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Mode of action
Levosimendan is a calcium sensitiser – it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.
Some of the Phase III studies in the extensive clinical program were the trials LIDO (200 patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and SURVIVE (1350). In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind studies.
In the SURVIVE study, despite a reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days. However, the drug was proven to be superior to dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they are hospitalized with acute decompensations.
In a meta-analysis of randomized controlled studies by Landoni et al. levosimendan is shown to reduce mortality and hospitalization.
The Orion Corporation originally developed levosimendan and applied for a new drug application in 1998 in the U.S. However the Food and Drug Administration (FDA) requested further trials be conducted and Orion withdrew the application in November 1999. Orion succeeded at obtaining approval to market the drug in Sweden in 2000. Since then around 55 other countries worldwide have approved the drug but it remains non licensed in the US, where it is currently under development for reduction in morbidity and mortality of cardiac surgery patients at risk of low cardiac output syndrome.
The use of levosimendan is contraindicated in patients with: moderate-to-severe renal impairment, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension and tachycardia, and/or history of torsades de pointes (Rossi, 2006).
Common adverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea (Rossi, 2006).
Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution 500ml to make 0.025mcg/kg of infusion . The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV)
- Papp, Z; Édes I, Fruhwald S, De Hert SG, Salmenperä M, Leppikangas H, Mebazaa A, Landoni G, Grossini E, Caimmi P, Morelli A, Guarracino F, Schwinger RH, Meyer S, Algotsson L, Wikström BG, Jörgensen K, Filippatos G, Parissis JT, González MJ, Parkhomenko A, Yilmaz MB, Kivikko M, Pollesello P, Follath F (2012). "Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan". Int J Cardiol 159 (2): 82–7. PMID 21784540. doi:10.1016/j.ijcard.2011.07.022.
- Nieminen, MS; Fruhwald S; Heunks LM; Suominen PK; Gordon AC; Kivikko M; Pollesello P (2013). "Levosimendan: current data, clinical use and future development". Heart Lung Vessel 5 (4): 227–45. PMC 3868185. PMID 24364017.
- Mebazaa, A; Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Põder P, Kivikko M, for the SURVIVE Investigators (2007). "Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial". JAMA 297 (17): 1883–91. PMID 17473298. doi:10.1001/jama.297.17.1883.
- Mebazaa, A; Nieminen MS; Filippatos GS; Cleland JG; Salon JE; Thakkar R; Padley RJ; Huang B; Cohen-Solal A (2009). "Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE". Eur J Heart Fail 11 (3): 304–11. PMC 2645051. PMID 19158152. doi:10.1093/eurjhf/hfn045.
- Landoni, G; Biondi-Zoccai G; Greco M; Greco T; Bignami E; Morelli A; Guarracino F; Zangrillo A (2012). "Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies". Crit Care Med 40 (2): 634–46. PMID 21963578. doi:10.1097/CCM.0b013e318232962a.
- Orion. "Simdax (levosimendan) Fact Sheet" (PDF). Orion. Retrieved 13 February 2014.
- OxygenBiotherapeutics. "Product Pipeline - Levosimendan development". OxygenBiotherapeutics. Retrieved 13 February 2014.
- Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.