Drug Review: Levosimendan




Introduction
Levosimendan is a novel positive inotropic agent belonging  to the category of  “inodilators”, which increases cardiac contractility along with vasodilatatory action . It improves myocardial contractility by its calcium-sensitizing action, without increasing myocardial oxygen demand and causes vasodilatation by opening ATP-sensitive potassium channels. It also has potentially anti-ischemic effects by opening mitochondrial adenosine triphosphate (ATP)-sensitive potassium channels.
Levosimendan helps in de-escalating catecholamine infusions, by its non-β-adrenergic actions, which decreases the tolerance to these drugs.

Mechanism of Action

Levosimendan is a pyridazole dinitrate derivative. It is a weak acid with a two basic mode of action.  One, it exerts positive inotropic effects by binding calcium dependent to troponin C during systole only.

Levosimendan, prolongs the cross-bridging time of actin-myosin filaments and acts on troponin C only when intracellular calcium levels are high, i.e., during systole. During diastole, when intracellular calcium levels are low, it has no effect on troponin C. Thus it improves systolic and diastolic myocardial function.

Drugs like digoxin, dobutamine, amrinone and milrinone, act by facilitating calcium binding to the protein troponin-C of the striated cardiac muscle, thereby activating the cardiac contractile proteins. The force of the heart’s contraction is thus dependent  on the amount of free calcium in the myocyte cytoplasm  during systole.

Cardiac troponin C can bind up to three calcium ions. The increasing calcium influx into the myoplasm results in excess of calcium in the sarcoplasmic reticulum and subsequent arrhythmias.

Unlike the catecholamines and the phosphodiesterase III inhibitors, levosimendan does not increase the level of intra-cardiomyocyte calcium and thus does not result in undesirable side effects like increased myocyte oxygen consumption and arrhythmias.

Secondly, Levosimendan is a potent vasodilator of arteries, veins and coronary vasculature. This effect is achieved by opening of ATP sensitive K channels in vascular smooth muscle cells, cardiac myocytes, and in mitochondria.

PK and PD

The drug is 95–98% is protein bound, mainly to albumin. Approximately 5% of a dose is converted in the intestines to a highly active metabolite, OR-1896. The elimination half-life of OR-1896 is 75–80 h (compared to 1 hour elimination half-life for levosimendan itself ).

This metabolite reaches a peak plasma concentration about 2- 5 days after the termination of a 24 hour infusion and exhibits hemodynamic effects similar to those of levosimendan. The long half-life of the active metabolite, OR-1896, ensure these effects last for up to 7 to 9 days after discontinuation of a 24-hour infusion of levosimendan.

Caution

Elimination of unchanged drug and its metabolites was significantly decreased in patients with mild-tomoderate renal failure, indicating a requirement for caution in these patients . Elimination of the active metabolite is prolonged in patients with liver and renal disease failure thus levosimendan should be used with caution here.

Levosimendan should be used with caution when used with other intravenous vasoactive drugs, like milrinone, due to the increased risk of hypotension. No pharmacokinetic interactions have been observed in patients receiving digoxin and levosimendan infusion.

Levosimendan is usually well tolerated and no increase in heart rate is reported in dose up to 1mg (i.e. 12mcg/kg). The drug has been shown to increase the cardiac output and ejection fraction, dose dependently. The increase in ejection fraction at low doses is due to an increase in stroke volume. The hemodynamic efficacy was not associated with an increase in myocardial oxygen consumption.

Dosage

The usual dosage of intravenous levosimendan is 6-12mcg/kg loading dose over 10 minutes followed by a continuous infusion at 0.05-0.2mcg/kg/min in 5% dextrose. The dose and duration of infusion should be individualized. If the patient develops hypotension or tachycardia the dose can be reduced to 0.05mcg/kg/min.

If the dose is tolerated and an increased hemodynamic response is required, the infusion rate can be increased to a max of 0.2mcg/kg/min. Infusions longer than 24 hours are not recommended in view of side effects.

Monitoring

While the patient is receiving continuous infusion of levosimendan, heart rate, ECG, blood pressure and urine
output should be closely monitored. Invasive monitoring has been recommended during continuous infusion.
Non-invasive monitoring is required for 72 hours after discontinuing the infusion. levosimendan is also available as oral preparation.

Side Effects and Contraindications:

The adverse effects are dose related and due to its vasodilator effect. Headache, dizziness, hypotension, and tachycardia are reported along with GI symptomps like nausea, vomiting, constipation and diarrhea. Rarely arrhythmias have been reported.

Other adverse effects reported with levosimendan include insomnia, decreased hemoglobin and hypokalemia. Levosimendan is contraindicated in patients with mechanical obstruction affecting ventricular filling/ outflow; severe hypotension and tachycardia, severe renal, hepatic failure; or history of Torsades de Pointes.

Evidence:

Pediatr Crit Care Med 2006:
A small study, 15 children, Retrospective cohort design published in March 2017 in PCCM demonstrated that levosimendan, can be safely  administered to infants and children with severe heart failure. The study also proved that levosimendan allowed substantial reductions in catecholamine  infusions and produced improvement in myocardial performance.

LIDO study (Levosimendan Infusion versus Dobutamine) study designed to compare the clinical and hemodynamic effects of levosimendan and dobutamine. The study showed that levosimendan improved hemodynamic performance more effectively than dobutamine. The benefit was accompanied by lower mortality in the levosimendan group.

RUSSLAN study
The study concluded that levosimendan at doses of 0.1-0.2mcg/kg/min did not induce hypotension or ischemia and reduced the risk of worsening heart failure and death in patients with left ventricular failure complicating acute myocardial infarction.

CASINO study 
(Calcium sensitizer or inotrope or none in low-output heart failure)
Survival benefit as compared to dobutamine and placebo. The mortality benefit in favor of  the levosimendan group.

The REVIVE-II
The study revealed that on the 5th day, more than 33% patients in the levosimendan group had improved and fewer than 30% in the levosimendan group worsened compared to the patients in the control group. The study however failed to demonstrate a survival benefit.

SURVIVE
survival of patients with acute heart failure in need of intravenous inotropic support) study.
This was the first study, which used mortality as an end point in evaluating the efficacy.  The study failed to demonstrate mortality benefits with levosimendan and also raised concerns over the apparent increased incidence of deleterious side effects.

References
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  10. Garratt C, Packer M, Colucci W, et al. Development of a comprehensive new endpoint for the evaluation of new treatments for acute decompensated heart failure: results with levosimendan in the REVIVE I study. Crit Care 2004; 8 (Suppl 1): P89.
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