LVEF as the mean value of preoperative LVEF <40% and a loading dose as administration of levosimendan with a bolus of which the concentration was >6 μg/kg and infusion time was <1 h [5, 6, 17]. Subgroup analysis was conducted for the primary end-point based on publication year. Sensitivity analysis was conducted to assess the robustness of the pooled results for perioperative mortality by sequentially removing one study at a time. Funnel plots and the Egger test were implemented to assess publication bias when the number of included studies was more than 10. A P-value of <0.05 was considered statistically significant. RESULTS A total of 1417 records were searched from the above 4 databases. After screening by title, abstract and full text, 30 articles met the eligibility criteria and were included in the final analysis [5–7, 11–13, 17–40]. The PRISMA flow chart of this study is shown in Fig. 1, and detailed study characteristics for individual trials are summarized in Table 1. The 6 domains for assessing the quality and risk of bias of the included studies are described in Table 2. Table 1: Characteristics of studies included in this meta-analysis Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Values are presented as mean ± SD or median (IQR). CABG: coronary artery bypass grafting; CG: control group; CPB: cardiopulmonary bypass; ECC: extracorporeal circulation; IQR: interquartile range; LG: levosimendan group; LVEF: left ventricular ejection fraction; SD: standard deviation. Table 1: Characteristics of studies included in this meta-analysis Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Values are presented as mean ± SD or median (IQR). CABG: coronary artery bypass grafting; CG: control group; CPB: cardiopulmonary bypass; ECC: extracorporeal circulation; IQR: interquartile range; LG: levosimendan group; LVEF: left ventricular ejection fraction; SD: standard deviation. Table 2: Risk of bias of the studies included in this meta-analysis Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  H: high; L: low; M: moderate. Table 2: Risk of bias of the studies included in this meta-analysis Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  H: high; L: low; M: moderate. Figure 1: View largeDownload slide The PRISMA flow diagram of the study selection process. Figure 1: View largeDownload slide The PRISMA flow diagram of the study selection process. Characteristics Of these 30 articles, 20 were published before 2015 [5–7, 17–33], and the remaining 10 articles were published after 2015 [11–13, 34–40]. There were 25 studies with data on perioperative mortality [5–7, 11–13, 17–26, 29, 31–35, 37–40], 24 studies with data on the duration of ICU stay [5, 7, 11, 12, 17, 19, 20, 22–24, 26, 28–40] and 19 studies with data on the duration of hospital stay [7, 11, 13, 17, 20, 23–27, 29, 31–33, 35, 37–40]; however, one of these studies only provided the median value of the duration of ICU and hospital stay without IQR value [33], and we were unable to contact the authors for the complete data; therefore, we decided to exclude this article from the analysis of the duration of ICU and hospital stays. The patients in 18 studies had damaged cardiac performance with a preoperative LVEF of <40% [5–7, 12, 13, 17–20, 22, 26, 27, 31–33, 37, 39, 40], and one [40] of the studies only reported the percentage of patients with preoperative LVEF <45% instead of the mean or median value of LVEF. Similarly, another study [25] reported the percentage of patients with preoperative LVEF >50% and was included in the preserved LVEF group. Fourteen studies introduced a protocol where levosimendan was administered with a loading dose [5–7, 17–19, 22–26, 29, 35, 36], and one of them reported that levosimendan was administered only with a bolus of 24 μg/kg over 10 min without a continued infusion [23]. A levosimendan infusion that started before cardiac surgery was reported in 22 studies [6, 7, 11–13, 21–27, 29–31, 33–35, 37–40]; in the other studies, administration of levosimendan was started after cardiac surgery [5, 17–20, 28, 32, 36]. The interventions in the control group included milrinone [19, 20, 36], dobutamine [5, 7, 18, 28], IABP [26], nitroglycerine [35] and placebo [6, 11–13, 21–25, 27, 30–34, 37–40], and 2 studies did not report a detailed intervention in the control group [17, 29]. Perioperative mortality A total of 25 studies consisting of 3239 patients were included in the meta-analysis for perioperative mortality; the pooled OR indicated that perioperative administration of levosimendan could reduce postoperative mortality when compared with the control group [5.8% (93/1604) vs 8.5% (139/1635); OR 0.66, 95% CI 0.50–0.86, P = 0.002; I2 = 17.1%]. However, subgroup analysis according to the publication years demonstrated that the benefit of levosimendan on mortality was seen only in the subgroup of trials published before 2015 (OR 0.44, 95% CI 0.30–0.66, P < 0.001; I2 = 0.0%), but not in the subgroup of trials published after 2015 (OR 0.91, 95% CI 0.63–1.31, P = 0.626; I2 = 0.9%) (Fig. 2). Figure 2: View largeDownload slide Forest plot of subgroup analysis for postoperative mortality based on publication year. CI: confidence interval; OR: odds ratio. Figure 2: View largeDownload slide Forest plot of subgroup analysis for postoperative mortality based on publication year. CI: confidence interval; OR: odds ratio. Meta-regression was performed to detect the source of heterogeneity between these studies and indicated that publication year (Coef. = 0.092, 95% CI 0.006–0.177; P = 0.037) was a factor that influenced the association between levosimendan and mortality (Fig. 3). Preoperative LVEF (low or preserved) (P = 0.055) and interventions in the control group (placebo or not) (P = 0.073) might influence the effect of levosimendan on mortality. However, differences in sample size (P = 0.109), loading dose (with or without) (P = 0.114) and starting time of administration (before or after surgery) (P = 0.779) were not associated with the effect of levosimendan on mortality. Figure 3: View largeDownload slide Meta-regression indicated that publication year influenced the association between levosimendan and mortality. An increase of 1 year in the Y-axis is associated with an increase of logOR value by 0.092. OR: odds ratio. Figure 3: View largeDownload slide Meta-regression indicated that publication year influenced the association between levosimendan and mortality. An increase of 1 year in the Y-axis is associated with an increase of logOR value by 0.092. OR: odds ratio. Duration of intensive care unit stay and hospital stay The duration of ICU stay was reported in 23 studies (2536 patients); the pooled result showed a reduction in the length of ICU stay in patients with the administration of levosimendan (SMD −0.32, 95% CI −0.58 to 0.06, P = 0.017; I2 = 88.0%) (Fig. 4); a reduction in the length of ICU stay was also found in a subgroup analysis of trials published before 2015 (SMD −0.51, 95% CI −0.94 to 0.09, P = 0.018; I2 = 88.3%). However, this benefit disappeared after stratified analysis for trials published after 2015 (SMD −0.03, 95% CI −0.32 to 0.27, P = 0.850; I2 = 81.2%). There were 18 studies (2047 patients) with data on the duration of hospital stay; the pooled SMD indicated that the administration of levosimendan was not associated with a shorter hospital stay (SMD −0.41, 95% CI −0.89 to 0.07, P = 0.094; I2 = 95.9%), regardless of the studies being published before 2015 (SMD −0.73, 95% CI −1.56 to 0.11, P = 0.088; I2 = 96.9%) or after 2015 (SMD 0.06, 95% CI −0.43 to 0.54, P = 0.821; I2 = 91.3%) (Fig. 5). Figure 4: View largeDownload slide Forest plot of subgroup analysis for the duration of intensive care unit stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Figure 4: View largeDownload slide Forest plot of subgroup analysis for the duration of intensive care unit stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Figure 5: View largeDownload slide Forest plot of subgroup analysis for the duration of hospital stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Figure 5: View largeDownload slide Forest plot of subgroup analysis for the duration of hospital stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Sensitivity analysis and publication bias As shown in Fig. 6, sensitivity analysis suggested that the overall effect of levosimendan on perioperative mortality was not changed after sequentially removing one study at a time. The study by Landoni et al. [11] was the main source of heterogeneity for these included studies, and the heterogeneity decreased significantly after excluding the study from this meta-analysis (OR 0.56, 95% CI 0.41–0.77; P < 0.001, I2 = 7.0%). Additionally, sensitivity analysis was conducted in the subgroup of trials published after 2015 and indicated that the effect of levosimendan on perioperative mortality was still unchanged. The funnel plot was visually symmetric for perioperative mortality, and the Egger test revealed no evidence of publication bias (P = 0.212) (Supplementary Material, Fig. S1). Figure 6: View largeDownload slide Sensitivity analysis for assessing the robustness of pooled OR for perioperative mortality. (A) The study of Landoni et al. is the main source of heterogeneity between the included studies. (B) The sensitivity analysis for the subgroup of trials published after 2015 is shown and the effect of levosimendan on perioperative mortality was unchanged after sequentially removing one study at a time is indicated. CI: confidence interval. Figure 6: View largeDownload slide Sensitivity analysis for assessing the robustness of pooled OR for perioperative mortality. (A) The study of Landoni et al. is the main source of heterogeneity between the included studies. (B) The sensitivity analysis for the subgroup of trials published after 2015 is shown and the effect of levosimendan on perioperative mortality was unchanged after sequentially removing one study at a time is indicated. CI: confidence interval. DISCUSSION This meta-analysis suggested that perioperative administration of levosimendan was associated with a reduction in postoperative mortality and length of ICU stay in patients undergoing cardiac surgery. However, subgroup analysis for trials published after 2015 revealed no significant benefits in reducing postoperative mortality or length of ICU stay and hospital stay with the use of levosimendan. To summarize, the evidence from studies published in the most recent 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. Levosimendan is a new calcium-sensitized positive inotropic agent that can improve myocardial contraction by enhancing calcium sensitivity of troponin C without increasing the intracellular calcium concentrations. Levosimendan does not affect the diastolic function or increase myocardial oxygen consumption; therefore, the application of levosimendan, if necessary, in patients with haemodynamic instability, such as undergoing cardiac surgery, is relatively safe compared with dobutamine or milrinone. However, the effect of levosimendan on postoperative mortality in patients undergoing cardiac surgery is still not well known. Although most articles have reported no reduction in mortality with the use of levosimendan, 3 previous meta-analyses [8–10] demonstrated that levosimendan is beneficial for postoperative mortality in patients undergoing cardiac surgery. These positive results from the 3 meta-analyses are mainly attributed to the large differences in the number of deaths between the levosimendan and control groups in 2 studies by Levin et al. [5, 6]. Subjects in 1 [5] of the 2 studies were patients receiving coronary surgery with low cardiac output syndrome. The aim of that study was to investigate the effectiveness of levosimendan, and the results suggested that the use of levosimendan resulted in a significantly lower postoperative mortality compared with dobutamine (6/69 vs 17/68; P < 0.05). The other study [6] also focused on the effectiveness of levosimendan in the same population and indicated that levosimendan had a significant mortality benefit compared with placebo (5/127 vs 16/125; P < 0.05). However, the 2 studies were conducted in the same hospital by the same research team, and some methodological factors in the studies, such as allocation concealment and blinding, are unclear, so it is hard to rule out the possibility of publication bias. After assessment of internal validity and risk of bias, the 2 studies were defined as moderate risk of bias and were considered low quality in our meta-analysis. Therefore, the beneficial effect of levosimendan on mortality shown in previous meta-analyses [8–10] must be further explained and re-evaluated. Recently, 3 multicentre randomized controlled trials, namely, the CHEETAH trial [11], LEVO-CTS trial [12] and LICORN trial [13], were published successively. They all showed a neutral effect of levosimendan on mortality after cardiac surgery. In the LEVO-CTS trial, a total of 849 patients undergoing cardiac surgery with an LVEF of 35% or less were included and randomly assigned to receive levosimendan (428 patients) or placebo (421 patients). The final results indicated that levosimendan was not associated with a significant reduction in 30-day mortality (15/428 vs 19/421; P = 0.25) or the duration of ICU stay [2.8 (1.6–4.8) vs 2.9 (1.8–4.9) days; P = 0.25] compared with placebo. The result was similar in the CHEETAH trial. There was also no significant difference in 30-day mortality (32/248 vs 33/258; P = 0.97) between the levosimendan group and the placebo group. Interestingly, the duration of ICU stay in the levosimendan group was slightly lower than that of the placebo group, although the difference was not significant [72 (46–114) vs 84 (48–139) h; P = 0.08], and the difference in hospital stay was also not significant [14 (8–21) vs 14 (9–21) days; P = 0.39]. In the LICORN trial, the use of levosimendan, compared with placebo, also did not result in a significant difference in 28-day mortality, in-hospital mortality or length of ICU stay or hospital stay. These results were different from that of previous meta-analyses [8–10], and the conflicting results lead us to question whether levosimendan could really improve clinical outcomes. Hence, we reassessed the effect of levosimendan on outcomes in patients undergoing cardiac surgery by including publications from the most recent 3 years in this meta-analysis to expand the sample size and conducted a stratified analysis according to the publication year. We found that perioperative administration of levosimendan was associated with a 2.7% reduction in postoperative mortality compared with the control group [OR 0.66, 95% CI 0.50–0.86, P = 0.002; I2 = 17.1%]. Similar to the results of the meta-analysis by Lim et al. [10], our meta-analysis also demonstrated a beneficial effect of levosimendan in reducing the length of ICU stay (SMD = −0.32, 95% CI: −0.58 to 0.06, P = 0.017; I2 = 88.0%). In addition, our meta-analysis revealed no significant reduction in length of hospital stay in patients with the use of levosimendan (SMD = −0.41, 95% CI: −0.89 to 0.07, P = 0.094; I2 = 95.9%), and similar results were observed in a meta-analysis by Landoni et al. [8]. Unfortunately, in our meta-analysis, subgroup analysis for trials published after 2015 suggested that levosimendan had no significant benefits in reducing postoperative mortality, length of ICU stay or hospital stay. The strength of our finding is based on the integration of larger data. Studies included in our meta-analysis are more comprehensive than in previous meta-analyses. A total of 25 randomized controlled trials, in which the number of subjects (3239 patients) is larger than that in previous meta-analyses [8–10], were included in the analysis of postoperative mortality. Furthermore, 3 multicentre randomized controlled trials published in 2017 were also included. Our meta-analysis for randomized controlled trials with a larger sample size would, to a large extent, decrease the sampling errors and selective bias and reveal the real effect of levosimendan on mortality more objectively and thus guide clinical medication decisions. In addition, a study by Levin et al. [5] included in our meta-analysis was missing in the meta-analysis by Lim et al. [10]. The missing data inevitably weakened the credibility of their work. Overall, the strength of data in our meta-analysis is more powerful than in previous meta-analyses. Limitations However, there are still several limitations in our meta-analysis. First, the mortality variables included in this meta-analysis are not uniform. Therefore, it was difficult to conduct a stratified analysis based on mortality, and we also have not conducted a meta-regression to detect whether the mortality variable is a source of the heterogeneity between studies. Similarly, the interventions in the control group, including milrinone, dobutamine, IABP, nitroglycerine and placebo, are different in the included studies. A meta-regression indicated that the mix of these interventions in the control group might cause heterogeneity between the studies. Disappointingly, we did not conduct a subgroup analysis according to the interventions in the control group, which is a methodological deficiency in this meta-analysis. Second, there is currently no official definition of a loading dose of levosimendan, and the doses of levosimendan were different in some of the studies. We summarized the loading dose from all of the included studies as a bolus of which the concentration was greater than 6 μg/kg and the infusion time was <1 h; this definition might result in a selective bias. Third, data on the duration of ICU stay and hospital stay in some of the studies were presented as the median (IQR) and was not converted to mean ± SD by using the method of Hozo et al. [15]; then SD was estimated using the formula: SD = IQR/1.35; therefore, this approximated calculation could impact the results and may be a source of the heterogeneity. Finally, some trials included in the study had a small sample size; thus, the small study effect should be considered in interpreting the results. The effect size of levosimendan can be overestimated by pooling the results from small studies, such as 2 studies by Levin et al. [5, 6], which can be eliminated by subsequent mega-trials [41]. CONCLUSION This meta-analysis suggested that perioperative use of levosimendan was associated with a reduction in postoperative mortality and length of ICU stay in patients undergoing cardiac surgery. However, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Funding This study was supported by the Natural Science Foundation of Ningbo [grant no. 2016A610139], Zhejiang Traditional Chinese Medicine Research Project [no. 2011ZZ001] and Zhejiang Medical and Health Science and Technology Project (no. 2017ZD001 and 2013KYB004). Conflict of interest: none declared. REFERENCES 1 Topkara VK, Cheema FH, Kesavaramanujam S, Mercando ML, Cheema AF, Namerow PB. Coronary artery bypass grafting in patients with low ejection fraction. Circulation  2005; 112: I344– 50. 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Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Interactive CardioVascular and Thoracic Surgery Oxford University Press

Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivy017
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Abstract

Abstract It is currently unknown whether levosimendan can improve clinical outcomes in patients undergoing cardiac surgery. This meta-analysis aimed to assess the effect of levosimendan on mortality and the duration of intensive care unit (ICU) and hospital stay in adult patients undergoing cardiac surgery. A comprehensive search for eligible articles was conducted in PubMed, OVID and Cochrane databases of clinical trials and the Web of Science from database inception to August 2017. Stata/SE 11.0 was used to calculate the pooled odds ratio for postoperative mortality and the pooled standardized mean difference (SMD) for the duration of ICU stay and hospital stay. A total of 30 randomized controlled trials were included in the final analysis; the pooled results indicated that perioperative administration of levosimendan was associated with a reduction in postoperative mortality [5.8% vs 8.5%; odds ratio 0.66, 95% confidence interval 0.50–0.86, P = 0.002; I2 = 17.1%; 25 trials; 3239 patients] and length of ICU stay (SMD −0.32, 95% CI −0.58 to 0.06, P = 0.017; I2 = 88.0%; 23 trials; 2536 patients) compared with the control group but not in length of hospital stay (SMD −0.41, 95% CI −0.89 to 0.07, P = 0.094; I2 = 95.9%; 18 trials; 2047 patients). A subanalysis was conducted for trials published after 2015, and it suggested that levosimendan could not reduce the postoperative mortality (odds ratio = 0.91, 95% CI 0.63–1.31, P = 0.626; I2 = 0.9%), length of ICU stay (SMD −0.03, 95% CI −0.32 to 0.27, P = 0.850; I2 = 81.2%) or length of hospital stay (SMD 0.06, 95%CI −0.43 to 0.54, P = 0.821; I2 = 91.3%). To summarize, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. Levosimendan, Cardiac surgery, Meta-analysis, Outcomes, Mortality INTRODUCTION Patients undergoing cardiac surgery are at high risk of cardiac dysfunction, and those events that occur in the perioperative period are associated with higher mortality and worse clinical outcomes [1, 2]. Therefore, perioperative administration of positive inotropic drugs is necessary for those patients at high risk of cardiac dysfunction. Conventional inotropic agents, such as dobutamine and milrinone, can significantly improve cardiac function and, unfortunately, are always accompanied by increased myocardial oxygen consumption and malignant arrhythmia events. Levosimendan, a calcium-sensitized positive inotropic drug, can strengthen the stabilization of calcium-induced conformational changes in tropomyosin by enhancing the calcium sensitivity of troponin C [3] without increasing the intracellular calcium concentrations; thus, levosimendan can improve myocardial contraction without affecting the diastolic function and increasing myocardial oxygen consumption [4]. Over the past decade, more than 30 studies have focused on the effect of levosimendan on cardiac performance and clinical outcomes in patients undergoing cardiac surgery. Unfortunately, most of them have not found a beneficial effect on mortality, though a few studies demonstrated that levosimendan could reduce mortality in patients undergoing cardiac surgery [5–7]. While all previous meta-analyses [8–10] concluded that perioperative administration of levosimendan was associated with a significant reduction in mortality, most trials conducted in the recent 3 years, 3 multicentre randomized controlled trials in particular [11–13], failed to identify any improvement in the survival rate after the use of levosimendan. These conflicting results should be accounted for to inform clinical decision-making and policies. Hence, we conducted this meta-analysis to pool data from all related trials, especially from trials published in the most recent 3 years, to reassess the effect of levosimendan on clinical outcomes in patients undergoing cardiac surgery. METHODS Search strategy PubMed, OVID, the Cochrane Database of Clinical Trials and the Web of Science were systematically searched for randomized controlled trials of perioperative administration of levosimendan in adult patients undergoing cardiac surgery from database inception to August 2017 by 3 authors (L.S., Y.W and X.G.). A general search was conducted to avoid missing relevant literature. The medical subject headings (MeSH) term ‘cardiac surgical procedures’ combined with the term ‘levosimendan’ was systematically searched in the different databases, and the detailed search strategy is shown in the Supplementary Appendix. There was no language restriction in this meta-analysis, and all other language articles that provided English abstracts were included and translated into English for further screening. Study selection All relevant articles were initially reviewed for title and abstract by 3 authors (P.L., Y.Z. and C.H.) independently using a questionnaire, and any disagreements were resolved by discussion and consensus. Then, eligible articles were included in a full-text review, and we contacted the authors by email for the full text when the full text was unavailable online. The inclusion criteria included prospective randomized controlled trials, adult patients (≥18 years) undergoing cardiac surgery and perioperative administration of levosimendan with no restriction on dose or time of administration. The primary end-point in this meta-analysis was postoperative mortality, including 30-day mortality, 28-day mortality, intensive care unit (ICU) mortality, in-hospital mortality and 60-day mortality. The secondary end-points were duration of ICU stay and hospital stay. An article assessing at least one of the above indicators was included in this study. The exclusion criteria included non-human experimental studies, non-intravenous application of levosimendan, heart transplantation, percutaneous coronary intervention and lack of data on end-points. Moreover, duplicate published studies were also excluded, and the most recent updated data were included in the final analysis. Data extraction and quality assessment Data were extracted by 2 authors (Z.X. and X.Z.) with a custom-made form, which included the name of the first author, publication year, number of subjects, sample size, control intervention, starting time of levosimendan administration, dose of levosimendan, duration of follow-up, type of cardiac surgery, preoperative left ventricular ejection infraction (LVEF), duration of ICU stay and hospital stay. The primary end-point was postoperative mortality, including 30-day mortality, 28-day mortality, ICU mortality and in-hospital mortality. In studies in which both in-hospital mortality and 30-day/28-day mortality were reported, the longer follow-up mortality was included for analysis. The secondary end-points were duration of ICU stay and duration of hospital stay. If necessary, the authors were contacted to provide the missing data on primary outcomes, and we removed those studies for which the authors could not provide the missing data for this meta-analysis. Internal validity and risk of bias were assessed independently by 2 reviewers (X.Z. and Z.X.) according to the Cochrane Collection methods [14] with standardized criteria, and 6 domains were assessed, including adequate sequence generation, allocation concealment, blinding, incomplete outcome data, free of selective reporting and free of other bias. We defined in advance that studies with a high or unclear risk of bias in no more than 2 domains would be considered to be of high quality. Statistical analysis All statistical tests were performed using Stata/SE 11.0 (StataCorp, College Station, TX, USA). A pooled odds ratio (OR) with a 95% confidence interval (CI) was calculated to assess the effect of levosimendan on mortality with the Peto method because death was a rare event in our included studies. Data on duration of ICU stay and hospital stay were pooled by using the standardized mean difference (SMD) with the inverse variance method due to the differences in time units of ICU stay. For continuous data reported as median with range, mean and standard deviation (SD) were estimated using the method of Hozo et al. [15]. If only the interquartile range (IQR) was available, then SD was estimated with the formula proposed by the Cochrane handbook: SD = IQR/1.35 [16]. Heterogeneity between studies was assessed by I2 with the corresponding χ2 test. The fixed-effect method was used in cases of low or moderate statistical inconsistency (I2 < 50%), and the random-effect method was used in cases of high statistical inconsistency (I2 ≥ 50%) to calculate the pooled SMD. Meta-regression was performed to detect the following factors: publication year, sample size, interventions in the control group, preoperative LVEF, whether levosimendan was administered with a loading dose and the starting time of administration, and whether this had an influence on the effect of levosimendan on perioperative mortality. We predefined low LVEF as the mean value of preoperative LVEF <40% and a loading dose as administration of levosimendan with a bolus of which the concentration was >6 μg/kg and infusion time was <1 h [5, 6, 17]. Subgroup analysis was conducted for the primary end-point based on publication year. Sensitivity analysis was conducted to assess the robustness of the pooled results for perioperative mortality by sequentially removing one study at a time. Funnel plots and the Egger test were implemented to assess publication bias when the number of included studies was more than 10. A P-value of <0.05 was considered statistically significant. RESULTS A total of 1417 records were searched from the above 4 databases. After screening by title, abstract and full text, 30 articles met the eligibility criteria and were included in the final analysis [5–7, 11–13, 17–40]. The PRISMA flow chart of this study is shown in Fig. 1, and detailed study characteristics for individual trials are summarized in Table 1. The 6 domains for assessing the quality and risk of bias of the included studies are described in Table 2. Table 1: Characteristics of studies included in this meta-analysis Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Values are presented as mean ± SD or median (IQR). CABG: coronary artery bypass grafting; CG: control group; CPB: cardiopulmonary bypass; ECC: extracorporeal circulation; IQR: interquartile range; LG: levosimendan group; LVEF: left ventricular ejection fraction; SD: standard deviation. Table 1: Characteristics of studies included in this meta-analysis Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Author  Type of cardiac surgery  Number (death/total)   Preoperative LVEF (%)   Dose of levosimendan  Time of administration  Intervention in the control group  Mortality  Hospital stay (days)   Intensive care unit stay   LG  CG  LG  CG  LG  CG  LG  CG  De Hert et al. [20]  Elective cardiac surgery + CPB  0/15  3/15  24 ± 6  27 ± 3  0.1 μg/kg/min, no bolus  After the surgery  Milrinone  30-day  10 (7–16)  12 (5–39)  62 (28–121) h  66 (24–936) h  Levin et al. [5]  Coronary surgery + ECC  6/69  17/68  36.6 ± 4.4  38.2 ± 5.2  10 μg/kg for 1 h, followed by 0.1 µg/kg/min for 24 h  After the surgery  Dobutamine  30-day or in- hospital    66 (58–74) h  158 (106–182) h  Shah et al. [33]  Off-pump CABG  1/25  3/25  22.5 ± 4.1  22.6 ± 3.4  200 μg/kg dose was dissolved in 50 ml normal saline, 2 ml/h for 24 h  Before the surgery  Placebo  30-day or in- hospital    53.8 (- -) h  59.6 (- -) h  Leppikangas et al. [24]  Undergoing aortic valve replacement with CABG  1/12  0/12  63 ± 9  69 ± 9  12 μg/kg in 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  8.6 ± 3.3  8.8 ± 5.6  25.3 ± 9.7 h  25.6 ± 10.1 h  Sharma et al. [32]  Undergoing on-pump CABG + mitral valve repair  1/20  3/20  23.6 ± 4.9  22.6 ± 0.9  200 mg/kg over 24 h  Before the surgery  Placebo  30-day or in- hospital  10.5 ± 2.0  14.2 ± 1.6  3.9 ± 1.8 days  8.15 ± 1.89 days  Alvarez et al. [18]  Low cardiac output after heart surgery + ECC  1/25  1/25  35.4 ± 4.4  33.6 ± 4.9  12 µg/kg over 15–20 min, followed by 0.2 µg/kg/min for 24 h  After the surgery  Dobutamine  In-hospital      Gandham et al. [28]  Undergoing mitral valve surgery + CPB      60.4 ± 1.6  59.3 ± 10.2  0.1 µg/kg/min  After the surgery  Dobutamine      2.56 ± 0.5 days  2.8 ± 0.66 days  Sahu et al. [35]  Undergoing elective on-pump CABG  0/15  0/15  57.0 ± 3.5  56.8 ± 2.0  10 µg/kg over 10 min, followed by 0.1 µg/kg/min for 24 h  Before the surgery  Nitroglycerine  30-day  12.3 ± 1.8  12.0 ± 1.7  33.3 ± 7.1 h  43.3 ± 17.2 h  Ersoy et al. [29]  Underwent valve surgery  0/10  0/10  46.8 ± 10.9  49.0 ± 12.0  12 μg/kg in 10 min, followed by 0.1 μg/kg/min for 24 h  Before the surgery  Control group  In-hospital  7.8 ± 2.4  5.8 ± 1.5  2.7 ± 2.1 days  1.4 ± 1.3 day  Anastasiadis et al. [37]  Undergoing CABG  0/16  2/16  35.7 ± 4.9  37.5 ± 3.4  0.1 μg/kg/min for 24 h without a loading dose  Before the surgery  Placebo  30-day  8.9 ± 2.1  11.3 ± 13.6  2.4 ± 0.7 days  2.6 ± 1.9 days  Juhl-Olsen et al. [34]  Scheduled for elective aortic valve replacement  0/10  0/10  62 (55–75)  62 (58–70)  0.1 μg/kg/min continued to the end of surgery  Before the surgery  Placebo  6-month    18.9 (15.7–30.6) h  20 (17.9–139.1) h  Erb et al. [31]  Elective CABG with or without valve surgery  1/17  3/16  22.0 ± 4.5  22.4 ± 5.5  0.1 μg/kg/min without bolus  Before the surgery  Placebo  30-day  12.5 (10.3–21.8)  13.5 (10.3–21.5)  3 (1.5–7) days  5 (4–13.8) days  Eriksson et al. [22]  On-pump CABG  0/30  2/30  36 ± 8  36 ± 8  12 μg/kg for 10 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day    2 (1–33) days  2 (1–31) days  Landoni et al. [11]  Perioperative cardiovascular dysfunction after cardiac surgery  32/248  33/258  50 (37–59)  50 (40–60)  0.025–0.2μg/kg/min for 48 h  After the surgery  Placebo  30-day  14 (8–21)  14 (9–21)  72 (46–114) h  84 (48–139) h  Baysal et al. [17]  Undergoing mitral valve surgery  4/64  10/64  35 (20–50)  37.5 (25–50)  6 μg/kg within 10 min followed by 0.1 μg/kg/min for 24 h  After the surgery  Control group  30-day  8 (7–38)  9 (7–37)  4 (1–4) days  5 (2–37) days  Mehta et al. [12]  Undergo cardiac surgery + CPB  15/428  19/421  26 (24–32)  27 (22–31)  0.2 μg/kg/min for 1 h and then 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  30-day    2.8 (1.6–4.8) days  2.9 (1.8–4.9) days  Lahtinen [25]  Undergo heart valve or combined heart valve and CABG + CPB  10/99  10/101      24 μg/kg over 30 min, followed by 0.2 μg/kg/min for 24 h  Before the surgery  Placebo  In-hospital and 30-day  16 ± 12  17 ± 26    Al-Shawaf et al. [19]  Elective CABG surgery  1/14  1/16  29 ± 6  31 ± 6  12 μg/kg over 10 min, followed by 0.1–0.2 μg/kg/min for 24 h  After the surgery  Milrinone  In-hospital    7.7 ± 10.5 days  13 ± 33 days  Tritapepe et al. [23]  Undergoing elective CABG  0/52  0/50  41.6 ± 10.7  44.1 ± 9.8  A bolus of 24 μg/kg over 10 min without continued infusion  Before the surgery  Placebo  30-day  11.1 ± 2.3  12.0 ± 2.5  24.8 ± 7.1 h  32.7 ± 12.9 h  Dogan et al. [27]  Elective CABG      26.3 ± 6.4  24.9 ± 1.1  24 μg/kg was dissolved in 500-ml Ringer’s lactate solution  Before the surgery  Placebo    5.3 ± 0.7  11.2 ± 1.2    Järvelä et al. [21]  Aortic valve surgery with or without CABG  1/12  0/12  50 ± 4  65 ± 5  0.2 μg/kg/min for 24 h  Before the surgery  Placebo  30-day      Lomivorotov et al. [26]  CABG + CPB  1/30  1/30  31 (28–33)  30 (29–33)  12 μg/kg over 10 min, followed by 0.1 g/kg/min over 24 h  Before the surgery  IABP  In-hospital  18 (14–32)  19 (15–22)  2 (1–3) days  3 (3–4) days  Levin et al. [6]  Undergoing CABG + CPB  5/127  16/125  17.6 ± 3.2  18.6 ± 2.1  10 μg/kg over 60 min, followed by 0.1 μg/kg/min for 23 h  Before the surgery  Placebo  In-hospital      Sahin et al. [7]  Elective CABG  0/47  2/68  29.5 ± 3.9  30.2 ± 4.2  15 µg/kg/min for 20 min, followed by 0.2 µg/kg/min for 18 h  Before the surgery  Dopamine or dobutamine  In-hospital  5.2 ± 5.8  6.1 ± 3.6  1.2 ± 2.3 day  1.6 ± 2.1 day  Atalay et al. [38]  Elective CABG in end-stage renal disease  1/25  4/33  44.6 ± 15.4  42.8 ± 13.9  3 µg/kg/min for 6 h, 0.03–0.05 µg/kg/min for 24 h  Before the surgery  Placebo  In-hospital  26.3 ± 7.2  4.1 ± 5.0  8.3 ± 3.6 day  4.1 ± 0.9 day  Kodalli et al. [30]  Elective off-pump CABG      58 ± 4  61 ± 2.5  0.1 µg/kg/min  Before the surgery  Placebo      3.3 ± 0.7 day  3.5 ± 0.6 day  Mishra et al. [36]  Undergoing mitral/aortic valve replacement      52.2 ± 11  54.28 ± 4.56  10 µg/kg for 10 min, followed by 0.1 µg/kg/min for 24 h  After the surgery  Milrinone      4.25 ± 1.71 day  4.56 ± 1.62 day  Cholley et al. [13]  CABG + CPB  12/167  9/168  ≤40  ≤40  0.1 µg/kg/min for 24 h  Before the surgery  Placebo  28-day, 180-day and in-hospital  7 (1–134)  7 (2–86)  4 (0–61) days  4 (1–42) days  Giannini et al. [39]  Percutaneous mitral valve repair with a MitraClip device  0/27  0/27      0.01 µg/kg/min for 24 h  Before the surgery  Other therapies  In-hospital  4 (4–6)  4 (3–6)    Kandasamy et al. [40]  Off-pump CABG          0.1 µg/kg/min  Before the surgery  Dobutamine    5.88 ± 0.6  6.85 ± 0.8  2.85 ± 0.7 day  3.2 ± 0.72 day  Values are presented as mean ± SD or median (IQR). CABG: coronary artery bypass grafting; CG: control group; CPB: cardiopulmonary bypass; ECC: extracorporeal circulation; IQR: interquartile range; LG: levosimendan group; LVEF: left ventricular ejection fraction; SD: standard deviation. Table 2: Risk of bias of the studies included in this meta-analysis Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  H: high; L: low; M: moderate. Table 2: Risk of bias of the studies included in this meta-analysis Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  Author  Adequate sequence generation  Allocation concealment  Blinding  Incomplete outcome data  Free of selective reporting  Free of other bias  Overall risk of bias  De Hert et al. [20]  +  +  +  Unclear  +  +  L  Levin et al. [5]  +  Unclear  Unclear  Unclear  +  +  M  Shah et al. [33]  Unclear  Unclear  +  Unclear  +  +  M  Leppikangas et al. [24]  Unclear  +  +  Unclear  +  +  L  Sharma et al. [32]  Unclear  Unclear  +  Unclear  +  +  M  Alvarez et al. [18]  Unclear  Unclear  —  Unclear  +  +  H  Gandham et al. [28]  +  Unclear  +  Unclear  +  +  L  Sahu et al. [35]  Unclear  Unclear  Unclear  Unclear  +  +  H  Ersoy et al. [29]  Unclear  Unclear  Unclear  Unclear  +  +  H  Anastasiadis et al. [37]  +  Unclear  +  Unclear  +  +  L  Juhl-Olsen et al. [34]  +  +  +  Unclear  +  +  L  Erb et al. [31]  +  +  +  Unclear  +  +  L  Eriksson et al. [22]  +  +  +  Unclear  +  +  L  Landoni et al. [11]  +  +  +  Unclear  +  +  L  Baysal et al. [17]  +  +  +  Unclear  +  +  L  Mehta et al. [12]  +  +  +  Unclear  +  +  L  Lahtinen [25]  +  +  +  Unclear  +  +  L  Al-Shawaf et al. [19]  Unclear  +  −  Unclear  +  +  H  Tritapepe et al. [23]  +  Unclear  +  Unclear  +  +  L  Dogan [27]  Unclear  Unclear  +  Unclear  +  +  M  Järvelä et al. [21]  +  +  +  Unclear  +  +  L  Lomivorotov et al. [26]  Unclear  +  Unclear  Unclear  +  +  M  Levin et al. [6]  Unclear  Unclear  +  Unclear  +  +  M  Sahin et al. [7]  Unclear  Unclear  —  Unclear  +  +  H  Atalay et al. [38]  Unclear  Unclear  +  Unclear  +  +  M  Kodalli et al. [30]  Unclear  Unclear  +  Unclear  +  +  M  Mishra et al. [36]  +  +  +  Unclear  +  +  L  Cholley et al. [13]  +  +  +  +  +  +  L  Giannini et al. [39]  Unclear  Unclear  −  Unclear  +  +  H  Kandasamy et al. [40]  +  Unclear  +  Unclear  +  +  L  H: high; L: low; M: moderate. Figure 1: View largeDownload slide The PRISMA flow diagram of the study selection process. Figure 1: View largeDownload slide The PRISMA flow diagram of the study selection process. Characteristics Of these 30 articles, 20 were published before 2015 [5–7, 17–33], and the remaining 10 articles were published after 2015 [11–13, 34–40]. There were 25 studies with data on perioperative mortality [5–7, 11–13, 17–26, 29, 31–35, 37–40], 24 studies with data on the duration of ICU stay [5, 7, 11, 12, 17, 19, 20, 22–24, 26, 28–40] and 19 studies with data on the duration of hospital stay [7, 11, 13, 17, 20, 23–27, 29, 31–33, 35, 37–40]; however, one of these studies only provided the median value of the duration of ICU and hospital stay without IQR value [33], and we were unable to contact the authors for the complete data; therefore, we decided to exclude this article from the analysis of the duration of ICU and hospital stays. The patients in 18 studies had damaged cardiac performance with a preoperative LVEF of <40% [5–7, 12, 13, 17–20, 22, 26, 27, 31–33, 37, 39, 40], and one [40] of the studies only reported the percentage of patients with preoperative LVEF <45% instead of the mean or median value of LVEF. Similarly, another study [25] reported the percentage of patients with preoperative LVEF >50% and was included in the preserved LVEF group. Fourteen studies introduced a protocol where levosimendan was administered with a loading dose [5–7, 17–19, 22–26, 29, 35, 36], and one of them reported that levosimendan was administered only with a bolus of 24 μg/kg over 10 min without a continued infusion [23]. A levosimendan infusion that started before cardiac surgery was reported in 22 studies [6, 7, 11–13, 21–27, 29–31, 33–35, 37–40]; in the other studies, administration of levosimendan was started after cardiac surgery [5, 17–20, 28, 32, 36]. The interventions in the control group included milrinone [19, 20, 36], dobutamine [5, 7, 18, 28], IABP [26], nitroglycerine [35] and placebo [6, 11–13, 21–25, 27, 30–34, 37–40], and 2 studies did not report a detailed intervention in the control group [17, 29]. Perioperative mortality A total of 25 studies consisting of 3239 patients were included in the meta-analysis for perioperative mortality; the pooled OR indicated that perioperative administration of levosimendan could reduce postoperative mortality when compared with the control group [5.8% (93/1604) vs 8.5% (139/1635); OR 0.66, 95% CI 0.50–0.86, P = 0.002; I2 = 17.1%]. However, subgroup analysis according to the publication years demonstrated that the benefit of levosimendan on mortality was seen only in the subgroup of trials published before 2015 (OR 0.44, 95% CI 0.30–0.66, P < 0.001; I2 = 0.0%), but not in the subgroup of trials published after 2015 (OR 0.91, 95% CI 0.63–1.31, P = 0.626; I2 = 0.9%) (Fig. 2). Figure 2: View largeDownload slide Forest plot of subgroup analysis for postoperative mortality based on publication year. CI: confidence interval; OR: odds ratio. Figure 2: View largeDownload slide Forest plot of subgroup analysis for postoperative mortality based on publication year. CI: confidence interval; OR: odds ratio. Meta-regression was performed to detect the source of heterogeneity between these studies and indicated that publication year (Coef. = 0.092, 95% CI 0.006–0.177; P = 0.037) was a factor that influenced the association between levosimendan and mortality (Fig. 3). Preoperative LVEF (low or preserved) (P = 0.055) and interventions in the control group (placebo or not) (P = 0.073) might influence the effect of levosimendan on mortality. However, differences in sample size (P = 0.109), loading dose (with or without) (P = 0.114) and starting time of administration (before or after surgery) (P = 0.779) were not associated with the effect of levosimendan on mortality. Figure 3: View largeDownload slide Meta-regression indicated that publication year influenced the association between levosimendan and mortality. An increase of 1 year in the Y-axis is associated with an increase of logOR value by 0.092. OR: odds ratio. Figure 3: View largeDownload slide Meta-regression indicated that publication year influenced the association between levosimendan and mortality. An increase of 1 year in the Y-axis is associated with an increase of logOR value by 0.092. OR: odds ratio. Duration of intensive care unit stay and hospital stay The duration of ICU stay was reported in 23 studies (2536 patients); the pooled result showed a reduction in the length of ICU stay in patients with the administration of levosimendan (SMD −0.32, 95% CI −0.58 to 0.06, P = 0.017; I2 = 88.0%) (Fig. 4); a reduction in the length of ICU stay was also found in a subgroup analysis of trials published before 2015 (SMD −0.51, 95% CI −0.94 to 0.09, P = 0.018; I2 = 88.3%). However, this benefit disappeared after stratified analysis for trials published after 2015 (SMD −0.03, 95% CI −0.32 to 0.27, P = 0.850; I2 = 81.2%). There were 18 studies (2047 patients) with data on the duration of hospital stay; the pooled SMD indicated that the administration of levosimendan was not associated with a shorter hospital stay (SMD −0.41, 95% CI −0.89 to 0.07, P = 0.094; I2 = 95.9%), regardless of the studies being published before 2015 (SMD −0.73, 95% CI −1.56 to 0.11, P = 0.088; I2 = 96.9%) or after 2015 (SMD 0.06, 95% CI −0.43 to 0.54, P = 0.821; I2 = 91.3%) (Fig. 5). Figure 4: View largeDownload slide Forest plot of subgroup analysis for the duration of intensive care unit stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Figure 4: View largeDownload slide Forest plot of subgroup analysis for the duration of intensive care unit stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Figure 5: View largeDownload slide Forest plot of subgroup analysis for the duration of hospital stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Figure 5: View largeDownload slide Forest plot of subgroup analysis for the duration of hospital stay based on publication year. CI: confidence interval; SMD: standardized mean difference. Sensitivity analysis and publication bias As shown in Fig. 6, sensitivity analysis suggested that the overall effect of levosimendan on perioperative mortality was not changed after sequentially removing one study at a time. The study by Landoni et al. [11] was the main source of heterogeneity for these included studies, and the heterogeneity decreased significantly after excluding the study from this meta-analysis (OR 0.56, 95% CI 0.41–0.77; P < 0.001, I2 = 7.0%). Additionally, sensitivity analysis was conducted in the subgroup of trials published after 2015 and indicated that the effect of levosimendan on perioperative mortality was still unchanged. The funnel plot was visually symmetric for perioperative mortality, and the Egger test revealed no evidence of publication bias (P = 0.212) (Supplementary Material, Fig. S1). Figure 6: View largeDownload slide Sensitivity analysis for assessing the robustness of pooled OR for perioperative mortality. (A) The study of Landoni et al. is the main source of heterogeneity between the included studies. (B) The sensitivity analysis for the subgroup of trials published after 2015 is shown and the effect of levosimendan on perioperative mortality was unchanged after sequentially removing one study at a time is indicated. CI: confidence interval. Figure 6: View largeDownload slide Sensitivity analysis for assessing the robustness of pooled OR for perioperative mortality. (A) The study of Landoni et al. is the main source of heterogeneity between the included studies. (B) The sensitivity analysis for the subgroup of trials published after 2015 is shown and the effect of levosimendan on perioperative mortality was unchanged after sequentially removing one study at a time is indicated. CI: confidence interval. DISCUSSION This meta-analysis suggested that perioperative administration of levosimendan was associated with a reduction in postoperative mortality and length of ICU stay in patients undergoing cardiac surgery. However, subgroup analysis for trials published after 2015 revealed no significant benefits in reducing postoperative mortality or length of ICU stay and hospital stay with the use of levosimendan. To summarize, the evidence from studies published in the most recent 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. Levosimendan is a new calcium-sensitized positive inotropic agent that can improve myocardial contraction by enhancing calcium sensitivity of troponin C without increasing the intracellular calcium concentrations. Levosimendan does not affect the diastolic function or increase myocardial oxygen consumption; therefore, the application of levosimendan, if necessary, in patients with haemodynamic instability, such as undergoing cardiac surgery, is relatively safe compared with dobutamine or milrinone. However, the effect of levosimendan on postoperative mortality in patients undergoing cardiac surgery is still not well known. Although most articles have reported no reduction in mortality with the use of levosimendan, 3 previous meta-analyses [8–10] demonstrated that levosimendan is beneficial for postoperative mortality in patients undergoing cardiac surgery. These positive results from the 3 meta-analyses are mainly attributed to the large differences in the number of deaths between the levosimendan and control groups in 2 studies by Levin et al. [5, 6]. Subjects in 1 [5] of the 2 studies were patients receiving coronary surgery with low cardiac output syndrome. The aim of that study was to investigate the effectiveness of levosimendan, and the results suggested that the use of levosimendan resulted in a significantly lower postoperative mortality compared with dobutamine (6/69 vs 17/68; P < 0.05). The other study [6] also focused on the effectiveness of levosimendan in the same population and indicated that levosimendan had a significant mortality benefit compared with placebo (5/127 vs 16/125; P < 0.05). However, the 2 studies were conducted in the same hospital by the same research team, and some methodological factors in the studies, such as allocation concealment and blinding, are unclear, so it is hard to rule out the possibility of publication bias. After assessment of internal validity and risk of bias, the 2 studies were defined as moderate risk of bias and were considered low quality in our meta-analysis. Therefore, the beneficial effect of levosimendan on mortality shown in previous meta-analyses [8–10] must be further explained and re-evaluated. Recently, 3 multicentre randomized controlled trials, namely, the CHEETAH trial [11], LEVO-CTS trial [12] and LICORN trial [13], were published successively. They all showed a neutral effect of levosimendan on mortality after cardiac surgery. In the LEVO-CTS trial, a total of 849 patients undergoing cardiac surgery with an LVEF of 35% or less were included and randomly assigned to receive levosimendan (428 patients) or placebo (421 patients). The final results indicated that levosimendan was not associated with a significant reduction in 30-day mortality (15/428 vs 19/421; P = 0.25) or the duration of ICU stay [2.8 (1.6–4.8) vs 2.9 (1.8–4.9) days; P = 0.25] compared with placebo. The result was similar in the CHEETAH trial. There was also no significant difference in 30-day mortality (32/248 vs 33/258; P = 0.97) between the levosimendan group and the placebo group. Interestingly, the duration of ICU stay in the levosimendan group was slightly lower than that of the placebo group, although the difference was not significant [72 (46–114) vs 84 (48–139) h; P = 0.08], and the difference in hospital stay was also not significant [14 (8–21) vs 14 (9–21) days; P = 0.39]. In the LICORN trial, the use of levosimendan, compared with placebo, also did not result in a significant difference in 28-day mortality, in-hospital mortality or length of ICU stay or hospital stay. These results were different from that of previous meta-analyses [8–10], and the conflicting results lead us to question whether levosimendan could really improve clinical outcomes. Hence, we reassessed the effect of levosimendan on outcomes in patients undergoing cardiac surgery by including publications from the most recent 3 years in this meta-analysis to expand the sample size and conducted a stratified analysis according to the publication year. We found that perioperative administration of levosimendan was associated with a 2.7% reduction in postoperative mortality compared with the control group [OR 0.66, 95% CI 0.50–0.86, P = 0.002; I2 = 17.1%]. Similar to the results of the meta-analysis by Lim et al. [10], our meta-analysis also demonstrated a beneficial effect of levosimendan in reducing the length of ICU stay (SMD = −0.32, 95% CI: −0.58 to 0.06, P = 0.017; I2 = 88.0%). In addition, our meta-analysis revealed no significant reduction in length of hospital stay in patients with the use of levosimendan (SMD = −0.41, 95% CI: −0.89 to 0.07, P = 0.094; I2 = 95.9%), and similar results were observed in a meta-analysis by Landoni et al. [8]. Unfortunately, in our meta-analysis, subgroup analysis for trials published after 2015 suggested that levosimendan had no significant benefits in reducing postoperative mortality, length of ICU stay or hospital stay. The strength of our finding is based on the integration of larger data. Studies included in our meta-analysis are more comprehensive than in previous meta-analyses. A total of 25 randomized controlled trials, in which the number of subjects (3239 patients) is larger than that in previous meta-analyses [8–10], were included in the analysis of postoperative mortality. Furthermore, 3 multicentre randomized controlled trials published in 2017 were also included. Our meta-analysis for randomized controlled trials with a larger sample size would, to a large extent, decrease the sampling errors and selective bias and reveal the real effect of levosimendan on mortality more objectively and thus guide clinical medication decisions. In addition, a study by Levin et al. [5] included in our meta-analysis was missing in the meta-analysis by Lim et al. [10]. The missing data inevitably weakened the credibility of their work. Overall, the strength of data in our meta-analysis is more powerful than in previous meta-analyses. Limitations However, there are still several limitations in our meta-analysis. First, the mortality variables included in this meta-analysis are not uniform. Therefore, it was difficult to conduct a stratified analysis based on mortality, and we also have not conducted a meta-regression to detect whether the mortality variable is a source of the heterogeneity between studies. Similarly, the interventions in the control group, including milrinone, dobutamine, IABP, nitroglycerine and placebo, are different in the included studies. A meta-regression indicated that the mix of these interventions in the control group might cause heterogeneity between the studies. Disappointingly, we did not conduct a subgroup analysis according to the interventions in the control group, which is a methodological deficiency in this meta-analysis. Second, there is currently no official definition of a loading dose of levosimendan, and the doses of levosimendan were different in some of the studies. We summarized the loading dose from all of the included studies as a bolus of which the concentration was greater than 6 μg/kg and the infusion time was <1 h; this definition might result in a selective bias. Third, data on the duration of ICU stay and hospital stay in some of the studies were presented as the median (IQR) and was not converted to mean ± SD by using the method of Hozo et al. [15]; then SD was estimated using the formula: SD = IQR/1.35; therefore, this approximated calculation could impact the results and may be a source of the heterogeneity. Finally, some trials included in the study had a small sample size; thus, the small study effect should be considered in interpreting the results. The effect size of levosimendan can be overestimated by pooling the results from small studies, such as 2 studies by Levin et al. [5, 6], which can be eliminated by subsequent mega-trials [41]. CONCLUSION This meta-analysis suggested that perioperative use of levosimendan was associated with a reduction in postoperative mortality and length of ICU stay in patients undergoing cardiac surgery. However, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery. SUPPLEMENTARY MATERIAL Supplementary material is available at ICVTS online. Funding This study was supported by the Natural Science Foundation of Ningbo [grant no. 2016A610139], Zhejiang Traditional Chinese Medicine Research Project [no. 2011ZZ001] and Zhejiang Medical and Health Science and Technology Project (no. 2017ZD001 and 2013KYB004). Conflict of interest: none declared. REFERENCES 1 Topkara VK, Cheema FH, Kesavaramanujam S, Mercando ML, Cheema AF, Namerow PB. Coronary artery bypass grafting in patients with low ejection fraction. Circulation  2005; 112: I344– 50. 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Journal

Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Feb 3, 2018

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