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Recent Patents on Cardiovascular Drug Discovery, 2009, 4, 22-24
Levosimendan for Heart-Operated Patients: What is the State of the Art? Georgios I. Tagarakis* and Nikolaos B. Tsilimingas Department of Cardiovascular and Thoracic Surgery, University of Thessaly, Larissa, Greece Received: September 25, 2008; Accepted: November 20, 2008; Revised: November 26, 2008
Abstract: Acute heart failure is a common clinical problem faced in cardiac surgery operating rooms and intensive care units. Levosimendan, an inotropic and vasodilating agent used widely in cases of acute heart failure for “cardiological” patients, has not gained global acceptance in its application for heart-operated ones. Herein, we are presenting a series of studies and patents concerning this medication, which, in general, support the use of levosimendan during and after heart surgery, despite the relatively high cost of administration. However, trials with larger samples of patients have to be performed in order to definitively establish this medication as a routinely administered drug for acute congestive heart failure after heart surgery.
Keywords: Acute heart failure, levosimendan, inotropic agent, vasodilation and heart surgery. GENERAL FEATURES - MODE OF ACTION PHARMACOKINETICS-PHARMACODYNAMICS Levosimendan (Simdax®, Orion Pharma, Espoo, Finland) is a relatively new, but already commonly used pharmacologic agent with its main indication being the inotropic support in patients with de novo or decompensated acute congestive heart failure. It is a dinitrate product of pyridazone, a mildly lipophile substance Fig. (1). N
NH N
N N
NH O
Levosimendan Systematic name (-)-(R)-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl) phenyl) carbonohydrazonoyl dicyanide
Fig. (1). Chemical structure and systematic name of levosimendan.
Its main action is mediated through the augmentation of the sensibility of the contractible muscle fibers towards calcium [1-4]. Levosimendan interacts with cardiac troponin C (cTnC), stabilizing the calcium-induced structural change in cTnC, and enhancing the interaction of cTnC with its neighbors on the thin filament, thus increasing contractility [2-6]. This way of action differentiates the substance from other inotropic agents, such as digoxin, dopamine, amrinone, milrinone, which facilitate the entrance of calcium into the sarcoplasmic network of the cells. *Address correspondence to this author at the Department of Cardiovascular and Thoracic Surgery, University Hospital of Thessaly, Mezourlo, Larissa, Greece; Tel: +302410681719; Fax: +302310912645; E-mail:
[email protected] 1574-8901/09 $100.00+.00
Levosimendan also affects the smooth muscle fibers of the vascular wall [7]. It binds to the ATP dependent potassium channels, thus causing vasodilation, a reduction to the systemic vascular resistance, the pulmonary capillary wedge pressure and finally the cardiac preload and afterload. Moreover, by opening the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect. Levosimendan is an active pharmacologic agent with a fast distribution. It presents linear pharmacokinetics both in healthy subjects as well as in patients with cardiac failure [8, 9]. It is metabolized through liver and excreted through kidneys, although it can be administered with caution to patients with mild renal or hepatic impairment. Its highest concentration can be detected 4.4 hours after the commencement of a continuous infusion of 0.2 μg/kg/min and the highest concentration of OR-1896, its active metabolite, can be detected 2-5 days after the infusion of 0.2 μg/kg/min of levosimendan for 24 hours. The hemiperiod of life (t1/2) is one hour both for healthy subjects as well as for patients with heart failure [8, 9]. Described adverse drug reactions (detected in about 1% of patients) associated with levosimendan treatment include: headache, hypotension, nausea, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischemia and hypokalaemia [10]. The use of levosimendan is contraindicated in patients with: Moderate-to-severe renal failure, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension and tachycardia, and history of torsades de pointes. Studies and Trials A series of studies and trials have been planned and completed with the aim of checking levosimendan for therapeutical benefits and advantages in cases of heart failure, both independently as well as in comparison with other inotropic agents. The RUSSLAN study [11], a doubleblind randomized study, has compared levosimendan with © 2009 Bentham Science Publishers Ltd.
Levosimendan and Cardiac Surgery
placebo in 504 patients with heart failure after heart infarction, showing a reduction of mortality after 6 and 24 hours and after 14 and 180 days in the levosimendan group. It also showed improvement of the patients’ subjective feeling of dyspnea and fatigue. REVIVE-1 [11] also compared levosimendan and placebo in 100 patients with heart failure and concluded to a reduced mortality and morbidity after 24 hours and 5 days. REVIVE-2 [12] used a larger sample (600 patients) showing no differences after 90 days, but a shorter hospitalization period in general and a reduction in serum brain natriuretic peptide (BNP) levels for patients with levosimendan. Similar findings are described in the drug US20080077025 [13]. The LIDO study [14] (203 participants) has concluded to an advantage of levosimendan against dobutamine as far as the reduction of mortality after 180 days is concerned. On the contrary, SURVIVE [15] showed no difference between the two substances as far as survival is concerned, although a more significant reduction of BNP levels was marked within the levosimendan group. Levosimendan and Heart Surgery Unfortunately, the studies that have been performed in order to establish the existence of potential benefits of heartoperated patients treated with levosimendan were based on relatively small samples of patients. However, people undergoing cardiac surgery of various kinds, seem to profit after treatment with the drug, as far as their preoperatively or postoperatively presented acute heart failure is concerned. Beiras-Fernandez et al. [16] concluded to benefits from such a treatment in 5 heart-transplanted patients with postoperative heart failure. Meyer et al. [17] have performed an animal-based experiment with rabbits which were submitted to open-chest heart surgery and proved the beneficial effect of levosimendan in the ventricular function postoperatively. In a study performed on 23 patients undergoing aortic valve replacement for aortic valve stenosis, Joergensen et al. [18] concluded that levosimendan, in addition to its beneficial inotropic effects, exerts a direct positive lusitropic effect in patients with LV hypertrophy as it shortens isovolumic relaxation time and improves LV filling. Lehmann et al. [19] have performed a retrospective study with 52 patients that were submitted to urgent operative coronary revascularization, showing an improvement in morbidity, but not in mortality or hospitalization duration in patients treated with levosimendan. Tasouli et al., based on a study with a sample of 45 patients, speak in favor of the utilization of levosimendan for heart-operated patients, with better results attributed to the drug in those cases in which the administration starts intraoperatively [20]. Finally, in a small randomized survey, Nijhawan et al. compared levosimendan versus placebo in patients undergoing cardiopulmonary bypass. The administration of the drug commenced 15 minutes before cardiopulmonary bypass and was terminated 6 hours after. The results showed a significant increase in cardiac output and a significant reduction in systemic vascular resistance in patients treated with levosimendan [21].
Recent Patents on Cardiovascular Drug Discovery, 2009, Vol. 4, No. 1
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least for “cardiological” patients. This is due to its action as a calcium sensitizer, pulmonary and systemic vasodilator and antiischemic cardioprotactive agent. A matter that still remains open, seeking further research and clarification, is the ideal pattern of co-administration with other agents used in cases of acute heart failure, including -blockers, although the common practice is to apply levosimendan in addition and after the previous utilization of other drugs, in cases where severe (NYHA IV stage) heart failure cannot be easily compensated. On the contrary to its establishment as a remedy for patients in cardiological intensive care units, the use of levosimendan has not been universally accepted in every day practice for the perioperative management of heart-operated patients. This can be attributed to the relatively higher financial costs in comparison to the other inotropic agents in use. It can also be attributed to the lack of series of studies with large samples of patients that would definitively establish this drug as a routine remedy for acute congestive heart failure after cardiac surgery. However, the already published pieces of research attribute levosimendan its first credits, making it a much-promising medication for the future. CONFLICT OF INTEREST None declared. REFERENCES [1]
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