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Levosimendan

A Review of its Use in the Management of Acute Decompensated Heart Failure

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Summary

Abstract

Levosimendan (Simdax®) is a calcium-sensitising drug that stabilises the troponin molecule in cardiac muscle, thus prolonging its effects on contractile proteins, with concomitant vasodilating properties. Intravenous levosimendan (12–24 μg/ kg loading dose followed by 0.1–0.2 μg/kg/min for 24 hours, adjusted for response and tolerability) is approved for the short-term treatment of acute severe decompensated heart failure.

Cardiac output increased by about 30% and pulmonary capillary wedge pressure and systemic vascular resistance decreased by about 17–29% in patients with decompensated heart failure receiving intravenous levosimendan.

In large, well controlled trials in patients with decompensated heart failure, intravenous levosimendan was significantly more effective than placebo or dobutamine for overall haemodynamic response rate (primary endpoint). Significant benefits were also seen for mortality (versus placebo or dobutamine) and for the combined risk of worsening heart failure or death (versus dobutamine). Improvements in key symptoms (dyspnoea and fatigue) have not been consistently demonstrated. Hospitalisation costs were similar for levosimendan and dobutamine; the total incremental (hospitalisation plus drug) cost per life-year saved (extrapolated to 3 years) for levosimendan relative to dobutamine was estimated at €3205 (year of costing 2000).

Levosimendan is generally well tolerated, with an adverse event profile at recommended dosages similar to that in patients receiving placebo. Cardiac rate/ rhythm disorders and headache were the most common events. At higher dosages, patients receiving levosimendan had higher rates of sinus tachycardia than those in placebo recipients. More patients receiving dobutamine than those receiving levosimendan experienced angina pectoris/chest pain/myocardial ischaemia or rate/rhythm disorders.

Conclusion: Intravenous levosimendan is an effective calcium-sensitising drug with vasodilatory and inotropic effects, and superior efficacy/tolerability to those of intravenous dobutamine in patients with acute decompensated heart failure. It may be associated with reduced mortality compared with both placebo and dobutamine. Levosimendan is generally well tolerated and may have less potential for cardiac rate/rhythm disorders than dobutamine. While evidence from well designed trials confirming the improved mortality over dobutamine and investigating haemodynamic efficacy and mortality versus other positive inotropes is required, intravenous levosimendan appears to be a useful addition to the treatment options for acute decompensated heart failure in patients with low cardiac output.

Pharmacodynamic Properties

Levosimendan, the active enantiomer of the pyridazinone-dinitrile derivative simendan, is a calcium-sensitising drug that binds to the calcium-saturated N-terminal domain of troponin-C in cardiac muscle. This results in stabilisation of the troponin molecule with subsequent prolongation of its effects on the contractile proteins. The pharmacodynamic vasodilating effects of levosimendan may also contribute to its mechanism of action. Phosphodiesterase type III inhibition appears to be more apparent at higher levosimendan concentrations. The role of the active metabolite OR-1896 has not yet been fully characterised.

Preclinical studies demonstrated the vasodilating and positive inotropic effects of levosimendan, which occurred without changes in cardiac relaxation. Clinical studies in healthy volunteers and in patients with decompensated heart failure confirmed the positive inotropic effects of intravenous levosimendan 6–24 μg/kg bolus doses followed by 0.1–0.4 μg/kg/min for 1–24 hours. Cardiac output was increased by about 30% in patients with decompensated heart failure, and pulmonary capillary wedge pressure (PCWP) was dose-dependently decreased by 17–28%. Intravenous levosimendan also increased stroke volume (by 21% and 28%), and decreased systemic vascular resistance (by 21–29%) in patients with decompensated heart failure. The haemodynamic effects of intravenous levosimendan were sustained for 24 hours after withdrawal of the drug.

While cardiac efficiency (the ratio of oxygen consumption to useful cardiac work) is improved with levosimendan in patients with heart failure, oxygen consumption appears not to be significantly altered (in contrast to increased oxygen consumption accompanying the improved efficiency in dobutamine recipients).

Treatment with intravenous levosimendan resulted in a mean increase in heart rate of 2–6 beats/min (3–8%) in patients with decompensated heart failure (versus an increase of 4 beats/min [5%] with dobutamine). Animal studies showed no increased likelihood of arrhythmias. The mean heart-rate-corrected QT (QTc) interval was increased (by ≤53ms) in both healthy volunteers and patients with decompensated heart failure receiving intravenous levosimendan, but the uncorrected QT interval was not changed in patients with normal cardiac function.

Concomitant intravenous levosimendan in patients with heart failure already receiving β-adrenoceptor antagonist (β-blocker) therapy tended to improve the haemodynamic effects of levosimendan, in contrast to attenuation of the changes in patients receiving dobutamine and β-blockers.

Pharmacokinetic Properties

Levosimendan has linear pharmacokinetics, with area under the plasma concentration-time curve and maximum plasma concentrations increasing dose-proportionally. The drug is rapidly distributed to a small volume (distribution half-life 0.1–0.3 hours); 95–98% is protein bound.

Levosimendan is extensively metabolised, with one known pharmacodynamically active metabolite (OR-1896). Plasma concentrations of OR-1896 can take up to 5 days to reach peak values, which remain substantially lower than those of the parent compound.

The elimination half-lives of unchanged levosimendan and OR-1896 were 0.6–1.4 hours and 77–81 hours, respectively. Elimination of unchanged drug plus metabolites, but not of levosimendan alone, was significantly decreased in patients with mild-to-moderate renal failure, indicating a requirement for caution in these patients.

Concomitant administration of itraconazole, ethanol or warfarin had no effect on levosimendan pharmacokinetics. Levosimendan had no clinically significant effects on the pharmacokinetics of warfarin or ethanol.

Therapeutic Efficacy

Three pivotal, large, randomised, double-blind trials have investigated the efficacy of intravenous levosimendan 6–24 μg/kg boluses followed by 0.1–0.4 μg/kg/ min for 6–24 hours in 146–504 patients with decompensated heart failure. Intravenous levosimendan at these dosages was more haemodynamically effective than placebo (6-hour administration) or intravenous dobutamine 5–10 μg/kg/ min (24-hour administration). Haemodynamic response (the primary efficacy variable in two of these trials) was defined as a ≥30% increase in cardiac output and a ≥25% decrease in PCWP at 24 hours (response rate with levosimendan 28% vs 15% with dobutamine; p < 0.05), or an increase in stroke volume of ≥25% (response rate 56% vs 4% with placebo; p < 0.001) or decrease in PCWP of ≥25% (response rate 43% vs 15% with placebo; p < 0.001) at 6 hours.

A significant improvement in dyspnoea symptoms (a secondary endpoint) was seen in levosimendan recipients (p = 0.001 vs placebo) in one of the two placebo-controlled trials, but neither trial found a difference in the incidence of fatigue. A worst-rank analysis (including patients who died, developed worsening heart failure or received new therapy for heart failure) of the second trial results, however, favoured levosimendan for both symptoms. There were no significant differences in the incidence of improved dyspnoea or fatigue between intravenous levosimendan (68% and 63%) and intravenous dobutamine (59% and 47%) recipients.

Two of the trials assessed the effects of levosimendan versus dobutamine or placebo on worsening heart failure or death (as secondary endpoints). Mortality with levosimendan was significantly lower than with dobutamine (at 31 [8% vs 17%] and 180 [26% vs 38%] days; both p < 0.05) or placebo (at 14 days [12% vs 20%; p < 0.05] but not at 180 days [23% vs 31%]). Levosimendan recipients also had significantly more days alive and out of hospital during the first 180 days than dobutamine recipients, and a significantly lower combined risk of death and worsening heart failure than placebo recipients during the infusion and for 24 hours after. Morbidity and mortality results were not dose-related.

Duration of hospitalisation and costs were similar in levosimendan and dobutamine recipients. The incremental cost of levosimendan per life-year saved (extrapolated to 3 years) relative to dobutamine was estimated as €3205 (year of costing 2000).

Tolerability

Levosimendan is generally well tolerated. Similar numbers of patients receiving levosimendan and placebo reported adverse events during phase III trials, and the incidence of specific events was also similar at recommended dosages. The most common adverse events were cardiac rate/rhythm disorders (10%) and headache (up to 14%). The proportion of patients experiencing clinically significant hypotension and/or ischaemia (the primary endpoint in one pivotal trial) was similar in levosimendan (pooled dosage groups) and placebo (13% and 11%) recipients. At higher dosage levels, sinus tachycardia occurred more often with levosimendan (5% vs 2%; p < 0.05 vs placebo).

Significantly more patients receiving dobutamine than those receiving levosimendan experienced angina pectoris/chest pain/myocardial ischaemia or rate/rhythm disorders. Changes in some haematological/biochemical laboratory parameters were significantly greater with levosimendan than with dobutamine.

Dosage and Administration

Intravenous levosimendan is approved in several European countries for the short-term treatment of acute decompensated severe heart failure in adults. The recommended loading dose is 12–24 μg/kg infused over 10 minutes, followed by 0.1–0.2 μg/kg/min for 24 hours. The rate of infusion should be adjusted according to response and tolerability.

ECG, blood pressure, heart rate and urine output should be monitored during treatment. Levosimendan is contraindicated in patients with conditions affecting ventricular filling/outflow, severe hypotension, tachycardia, severe renal or hepatic impairment, or torsade de pointes. It should be used with caution in patients with mild-to-moderate renal or hepatic impairment, ischaemic cardiovascular disease with anaemia, hypotension, tachycardia, atrial fibrillation, coronary ischaemia or long QTc intervals.

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  1. Use of a tradename is for identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis Data Information BV, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Carmen A. Innes & Antona J. Wagstaff

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  1. Carmen A. Innes
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  2. Antona J. Wagstaff
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Correspondence to Antona J. Wagstaff.

Additional information

Various sections of the manuscript reviewed by: J. Du Toit, Department of Medical Physiology and Biochemistry, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa; M. Endoh, Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan; S. Katz, Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York, New York, USA; L. Lehtonen, Department of Clinical Pharmacology, Helsinki University Central Hospital, Helsinki, Finland; G.Y.H. Lip, University Department of Medicine, Haemostasis Thrombosis and Vascular Biology Unit, City Hospital, Birmingham, UK; P. Tassani, Institut für Anaesthesiologie, Deutsches Herzzentrum München, Munich, Germany; L. Toivonen, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

Data Selection

Sources: Medical literature published in any language since 1980 on levosimendan, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline, EMBASE and AdisBase search terms were ‘levosimendan’ or ‘OR-1259’. Searches were last updated 4 Nov 2003.

Selection: Studies in patients with acute decompensated heart failure who received intravenous levosimendan. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: levosimendan, acute decompensated heart failure, intravenous, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Innes, C.A., Wagstaff, A.J. Levosimendan. Drugs 63, 2651–2671 (2003). https://doi.org/10.2165/00003495-200363230-00009

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