🎰 A review of levosimendan in the treatment of heart failure

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This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug. Keywords: Levosimendan. Heart​.


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Levosimendan reduces the frequency of hospitalization in advanced heart failure patients

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This study aims to review other important studies about levosimendan by revealing the underlying mechanisms of its activity, efficiency, and safety.


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Сalcium sensitizers. Levosimendan. Mechanism of action, side effects, indications, dosage

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Use of levosimendan in acute and advanced heart failure: short review on available real-world data. Eugene Pashkovetsky, Chhaya Aggarwal.


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Levosimendan in Patients With Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery

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This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug. Keywords: Levosimendan. Heart​.


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ESC TV at ACC.17 - LEVO-CTS: Levosimendan - Patients With Left Ventricular Systolic Dysfunction

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Use of levosimendan in acute and advanced heart failure: short review on available real-world data. Eugene Pashkovetsky, Chhaya Aggarwal.


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An update on the use of levosimendan in cardiac surgery (Russian)

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There is no benefit from levosimendan in patients with septic shock. The two large Review; Open Access; Published: 29 November


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Levosimendan shows respiratory benefits in patients with ALS

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Levosimendan has been actively evaluated for its effects on renal function in HF. The balance of the evidence, as summarized in a recent review.


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Evidence, recommendations, and limitations for levosimendan in CABG surgery

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There is no benefit from levosimendan in patients with septic shock. The two large Review; Open Access; Published: 29 November


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LEVO CTS Primary Outcomes for Cardiac Surgery with Levosimendan

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This study aims to review other important studies about levosimendan by revealing the underlying mechanisms of its activity, efficiency, and safety.


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Levosimendan - A/Prof Anthony Delany

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Use of levosimendan in acute and advanced heart failure: short review on available real-world data. Eugene Pashkovetsky, Chhaya Aggarwal.


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An update on the use of levosimendan in cardiac surgery

Despite interesting and unique pharmacological properties, levosimendan has not proven a clear superiority to placebo in the patient populations that have been enrolled in the various recent multicenter randomized controlled trials. Levosimendan might potentially remain useful in case of septic shock patients admitted with beta-blocker therapies that could participate to their circulatory failure. There is currently no high-quality study dealing with the use of levosimendan in cardiogenic shock. Shortly after, several metaanalyses suggested that levosimendan was able to reduce mortality in patients with poor left ventricular ejection fraction following cardiac surgery, placing this drug under the spotlight in the surgical environment [ 4 , 5 , 6 ]. However, the subgroup of those who underwent isolated CABG appeared to have a reduction in mortality. However, the pharmacodynamic effects of levosimendan are still considered potentially very useful in a number of specific situations. The largest set of data was obtained in patients with pulmonary hypertension and right ventricular failure as a consequence of severe LV failure group 2 [ 60 , 61 , 62 , 63 ]. A new RCT LevoHeartShock, NCT is about to start to compare levosimendan versus placebo on top of conventional adrenergic inotrope therapy on a combined morbidity-mortality endpoint in patients with cardiogenic shock. Levosimendan has been advocated as the first choice inotropic support when mechanical circulatory assist devices are not available [ 52 , 53 , 54 ]. The LevoRep study was the first multicenter RCT evaluating the effect of 4 injections of levosimendan 0. It should also be clearly noted that levosimendan has not demonstrated a clear superiority to other inotropes in well-designed trials. Moreover, as mentioned earlier, levosimendan acts independently of beta-adrenergic receptors activation and is therefore not sensitive to the action of beta-blockers. In patients with septic shock, however, the cardiovascular dysfunction reflected using the SOFA score was more profound in patients receiving levosimendan [ 24 ]. A multicenter randomized controlled trial is about to start to test the hypothesis that levosimendan in addition to standard care facilitates the weaning from VA ECMO. More studies are needed to provide a higher level of proof regarding these indications. Takotsubo syndrome may represent an ideal target for this non-adrenergic inotrope, but this statement also relies on expert opinion. Much less data is available on other forms of pulmonary hypertension groups 1, 3, 4, and 5. Therefore, the strategy of repetitive infusions cannot be considered as an alternative to them, but alleviates the symptoms and improves the quality of life in patients awaiting transplantation or in those who are ineligible for more invasive approaches. There is experimental evidence attesting for the ability of levosimendan to reverse, in part, pulmonary vasoconstriction and improve right ventricular function in various animal models of pulmonary hypertension [ 55 , 56 , 57 , 58 ]. These authors did not observe any benefit from using levosimendan in any subgroup classified by a variety of biomarker cut-off thresholds [ 73 ]. Repeated infusions of levosimendan are increasingly used to facilitate weaning from dobutamine and avoid prolonged hospitalizations in patients with end-stage heart failure, awaiting heart transplantation or left ventricular assist device implantation. There is no benefit from levosimendan in patients with septic shock. Based on these possible beneficial hemodynamic effects, levosimendan is now considered the first-choice drug in patients with acute decompensated heart failure and on beta-blockers, if beta-blockade is thought to be contributing to hypotension with subsequent hypoperfusion class IIb, evidence level C [ 35 , 36 ]. Some shock states related to ischemia-reperfusion injury lead to a sepsis-like syndrome with low systemic vascular resistance [ 46 , 47 ], while others, on the contrary, present with maintained arterial pressure and signs of end-organ hypoperfusion due to a dramatic increase in systemic vascular resistance [ 48 ]. Patient data, however, is still very scant and heterogeneous, involving patients with various types of pulmonary hypertension and right heart failure, and often with contradictory results [ 59 ]. A new study will be required to confirm this exploratory finding. A large multicenter randomized controlled trial assessed the effect of levosimendan on organ dysfunction in adult patients with septic shock at day 28, but failed to show a reduction in organ dysfunction or mortality when added to standard care [ 24 ]. An uncontrolled drop in myocardial oxygen delivery might precipitate right ventricular failure and result in acute cardiogenic shock. Potential indications for levosimendan. Levosimendan is a potent vasodilator through the opening of ATP-dependent potassium channels in vascular smooth muscles [ 17 , 18 ]. Levosimendan has a pharmacodynamic profile combining inotropic and vasodilating effects inodilator , and a nearly unique among inotropes myocardial protective effect. Patients with symptomatic advanced heart failure despite optimal medical treatment are sometimes unable to be discharged because they are dependent on dobutamine infusions that cannot be weaned off. Indeed, the use of adrenergic inotropes or phosphodiesterase inhibitors should be regarded as contraindicated in this situation as further activation of catecholamine receptors or their downstream molecular pathways might worsen the clinical status and prognosis of patients with Takotsubo syndrome and cardiogenic shock. No data suggests differences in outcome between dobutamine and levosimendan in septic shock patients. Moreover, patients who were assigned to receive levosimendan required more norepinephrine, were less likely to be weaned from mechanical ventilation, and had more atrial fibrillation. The benefit observed could be due to the effect of the drug on the pulmonary vasculature and the improvement in RV contractility or, alternatively, be secondary to the improvement in LV function resulting in less pulmonary congestion. However, despite an attractive rationale, only a few studies support the effectiveness of levosimendan to facilitate the weaning of VA ECMO and they are always retrospective [ 69 , 71 ]. The need for randomized studies in this topic is strongly supported by two recent recommendations of the American Heart Association and the Cochrane collaboration [ 48 , 50 ]. In an animal model of acute intoxication with propranolol, Leppikangas et al. The drug undergoes hepatic metabolism acetylation followed by renal excretion. However, levosimendan and its metabolite have also been shown to inhibit phosphodiesterase III [ 16 ], an action that may participate to the positive inotropic effect via the c-AMP pathway, but that might, in turn, increase myocardial oxygen consumption. The unique pharmacological properties of this drug raised a major interest among physicians in charge of patients with heart failure, both in the medical and the surgical environments. Although attractive, the idea of using levosimendan to treat right ventricular failure should be considered very carefully: the potential benefits resulting from pulmonary vasodilatation and RV contractility improvement might be outweighed by the decrease in systemic arterial pressure and the subsequent reduction in right coronary perfusion pressure. New trials are under way to confirm or refute the potential usefulness of levosimendan to facilitate weaning from veno-arterial ECMO, to treat cardiogenic shock due to left or right ventricular failure because the current evidence is mostly retrospective and requires confirmation with better-designed studies. Due to a very interesting pharmacological profile, levosimendan has raised a lot of interest in the field of heart failure management. The infusion of dobutamine produces a dose-dependent rise in cardiac output, mainly by increasing heart rate rather than stroke volume [ 27 ]. Finally, the very long half-life of levosimendan is a double-edged sword. However, many physicians still do not perceive the risk of complications associated with these drugs and keep using them routinely, sometimes despite a lack of evidence for their usefulness. The worsening in myocardial energy imbalance likely participates to the detrimental effects of the classical inotropic drugs, especially in situations of myocardial reperfusion injury [ 26 ]. Therefore, this inotropic effect does not generate a direct significant increase in myocardial oxygen consumption, since most of the myocardial energy expenditure is related to the diastolic uptake of calcium in the sarcoplasmic reticulum [ 14 , 15 ]. Very limited data exists regarding the effectiveness of repetitive infusions of levosimendan [ 37 , 38 , 39 , 40 , 41 ]. Experimentally, in septic rabbits, levosimendan yields a similar improvement in left ventricular systolic function, when compared to dobutamine or milrinone, but improves diastolic function to a greater extent [ 72 ]. Unlike dobutamine, levosimendan increases moderately myocardial oxygen consumption, does not alter diastolic function, and has less direct pro-arrhythmic effects [ 49 ]. Moreover, since the duration of VA ECMO is directly correlated to complications, the weaning of the device should be attempted as soon as possible. The most recent meta-analysis performed using a few studies with a high risk of bias, reports that, when compared to dobutamine, levosimendan did not affect short and long-term mortality, ischemic events, acute kidney injury, dysrhythmias, or hospital length of stay [ 50 ]. Levosimendan remains a potentially useful inodilator agent in a number of specific situations due to its unique pharmacological properties. Such patients are at high-risk of death and may be waiting for a heart transplantation or a long-term mechanical assist device or, in contrast, may not be eligible for these therapeutic options. In patients having a postoperative low cardiac output syndrome following cardiac surgery, a large multicenter RCT failed to show a benefit of levosimendan on mortality [ 9 ]. The most frequent adverse event associated with levosimendan administration is hypotension requiring norepinephrine infusion, although its prevalence was not significantly greater with respect to placebo [ 7 , 8 , 9 ] or dobutamine [ 3 ] in the largest RCTs published. The hypothesis to be tested is that the early use of levosimendan, by authorizing the discontinuation of dobutamine, would avoid the undesirable effects of catecholamines, accelerate the resolution of signs of low cardiac output, and facilitate myocardial recovery. Patients with decompensated heart failure requiring inotropic support and receiving beta-blockers represent the most widely accepted indication. Nevertheless, the longer half-life, as compared to catecholamines, may change the way clinicians manage side effects e. Consequently, if the failing left ventricle is unable to eject against the retrograde flow of the VA ECMO, it may dilate and the resulting congestion may lead to pulmonary edema. It has been associated with a variety of myocardial protective effects against ischemia preconditioning, postconditioning, anti-stunning, and anti-apoptotic effects that are related to the opening of the same channels within the mitochondria of cardiac myocytes [ 19 , 20 ], but the clinical evidence supporting these experimental findings is limited [ 21 ]. Levosimendan is also a potent vasodilator, which in the context of vasoplegic patients or in vasopressor-dependent patients might be associated to hypotension leading to increased vasopressor requirement. This exploratory finding is a strong incentive to re-evaluate the preoperative infusion of levosimendan prior to CABG surgery in patients with poor LVEF. Although dobutamine is currently the first-line drug used for patients in cardiogenic shock [ 65 , 66 ], the specific features of levosimendan are of interest in this situation [ 67 , 68 , 69 , 70 ]. There are, however, potential difficulties to use levosimendan in cardiogenic shock. Veno-arterial extra-corporeal membrane oxygenation VA ECMO is used to restore adequate perfusion to vital organs in patients suffering from refractory cardiogenic shock [ 64 ]. Unfortunately, all the large randomized controlled trials have failed to demonstrate a clear superiority of this drug over placebo, when used on top of usual catecholamines, in the populations that they have tested.{/INSERTKEYS}{/PARAGRAPH} This property is particularly interesting to wean the patient from catecholamines, but on the other hand, it may be difficult to rapidly reverse the vasodilation once the drug has been administered. In , the SURVIVE study, a large international multicenter randomized controlled trial RCT , comparing levosimendan with dobutamine in patients with decompensated heart failure failed to show a difference between the two drugs on mortality at day [ 3 ]. To date, there have been no randomized trials to define the optimal management of patients with suspected Takotsubo syndrome. The incidence of serious adverse events was not different between treatment and placebo groups, reflecting the safety of repetitive infusions of levosimendan. All these characteristics offer opportunities to provide an ideal therapeutic response to specific situations. To avoid this complication , low doses of positive inotropic drugs are commonly administered in order to maintain left ventricular ejection and avoid upstream congestion. In addition, exploratory findings in favor of levosimendan were also reported from subgroup analyses of the LIDO and SURVIVE studies, comparing patients receiving beta-blockers versus those not receiving these drugs [ 1 , 34 ]. This explains an increased contractility which is not associated with a raise in intracytoplasmic calcium concentration [ 13 ]. This is supported by a few experimental and clinical studies. Takotsubo syndrome is a form of acute myocardial stunning in which catecholamines appear to have a central role in the pathophysiology, as there is no occlusive coronary artery disease to explain the pattern of temporary LV dysfunction observed. However, it is important to mention that although mortality and readmission rates decreased with levosimendan, they remained much higher in comparison to those observed when heart transplantation or mechanical circulatory assist devices could be carried out. These trials also found a greater proportion of patients receiving levosimendan developing atrial fibrillation, but the difference with the comparator group reached statistical significance only in medical heart failure and septic shock patients [ 3 , 24 ]. This approach is mainly supported by encouraging case reports and the pathophysiological rationale. Patients receiving beta-blockers BB in an acute or chronic setting have an altered beta-adrenergic receptor function and are therefore unlikely to respond optimally to catecholamines. Two of these studies addressed the question of the effectiveness of levosimendan as a prophylactic treatment administration at the time of anesthesia induction: pharmacological preconditioning for the prevention of postoperative low cardiac output syndrome LCOS in patients with poor left ventricular ejection fraction LVEF undergoing on-pump cardiac surgery [ 7 , 8 ], and one study evaluated its effectiveness in reducing mortality at day 30 in patients developing post-bypass LCOS [ 9 ]. A recent meta-analysis confirmed the potential usefulness of this approach, despite the heterogeneity of the existing studies [ 42 ]. But in , three randomized controlled trials comparing levosimendan with placebo on top of standard care in cardiac surgical patients failed to reach statistical significance. Levosimendan was developed in the early s in Finland and became available for prescription starting in It has been used since then in more than 60 countries. Similarly, the use of catecholamines or phosphodiesterase III inhibitors in patients with acute heart failure is associated with an increase in mortality in the medical setting [ 30 , 31 ]. Levosimendan is often responsible for systemic arterial hypotension resulting in increased requirements for vasopressors, but also an increase in cardiac index and cardiac power, a decrease in left ventricular pressure, and an increase in SVO 2 [ 51 ]. The two large trials evaluating the prophylactic administration of levosimendan pharmacological preconditioning in cardiac surgical patients with poor left ventricular ejection fraction could not show a significant reduction in their composite endpoints reflecting low cardiac output syndrome with respect to placebo. The catecholamines especially dobutamine are the most frequently used during the perioperative period. {PARAGRAPH}{INSERTKEYS}Metrics details. The improvement in the 6-min walk test primary outcome was not significant, and the hazard ratio for the survival free of events was 0. Major adverse cardiac events ventricular arrhythmias and myocardial infarction , stroke, renal replacement therapy, and all-cause mortality short- and long-term increase when these agents are used during the perioperative period [ 28 , 29 ]. In addition, we have no clue regarding the ideal dosing and timing to initiate levosimendan infusion in patients suffering from cardiogenic shock and treated by VA ECMO. However, VA ECMO with femoral artery cannulation provokes an increase in left ventricular afterload while residual blood flow from the pulmonary and bronchial circulations keep flowing towards the left ventricle. In such situations, repetitive infusions of levosimendan may offer the advantage of a prolonged inotropic effect with the possibility of improving the clinical symptomatology and allowing hospital discharge.