Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use

Abstract

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

FIGURE 1.

Early molecular model of the levosimendan–cTnC complex: The dihydropyridazinone ring of levosimendan is enclosed within a hydrophobic cleft formed by the amino acid residues Phe²⁰, Ala²², Ala²³, Phe²⁴, Val²⁸, and Phe⁷⁷, and the phenyl ring of levosimendan is aligned to Met⁸¹, Cys⁸⁴, and Met⁸⁵. Source: Pollesello et al Reproduced with permission from the American Society for Biochemistry and Molecular Biology. cTnC = cardiac troponin C.

FIGURE 2.

Mode of actions and pharmacologic effects of levosimendan: The mechanisms of action in the blue boxes contribute to the cardiovascular effects of the drug. Dotted lines mark pathways that are still not fully elucidated. EC₅₀, half maximal effective concentration; K_ATP, adenosine triphosphate–dependent potassium channels; PDE III, IV, phosphodiesterase isoforms in cardiac tissue. Adapted from: Al-Chalabi et al Used with permission from Wolters Kluwer Health.

FIGURE 3.

Change in CO and PCWP: Change from baseline at the conclusion of a 24-hour infusion of levosimendan (given as a 10-minute bolus of 6–24 µg/kg, then an infusion of 0.05–0.6 µg/kg/min), placebo, or dobutamine (6 µg/kg/min) in patients with stable HF. DOB, dobutamine; PBO, placebo. Data from: Nieminen et al.

FIGURE 4.

Pharmacokinetics of levosimendan: A, Differences in the area under the receiver operating characteristics curve (AUC) for changes in Doppler echocardiography–derived PCWP and CO in patients with acute HF treated with levosimendan or placebo (n = 11 in both groups) for 24 hours. Due to of the formation of the active metabolite, the hemodynamic effects are maintained several days after stopping levosimendan infusion. B, Median change in N-terminal prohormone atrial natriuretic peptide (NT-proANP) over 14 days in patients with HF receiving levosimendan or placebo (n = 11 in both groups) for 24 hours. Source: Lilleberg et al Reproduced with permission from John Wiley and Sons.

FIGURE 5.

Effect of levosimendan on survival in the regulatory clinical trials: Meta-analysis of the clinical trials considered by regulatory authorities for the introduction of levosimendan. *Pooled statistic calculated using the Cochran–Mantel–Haenszel test, controlling for study. Source: Pollesello et al. Reproduced with permission from Elsevier.

FIGURE 6.

Results of 64 meta-analyses of levosimendan clinical trials. Refer to the supplementary material for details of the individual meta-analyses.