teaser
Eero Mervaala, MD, PhD
Professor, Institute of Biomedicine
University of Helsinki
Finland
Jouko Levijoki, Msc (Pharma)
Oncology and Critical Care, Research
Orion Corporation Orion Pharma Ltd
Espoo, Finland
Martti Ovaska, PhD
Medicinal Chemistry, Research
Orion Corporation Orion Pharma Ltd
Espoo, Finland
Heart failure is a condition in which the heart no longer provides adequate blood supply to meet the body’s demands. Failure in blood supply leads to typical symptoms, such as breathlessness at rest or on exercise, fatigue, tiredness, and signs of fluid retention. Heart failure is an enormous medical and societal burden. In Europe there are at least 15 million patients with heart failure. Despite marked improvements in the prevention and treatment of heart failure, the prognosis of heart failure has remained poor; about 50% of patients suffering from heart failure die within five years of diagnosis, and 40% of patients admitted to hospital with heart failure are dead or readmitted within one year.
Intravenous inotropic drugs are widely used in the short term to treat the haemodynamic disturbances of acute heart failure, defined as a rapid onset or change in the signs and symptoms of heart failure, resulting in the need for urgent therapy. Classical inotropic agents, such as sympathomimetic amines, having β-adrenergic activity (for example, dopamine, dobutamine) and phosphodiesterase (PDE) inhibitors (milrinone and enoximone) acting via the β-adrenergic–cAMP–protein kinase A signalling pathway, increase the intracellular Ca2+ transiently and therefore force of contraction through an increase in the Ca2+ saturation of cardiac troponin C. However, myocardial force augmentation due to increased intracellular Ca2+ concentration is associated with a substantial increase in myocardial oxygen demand, and such inotropic agents can potentially induce ischaemia, arrhythmias and even death. In fact, data from individual studies and meta-analyses suggest that the use of intravenous inotropes may be associated with a worsened long-term prognosis, despite some improvements in symptoms.Problems associated with existing intravenous inotropic agents are summarised in Table 1. Levosimendan is a novel calcium sensitiser developed for intravenous short-term treatment of acutely decompensated severe chronic heart failure. Levosimendan is proven to be effective and well tolerated in large-scale clinical studies of hospitalised patients with heart failure. About 440,000 patients worldwide have been treated with levosimendan.
Mode of action
Levosimendan is a positive inotropic compound with vasodilatory properties. The mechanism of action for levosimendan involves three clinically relevant features that are specific to the cardiovascular system: 1) positive inotropy via calcium sensitisation of the cardiac troponin C, 2) vasodilation via opening of vascular adenosine triphosphate (ATP)-sensitive K+ channels and 3) cardioprotection via mitochondrial ATP-sensitive K+ channel opening, energy sparing and neurohumoral modulation. Levosimendan is also a highly selective inhibitor of the PDE III isoform. Whether PDE III inhibition contributes to the inotropic and vasodilatory actions of levosimendan remains unclear. The cardiovascular effects of levosimendan are summarised in Figure 1.
Calcium sensitisation
Levosimendan increases cardiac contractility by sensitising the contractile proteins to calcium. Levosimendan binds to the calcium-saturated N-terminal domain of troponin C in cardiac muscle in a calcium-dependent manner and stabilises the troponin molecule with subsequent prolongation of its effect on the contractile proteins.Binding of levosimendan to the N-terminal domain of cardiac troponin C is illustrated in Figure 2. Stabilisation of the troponin C molecule results in an increased amount of actin-myosin interactions and, therefore, increased force of contraction. Levosimendan binds to troponin C in a calcium-dependent manner, especially in the beginning of systole, and detaches in diastole, increasing the force of contraction without shortening the relaxation time or impairing diastolic function. The positive inotropic effect of levosimendan has been demonstrated in several in vitro experiments carried out in, for example, skin fibres and isolated hearts. As with in vitro studies, levosimendan induces dose-dependent positive inotropy after intravenous and oral administration in normal and diseased conditions like acute and chronic heart failure or sepsis. The unique feature of levosimendan is that, despite an increased positive inotropic effect, it does not increase myocardial oxygen consumption. Levosimendan is a highly selective inhibitor of the PDE III isoform and, at least in higher concentrations, levosimendan causes accumulation of cyclic adenosine monophosphate (cAMP) with resultant increased influx of calcium into the myocyte. However, it is suggested that, at lower doses, PDE III inhibition does not make a substantial contribution to the inotropic or vasodilator effects of levosimendan.
Vasodilation
Levosimendan has a pronounced vasodilatory effect through opening of the ATP-sensitive K+ channels and consequent hyperpolarisation of the vascular smooth muscle cells. This has been shown in arterial and venous preparations, as well as in coronary arteries.The composition of vascular K+ channels mediating the vasodilatory effects of levosimendan may depend on vascular type and diameter. Although levosimendan preferentially stimulates ATP-sensitive K+ channels, other types of K+ channels (voltage-gated K+ channels, Ca2+-activated K+ channels) may also be involved. At high concentrations of levosimendan, accumulation of cAMP due to PDE III inhibition may possibly participate in vasorelaxation.
Cardioprotection
The use of levosimendan is associated with reduction in preload and afterload as well as with increased coronary blood flow.Furthermore, data from clinical and experimental studies suggest that levosimendan ameliorates neurohumoral activation, oxidative stress, pathological cardiac remodelling and cardiomyocyte apoptosis. It is believed that the cardioprotective effects of levosimendan are largely mediated via the opening of mitochondrial KATP channels.
Pharmacokinetics
Levosimendan shows linear pharmacokinetics in a therapeutic dose of 0.05-0.2μg/kg/min. It has a volume of distribution of 0.2L/kg. Levosimendan binds strongly (97-98%) to plasma proteins, mainly albumin, and has a clearance of 3.0mL/min/kg. Levosimendan is rapidly metabolised by conjugation to cyclic or N-acetylated cysteinylglycine and cysteine conjugates, with an elimination half-life of approximately 1 hour. Levosimendan is mainly excreted as metabolites in urine (54%) and faeces (44%), whereas only a small proportion (less than 0.05%) of the levosimendan dose is excreted unchanged in urine. The pharmacokinetics of levosimendan are not affected by age, ethnic origin or gender. However, volume of distribution and total clearance are dependent on weight. About 5% of the total dose of levosimendan is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855), which is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The elimination half-lives of the metabolites are 70 to 80 hours. OR-1896 is the active metabolite. Based on in vitro studies, OR-1855 is 25 times less potent as a positive inotropic compound compared to levosimendan; however, in vivo studies have revealed that OR-1855 is practically inactive. In patients, protein binding values for OR-1855 and OR-1896 are 39% and 42% respectively. After discontinuation of a 24-hour levosimendan infusion, peak plasma concentrations of the main circulating metabolites are reached after about 2 days and their haemodynamic effects last up to seven to nine days. OR-1855 and OR-1896 undergo conjugation or renal filtration and are excreted predominantly in urine.
In subjects with mild to moderate renal impairment, the pharmacokinetics of levosimendan are unaltered. In severe renal failure and end-stage renal disease patients undergoing haemodialysis, the elimination half-life of the levosimendan metabolites is prolonged 1.5-fold, and their area-under-the-curve and plasma peak concentration is increased two-fold. The dose of levosimendan should therefore be reduced when the drug is used for the treatment of congestive heart failure in patients with severe renal insufficiency.
In subjects with moderate hepatic impairment, the pharmacokinetics of levosimendan are unaltered, whereas the elimination of the metabolites is prolonged. However, since the maximum duration of levosimendan infusion is only 24 hours, no dosing adjustments are required in patients with impaired hepatic function.
The use of levosimendan is not recommended in children according to the Summary of Product Characteristics (SmPC). However, limited data indicate that the pharmacokinetics of levosimendan after a single dose in children (aged 3 months to 6 years) are similar to those in adults. The pharmacokinetics of the active metabolite OR-1896 have not been investigated in children.
Levosimendan can be used concomitantly with beta-blockers, digoxin, itraconazole, warfarin, felodipine, isosorbide mononitrate and captopril. Clinical interaction studies confirmed that levosimendan does not inhibit CYP3A4 or CYP2C9. In addition, metabolism of levosimendan is not affected by CYP3A inhibitors.
Clinical implications
According to the European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure (2008), inotropic agents should only be administered in patients with low systolic blood pressure or a low measured cardiac index in the presence of signs of hypoperfusion or congestion. A Class IIa recommendation at level of evidence B has been formulated for levosimendan in the ESC guidelines.
Headache and hypotension have been the most frequently reported adverse events in levosimendan-treated patients in randomised clinical trials. Atrial fibrillation, hypokalaemia and tachycardia have also been reported in some clinical studies. Whether levosimendan produces statistically significant evidence of survival benefit remains unclear. Interestingly, a very recent meta-analysis of data from 5,480 patients in 45 randomised clinical trials suggests that levosimendan might reduce the overall mortality rate and hospital stay in cardiac surgery and the cardiology settings of adult patients. In addition to its recommended use in the treatment of acute decompensated heart failure, levosimendan has also found increasing off-label use for other cardiovascular symptoms in acute cardiovascular events and in intensive care units. Ischaemic heart disease and septic shock, as well as perioperative cardiac support, are conditions where the use of levosimendan has been shown to exert beneficial cardiovascular effects.
References
1. Dickstein K, Cohen-Solal A, Filippatos G et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29: 2388–442.
2. Nieminen MS, Brutsaert D, Dickstein K et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006; 27: 2725–36.
3. Leier CV, Binkley PF. Parenteral inotropic support for advanced congestive heart failure. Prog Cardiovasc Dis 1998; 41: 207–24.
4. O’Connor CM, Gattis WA, Uretsky BF et al. Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST). Am Heart J 1999; 138: 78–86.
5. Landoni G, Biondi-Zoccal G Greco M et al. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med 2011; Sep 29 [Epub ahead of print].
6. Haikala H, Kaivola G, Nissinen G et al. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 1995; 27: 1859–66.
7. Pollesello P, Ovaska M, Kaivola J et al. Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C. A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study. J Biol Chem 1994; 269: 28584–90.
8. Levijoki J, Polleselo P, Kaivola J et al. Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. J Mol Cell Cardiol 2000; 32: 479–91.
9. Deschodt-Arsac V, Calmettes G, Raffard G et al. Absence of mitochondrial activation during levosimendan inotropic action in perfused paced guinea pig hearts as demonstrated by modular control analysis. Am J Physiol Regul Integr Comp Physiol 2010; 299: R786–92.
10. Papp Z, Edes I, Fruhwald S et al. Levosimendan: Molecular mechanisms and clinical implications Consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2011 Jul 23 [Epub ahead of print].
11. Yokoshiki H, Kitsube Y, Sunagawa M et al. The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells. J Pharmacol Exp Ther 1997; 283: 375–83.
12. Erdei N, Papp Z, Pollesello P et al. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol 2006; 148: 696–702.
13. Hohn J, Pataricza J, Petri A et al. Levosimendan interacts with potassium channel blockers in human saphenous veins. Basic Clin Pharmacol Toxicol 2004; 94: 271–73.
14. Gruhn N, Nielsen-Kudsk JE, Thielgaard S et al. Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties. J Cardiovasc Pharmacol 1998; 31: 741–49.
15. Lilleberg J, Nieminen MS, Akkila J et al. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998; 19: 660–68.
16. Harkin CP, Pagel PS, Tessmer JP et al. Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs. J Cardiovasc Pharmacol 1995; 26: 179–88.
17. Parissis JT, Paraskavaidis I, Bistola V et al. Effects of levosimendan on right ventricular function in patients with advanced heart failure. Am J Cardiol 2006; 98: 1489–92.
18. Parissis JT, Andreadou I, Markantonis SL et al. Effects of Levosimendan on circulating markers of oxidative and nitrosative stress in patients with advanced heart failure. Atherosclerosis 2007; 195: e210–5.
19. Kyrzopoulos S, Adamopoulos S, Parissis JT et al. Levosimendan reduces plasma B-type natriuretic peptide and interleukin 6, and improves central hemodynamics in severe heart failure patients. Int J Cardiol 2005; 99: 409–13.
20. Louhelainen M, Vahtola E, Kaheinen P et al. Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats. Br J Pharmacol 2007; 150: 851–61.
21. Louhelainen M, Vahtola E, Forsten H et al. Oral levosimendan prevents postinfarct heart failure and cardiac remodeling in diabetic Goto-Kakizaki rats. J Hypertens 2009; 27: 2094–107.
22. Jonsson EN, Antila S, McFadyen L et al. Population pharmacokinetics of levosimendan in patients with congestive heart failure. Br J Clin Pharmacol 2003; 55: 544–51.
23. Puttonen J, Kantele S, Kivikko M et al. Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites. Clin Pharmacokinet 2007; 46: 235–46.
24. Puttonen J, Kantele S, Ruck A, Ramela M, Häkkinen S, et al. Pharmacokinetics of intravenous levosimendan and its metabolites in subjects with hepatic impairment. J Clin Pharmacol 2008; 48: 445–54.
25. Antila S, Sundberg S, Lehtonen LA. Clinical pharmacology of levosimendan. Clin Pharmacokinet 2007; 46: 535–52.
