Levosimendan for patients with severely reduced left ventricular systolic function and/or low cardiac output syndrome undergoing cardiac surgery: a systematic review and meta-analysis

Over the last two decades, the risk profile of patients undergoing cardiac surgery has increased significantly [1, 2], and currently more than 1 million cardiac surgery procedures are performed annually in the United States and Europe [3]. Older patients and those with a higher degree of comorbidities are currently referred for cardiac surgery [4], and, even if such patients may benefit from cardiac surgery, they are at increased risk for perioperative complications that result in high morbidity and mortality [5]. Patients with a severely depressed left ventricular ejection fraction (LVEF < 35%) are particularly at increased risk of developing postoperative low cardiac output syndrome (LCOS) [6], which in turn is associated with higher mortality [7].

Levosimendan, a calcium-sensitizing inotrope and an ATP-sensitive potassium channel (K_ATP) opener, has been investigated as a pharmacological strategy to decrease mortality in cardiac surgery [8‐10]. The intraoperative and postoperative use of levosimendan is mainly a rescue strategy for patients with difficult weaning from cardiopulmonary bypass (CPB) or in cases of LCOS. One recent meta-analysis showed that levosimendan seems to be the most effective drug in decreasing mortality after cardiac surgery [11], and another showed that the reduction in mortality and postoperative complications is driven by studies where levosimendan was used in patients with low LVEF [12].

Two randomized controlled trials (RCTs) published at the beginning of 2017 have not shown beneficial effects of the use of levosimendan compared with placebo in patients with preoperative severely depressed LVEF [13] or in a mixed population of patients with either preoperative severely depressed LVEF or profound intra-/postoperative cardiovascular dysfunction [14]. Nonetheless, researchers in the first study reported a beneficial effect in a subgroup of patients with a more severe reduction of LVEF [13]. Therefore, we aimed to conduct a new meta-analysis in light of the recently published RCTs, specifically examining the efficacy of levosimendan compared with placebo in decreasing mortality and need for renal replacement therapy (RRT) in high-risk cardiac surgery.

Our systematic search identified a total of 601 findings via an NHS Library Evidence search. No other findings were retrieved manually. After removal of duplicates, 423 findings were screened and 171 were excluded because they were not focused on the topic of interest. As shown in the PRISMA flow diagram in Additional file 2, after the evaluation of the remaining 252 findings, only 6 RCTs were judged to be of interest for our quantitative analyses: 5 RCTs included only patients with preoperative severely depressed LVEF [13, 19‐22], and 1 RCT included both patients with preoperative severely depressed LVEF and patients with intra-/postoperative LCOS [14]. No study was focused only on patients with intra-/postoperative LCOS. A list of the RCTs excluded despite enrolling patients with severely depressed LVEF (i.e., control subjects receiving milrinone or dobutamine) is provided separately (Additional file 3). Overall, data for up to 1728 patients were available, and data for up to 1224 patients were available for the subgroup of patients with preoperative severely reduced LVEF. Table 2 shows the characteristics of these studies, also including the timing of drug administration. Table 3 summarizes the results of primary and secondary outcome analyses.

We conducted the present meta-analysis because of the discordance between the results of two recent large RCTs investigating the use of levosimendan in high-risk patients undergoing cardiac surgery [13, 14] and the results of previously published meta-analyses [11, 12]. The two recent RCTs failed to show a beneficial effect of levosimendan compared with placebo [13, 14], whereas the two meta-analyses had opposite results [11, 12]. Another reason for conducting our study was the evidence in one RCT of a beneficial effect of levosimendan in the subgroup of patients with more severe reduction of LVEF (<25%) and in those undergoing isolated coronary artery bypass grafting (CABG); moreover, such RCTs showed a trend toward lower mortality at 90 days for levosimendan (4.7% vs placebo 7.1%, p = 0.12) [13].

Although the two recent RCTs included a broader spectrum of cardiac surgical interventions and were not focused exclusively on patients undergoing CABG [13, 14], previous studies were focused mostly on patients with coronary artery disease undergoing CABG (isolated [20, 21] or CABG with or without valve surgery [19, 22]). Moreover, such studies have used a more restrictive cutoff for preoperative LVEF (<25% [20] or < 30% [19, 21, 22]).

The primary endpoint of our meta-analysis was the difference in mortality and need for postoperative RRT in high-risk patients undergoing cardiac surgery receiving levosimendan compared with placebo. We therefore excluded studies comparing levosimendan with other pharmacological strategies, such as dobutamine and milrinone. We found only six RCTs comprising over 1700 patients, 1200 of whom over belonged to the subgroup of patients with preoperative severely reduced LVEF only (<35%). We investigated mortality and the need for postoperative RRT as primary outcomes. Whereas overall mortality was not different, levosimendan compared with placebo significantly reduced mortality in the subgroup of patients with preoperative severely reduced LVEF. Moreover, levosimendan significantly decreased the need for postoperative RRT after cardiac surgery, both overall and in the subgroup of patients with preoperative severely reduced LVEF (<35%).

These findings are not surprising, because even the larger RCT [13] showed a trend toward beneficial effects of levosimendan in patients with more depressed LVEF (<25%) and also among those with more advanced chronic kidney disease (estimated glomerular filtration rate < 60 ml/minute). Several aspects, however, should be taken into account. Levosimendan is a calcium-sensitizing inotrope as well as a K_ATP opener, and it has organ-protective properties. The opening of K_ATP channels located in the plasma membrane of vascular smooth muscle cells and at the level of mitochondria improves energy homeostasis, protecting the heart from calcium overload and oxidative injury [23, 24] and optimizing mitochondrial energy balance [24]. At coronary artery levels, levosimendan produces vasodilation through the increase in extracellular potassium, resulting in an increase in blood flow to ischemic myocardial regions [25]. This ultimately results in improved myocardial function, as shown by enhanced arterial-ventricular coupling [26]. For such reasons, patients with coronary artery disease undergoing CABG may experience a greater benefit from levosimendan by additive protection in areas at high risk of perioperative myocardial injury. Therefore, it is likely that our results differ from those of the recent RCTs, because our meta-analysis also included four studies that randomized only patients undergoing CABG (with or without valve surgery). A favorable effect of levosimendan might have been blunted in the larger RCTs that included a wider spectrum of patients undergoing cardiac surgery.

The advantageous renal effects of levosimendan are reinforced by a lower number of patients with postoperative AKI according to the RIFLE criteria. We believe that such results can be attributed primarily to an improvement in systemic hemodynamics. The increase in cardiac output and the reduction in right-sided pressures, including central venous pressure [27], may decrease renal vein pressure. Such effects may increase renal flow per se. Additionally, because renal blood flow depends on vascular resistance, the local vasodilation obtained by levosimendan through the K_ATP channels in the afferent arterioles increases renal perfusion, thus increasing glomerular filtration pressure and filtration rate. Such effects on renal arterioles are different from those of other inotropes/vasoconstrictor agents. Also, nonhemodynamic effects such as preconditioning, anti-inflammatory effects, and antiapoptotic properties may have played a role in improving renal function [28].

The preoperative use of levosimendan has also been studied in CABG patients with preserved LVEF, and, although a reduction in myocardial injury and an increase in cardiac index in the levosimendan group were shown, the study failed to show a clear benefit of this strategy [29]. In the studies included in our meta-analysis, levosimendan has been used with varying timing of administration. In three studies, levosimendan has been given preoperatively 24 h before surgery [20‐22], whereas researchers in two studies initiated drug administration just before surgery [13, 19], and another study included mainly patients after difficult weaning from CPB or patients who developed profound cardiovascular dysfunction in the ICU [14].

It is interesting to note that levosimendan was associated with a lower incidence of LCOS in the subgroup of patients with low LVEF only and with a trend toward lower use of mechanical circulatory support, both overall and in the subgroup of patients with low LVEF only. In our study, we did not perform a comparison between levosimendan and other inotropes. Levosimendan has a mechanism different from that of other inotropes, which typically increase intracellular calcium levels with subsequent higher myocardial oxygen demand, adverse effects [30], and higher mortality [31, 32]. The rise of intracellular calcium levels does not happen with levosimendan, and therefore the drug does not increase in myocardial oxygen consumption [33].

One of the main issues with the use of levosimendan is related to its pharmacological properties. Beneficial ischemic myocardial preconditioning may be obtained if administration of the drug is performed several hours before the insult [9], but, as reported above, researchers in only three studies admitted patients to the ICU 24 h before surgery in order to start the drug infusion [20‐22]. In two other studies, investigators started the administration of levosimendan after anesthesia induction without a bolus [13, 19], and in one study, researchers used levosimendan mainly for difficult weaning from CPB or for postoperative LCOS [14]. It should be noted that when levosimendan is used at the beginning of surgery, it may be useful to administer a drug bolus to reach a peak concentration that is then maintained by infusion [9]. Therefore, in these studies, the beneficial effects of levosimendan may have been reduced by the late administration, the absence of a bolus, and possibly a dilution through the CPB circuit. It should be noted that bolus administration increases the risk of hypotension requiring the administration of noradrenaline, especially when given in a high dose (24 μg/kg) [34]; however, the experts of the European consensus on the use of perioperative levosimendan do not recommend a bolus, and in cases where a bolus is administered, they mostly suggest lower dosages (6 μg/kg, 67%; 12 μg/kg, 29%; 24 μg/kg, 4%) [9].

Another fundamental aspect in the cardiac surgery patient is the presence of diastolic dysfunction associated with depression of contractility. In these cases, levosimendan has shown improvements [35] or neutral effects on diastolic function [36], which instead is worsened by the use of catecholamines [30] and unchanged by inhibitors of phosphodiesterase [37, 38]. A large number of patients undergoing cardiac surgery are currently treated with beta-blockers, and levosimendan can offer advantages because it does not interfere with the receptor-mediated mechanisms of catecholamines and does not impair left ventricular diastolic function [39, 40]. Most of the patients with heart failure and/or severe systolic dysfunction are treated with beta-blockers [41, 42]. It is worth noting that, apart from two small studies (Shah et al. [21] and Sharma et al. [22], where a minority of patients were receiving beta-blockade therapy [14% and 12.5%, respectively]), most of the patients in the other studies of our meta-analysis were treated with beta-blockade therapy (Mehta et al. [13], ~ 80%; Landoni et al., [14], > 60%; Levin et al. [20], ~ 85%; Erb et al. [19], > 90%). Whether patients with preoperative treatment with beta-blockers may benefit more from levosimendan remains speculative and should be explored in subgroup analyses. Furthermore, levosimendan could offer advantages in patients with right ventricular systolic and diastolic dysfunction, with or without associated pulmonary hypertension [43‐45].

Levosimendan reduces mortality in patients with preoperative severely reduced ejection fraction (<35%). Moreover, levosimendan significantly reduces the need for RRT after high-risk cardiac surgery.