Levosimendan
Levosimendan is an inodilator, meaning it provides inotropy with vasodilation. It has been licensed in Europe since the 2000s for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate.[101]Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use. J Cardiovasc Pharmacol. 2020 Jul;76(1):4-22.
https://www.doi.org/10.1097/FJC.0000000000000859
http://www.ncbi.nlm.nih.gov/pubmed/32639325?tool=bestpractice.com
It is not approved for use in the US but remains under active clinical investigation.[101]Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use. J Cardiovasc Pharmacol. 2020 Jul;76(1):4-22.
https://www.doi.org/10.1097/FJC.0000000000000859
http://www.ncbi.nlm.nih.gov/pubmed/32639325?tool=bestpractice.com
Randomised controlled trials in adults have shown that levosimendan improves clinical outcomes and is generally well tolerated.[102]Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013 Apr;1(2):103-11.
https://www.doi.org/10.1016/j.jchf.2012.12.004
http://www.ncbi.nlm.nih.gov/pubmed/24621834?tool=bestpractice.com
[103]Moiseyev VS, Põder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J. 2002 Sep;23(18):1422-32.
https://www.doi.org/10.1053/euhj.2001.3158
http://www.ncbi.nlm.nih.gov/pubmed/12208222?tool=bestpractice.com
Evidence of levosimendan improving mortality versus other inodilators such as dobutamine remains conflicting.[104]Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002 Jul 20;360(9328):196-202.
http://www.ncbi.nlm.nih.gov/pubmed/12133653?tool=bestpractice.com
[105]Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007 May 2;297(17):1883-91.
https://www.doi.org/10.1001/jama.297.17.1883
http://www.ncbi.nlm.nih.gov/pubmed/17473298?tool=bestpractice.com
Levosimendan has also demonstrated efficacy in the paediatric population with an acceptable safety profile. Results from a single-centre retrospective study suggested that levosimendan may reduce the need for mechanical circulatory support in children undergoing cardiac surgery or with decompensated heart failure.[106]Suominen PK. Single-center experience with levosimendan in children undergoing cardiac surgery and in children with decompensated heart failure. BMC Anesthesiol. 2011 Oct 5;11:18.
https://www.doi.org/10.1186/1471-2253-11-18
http://www.ncbi.nlm.nih.gov/pubmed/21974814?tool=bestpractice.com
Other studies have shown that levosimendan has similar efficacy to or is superior to milrinone in neonates and children.[107]Pellicer A, Riera J, Lopez-Ortego P, et al. Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery. Pediatr Res. 2013 Jan;73(1):95-103.
https://www.doi.org/10.1038/pr.2012.154
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[108]Momeni M, Rubay J, Matta A, et al. Levosimendan in congenital cardiac surgery: a randomized, double-blind clinical trial. J Cardiothorac Vasc Anesth. 2011 Jun;25(3):419-24.
http://www.ncbi.nlm.nih.gov/pubmed/20829069?tool=bestpractice.com
Despite these findings, robust clinical trial evidence for levosimendan in paediatric patients remains lacking.[101]Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use. J Cardiovasc Pharmacol. 2020 Jul;76(1):4-22.
https://www.doi.org/10.1097/FJC.0000000000000859
http://www.ncbi.nlm.nih.gov/pubmed/32639325?tool=bestpractice.com
Levosimendan is being investigated for other indications including pulmonary hypertension and septic shock.[109]Conti N, Gatti M, Raschi E, et al. Evidence and current use of levosimendan in the treatment of heart failure: filling the gap. Drug Des Devel Ther. 2021;15:3391-409.
https://www.doi.org/10.2147/DDDT.S295214
http://www.ncbi.nlm.nih.gov/pubmed/34376973?tool=bestpractice.com
It failed to demonstrate superiority to placebo in patients with amyotrophic lateral sclerosis.[110]Cudkowicz M, Genge A, Maragakis N, et al. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2021 Oct;20(10):821-31.
http://www.ncbi.nlm.nih.gov/pubmed/34536404?tool=bestpractice.com