Levosimendan: A Review of its Use in the Management of Acute Decompensated Heart Failure

Drugs

Volumn 63, Issue 23, 2003, Pages 2651-2671

  Innes, Carmen A ^a   Wagstaff, Antona J ^a  

^a ADIS INTERNATIONAL LIMITED   (New Zealand)

Author keywords

Acute decompensated heart failure; Intravenous; Levosimendan; Pharmacodynamics; Pharmacokinetics; Therapeutic use; Tolerability

Indexed keywords

ALDOSTERONE RECEPTOR; ALDOSTERONE RECEPTOR BLOCKING AGENT; ANGIOTENSIN RECEPTOR ANTAGONIST; ANTIARRHYTHMIC AGENT; ANTICOAGULANT AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CAPTOPRIL; CARDIAC GLYCOSIDE; CARVEDILOL; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; DOBUTAMINE; DRUG METABOLITE; ENOXIMONE; FELODIPINE; GLYCERYL TRINITRATE; INOTROPIC AGENT; ISOSORBIDE MONONITRATE; ITRACONAZOLE; LEVOSIMENDAN; MILRINONE; N [4 (1,4,5,6 TETRAHYDRO 4 METHYL 6 OXO 3 PYRIDAZINYL)PHENYL]ACETAMIDE; NESIRITIDE; NITROPRUSSIDE SODIUM; OPIATE; PHOSPHODIESTERASE INHIBITOR; RECEPTOR BLOCKING AGENT; UNCLASSIFIED DRUG; VASODILATOR AGENT; WARFARIN;

ACUTE DECOMPENSATED HEART FAILURE; ANGINA PECTORIS; AREA UNDER THE CURVE; CLINICAL TRIAL; CONTINUOUS INFUSION; CYANIDE POISONING; DISEASE EXACERBATION; DOSE RESPONSE; DRUG ABSORPTION; DRUG ALCOHOL INTERACTION; DRUG ANTAGONISM; DRUG BLOOD LEVEL; DRUG CONTRAINDICATION; DRUG COST; DRUG DISTRIBUTION; DRUG EFFECT; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG STRUCTURE; DRUG TOLERABILITY; DYSPNEA; FATIGUE; GASTROINTESTINAL SYMPTOM; HEADACHE; HEART ARRHYTHMIA; HEART ATRIUM ARRHYTHMIA; HEART ATRIUM FIBRILLATION; HEART DISEASE; HEART FAILURE; HEART MUSCLE ISCHEMIA; HEART RUPTURE; HEART VENTRICLE EXTRASYSTOLE; HEMODYNAMICS; HOSPITAL COST; HUMAN; HYPERTENSION; HYPOTENSION; INOTROPISM; LUNG EDEMA; MIGRAINE; MORBIDITY; MORTALITY; NAUSEA; NONHUMAN; REVIEW; TACHYCARDIA; THORAX PAIN; VASODILATATION;

ACUTE DISEASE; ANIMALS; CARDIOTONIC AGENTS; HEART FAILURE, CONGESTIVE; HEMODYNAMIC PROCESSES; HUMANS; HYDRAZONES; PYRIDAZINES; RANDOMIZED CONTROLLED TRIALS;

ANGINA;

EID: 0345376061     PISSN: 00126667     EISSN: None     Source Type: Journal    
DOI: 10.2165/00003495-200363230-00009     Document Type: Review

References (87)

1. Patel AR, Konstam MA. Recent advances in the treatment of heart failure. Circ J 2002 Feb; 66: 117-21
2. Lehtonen LA. Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties. Expert Opin Investig Drugs 2001 May; 10 (5): 955-70
3. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Task force for the diagnosis and treatment of chronic heart failure. European Society of Cardiology. Eur Heart J 2001; 22: 1527-60
4. Cleland JGF, McGowan J. Levosimendan: a new era for inodilator therapy for heart failure? Curr Opin Cardiol 2002 May; 17(3): 257-65
5. Mills RM, Hobbs RE. Drug treatment of patients with decompensated heart failure. Am J Cardiovasc Drugs 2001; 1 (2): 119-25
6. Greenberg B, Borghi C, Perrone S. Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan? Eur J Heart Fail 2003 Jan: 5 (1): 13-21
7. Haikala H, Lindén I-B. Mechanisms of action of calcium-sensitizing drugs. J Cardiovasc Pharmacol 1995; 26 Suppl. 1: S10-9
8. Figgitt DP, Gillies PS, Goa KL. Levosimendan. Drugs 2001; 61 (5): 613-27
9. Levijoki J, Pollesello 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 Mar; 32 (3): 479-91
10. Haikala H, Kaivola J, Nissinen E, et al. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 1995 Sep; 27 (9): 1859-66
11. Lee JA, Allen DG. Calcium sensitisers: a new approach to increasing the strength of the heart. BMJ 1990 Mar 3; 300: 551-2
12. 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 Nov 18; 269 (46): 28584-90
13. Sorsa T, Heikkinen S, Abbott MB, et al. Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem 2001 Mar 23; 276 (12): 9337-43
14. Sorsa T, Pollesello P, Permi P, et al. Interaction of levosimendan with cardiac troponin C in the presence of cardiac troponin I peptides. J Mol Cell Cardiol 2003 Sep; 35 (9): 1055-61
15. Kleerekoper Q, Putkey JA. Drug binding to cardiac troponin C. J Biol Chem 1999 Aug 20; 274 (34): 23932-9
16. Haikala H, Nissinen E, Etemadzadeh E, et al. Troponin C-mediated calcium sensitization induced by levosimendan does not impair relaxation. J Cardiovasc Pharmacol 1995; 25: 794-801
17. Edes I, Kiss E, Kitada Y, et al. Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res 1995; 77: 107-13
18. Lancaster MK, Cook SJ. The effects of levosimendan on [Ca2+]i in guinea-pig isolated ventricular myocytes. Eur J Pharmacol 1997; 339: 97-100
19. Boknik P, Neumann J, Kaspareit G, et al. Mechanisms of the contractile effects of levosimendan in the mammalian heart. J Pharmacol Exp Ther 1997; 280 (1): 277-83
20. Ajiro Y, Hagiwara N, Katsube Y, et al. Levosimendan increases L-type Ca2+ current via phosphodiesterase-3 inhibition in human cardiac myocytes. Eur J Pharmacol 2002 Jan 18; 435 (1): 27-33
21. Afanas'ev SA, Timofeev VYu, Karpov RS. Troponin component of cardiotonic effects of levosimendan on isolated myocardium from patients with chronic heart failure. Bull Exp Biol Med 1999; 128 (10): 1052-3
22. Hasenfuss G, Pieske B, Kretschmann B, et al. Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. J Cardiovasc Pharmacol 1995; 26 Suppl. 1: S45-51
23. Varró A, Papp JG. Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed? J Cardio Pharmacol 1995; 26 Suppl. 1: S32-44
24. Haikala H, Kaheinen P, Levijoki J, et al. The role of cAMP-and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res 1997; 34: 536-46
25. Gruhn N, Nielsen-Kudsk JE, Theilgaard S, et al. Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties. J Cardiovasc Pharmacol 1998; 31: 741-9
26. Takahashi R, Talukder MAH, Endoh M. Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium. J Cardiovasc Pharmacol 2000; 36: 118-25
27. Takahashi R, Talukder MAH, Endoh M. Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium. Eur J Pharmacol 2000 Jul 14; 400 (1): 103-12
28. Kopustinskiene DM, Pollesello P, Saris N-EL. Levosimendan is a mitochondrial KATP channel opener. Eur J Pharmacol 2001 Oct 12; 428 (3): 311-4
29. Udvary É, Papp JG, Végh Á. Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction. Br J Pharmacol 1995; 114: 656-61
30. Hasenfuss G, Pieske B, Castell M, et al. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 1998 Nov 17; 98 (20): 2141-7
31. Brixius K, Reicke S, Schwinger RH. Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium. Am J Physiol Heart Circ Physiol 2002 Jan; 282 (1): H131-7
32. Janssen PM, Datz N, Zeitz O, et al. Levosimendan improves diastolic and systolic function in failing human myocardium. Eur J Pharmacol 2000 Sep 15; 404 (1-2): 191-9
33. Pataricza J, Hōhn J, Petri A, et al. Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol 2000 Feb; 52 (2): 213-7
34. Krassoí I, Pataricza J, Kun A, et al. Calcium-dependent vasorelaxant capacity of levosimendan in porcine and human epicardial coronary artery preparations [letter]. Cardiovasc Drugs Ther 2000 Dec; 14 (6): 691-3
35. Bowman P, Haikala H, Paul RJ. Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. J Pharmacol Exp Ther 1999; 288 (1): 316-25
36. 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
37. Pagel PS, Hettrick DA, Warltier DC. Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency. Basic Res Cardiol 1996; 91 (4): 296-307
38. du Toit E, Hofmann D, McCarthy J, et al. Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model. Heart 2001 Jul; 86(1): 81-7
39. Tassani P, Schad H, Heimisch W, et al. Effect of the calcium sensitizer levosimendan on the performance of ischaemic myocardium in anaesthetised pigs. Cardiovasc Drugs Ther 2002 Sep; 16 (5): 435-41
40. De Witt BJ, Ibrahim IN, Bayer E, et al. An analysis of responses to levosimendan in the pulmonary vascular bed of the cat. Anesth Analg 2002 Jun; 94 (6): 1427-33
41. Lochner A, Colesky F, Genade S. Effect of a calcium-sensitizing agent, levosimendan, on the postcardioplegic inotropic response of the myocardium. Cardiovasc Drugs Ther 2000 Jun; 14(3): 271-81
42. Pagel SP, Harkin CP, Hettrick DA, et al. Levosimendan (OR-1259), a myofilament calcium sensitizer, enhances myocardial contractility but does not alter isovolumic relaxation in conscious and anesthetized dogs. Anesthesiology 1994; 81: 974-87
43. Jamali IN, Kersten JR, Pagel PS, et al. Intracoronary levosimendan enhances contractile function of stunned myocardium. Anesth Analg 1997; 85: 23-9
44. Pagel PS, McGough MF, Hettrick DA, et al. Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy. J Cardiovasc Pharmacol 1997; 29: 563-73
45. Kersten JR, Montgomery MW, Pagel PS, et al. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of KATP channels. Anesth Analg 2000 Jan; 90 (1): 5-11
46. Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther 2000 Nov; 68 (5): 522-31
47. Sundberg S, Lehtonen L. Haemodynamic interactions between the novel calcium sensitiser levosimendan and isosorbide-5-mononitrate in healthy subjects. Eur J Clin Pharmacol 2000; 55 (11-12): 793-9
48. Sundberg S, Antila S, Scheinin H, et al. Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals. Int J Clin Pharmacol Ther 1998 Dec; 36 (12): 629-35
49. Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther 1997 May; 61 (5): 596-607
50. Follath F, Cleland JGF, 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
51. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation 2000 Oct 31; 102 (18): 2222-7
52. Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation 2003 Jan 7; 107 (1): 81-6
53. Berger R, Huelsmann M, Bojic A, et al. Short-term effects of levosimendan versus prostaglandin E1 on haemodynamics and BNP plasma levels in patients with chronic heart failure [abstract no. P3654]. Eur Heart J 2002; 23 (Abstr. Suppl.): 712
54. Papazoglou P, Anastasiou-Nana M, Tsagalou E, et al. Hemodynamic effects of levosimendan in addition to dobutamine infusion in patients with advanced heart failure intractable to dobutamine infusion alone [abstract no. 1184-78]. J Am Coll Cardiol 2003 Mar 19; 41 Suppl. A: 206A
55. Sundberg S, Lilleberg J, Nieminen MS, et al. Hemodynamic and neurohumoral effects of levosimendan, a new calcium sensitizer, at rest and during exercise in healthy men. Am J Cardiol 1995; 75: 1061-6
56. Lilleberg J, Sundberg S, Häyhä M, et al. Haemodynamic dose-efficacy of levosimendan in healthy volunteers. Eur J Clin Pharmacol 1994; 47 (3): 267-74
57. Kivikko M. Antila S, Eha J, et al. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 2002 Jan; 42 (1): 43-51
58. Toivonen L, Viitasalo M, Sundberg S, et al. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function. J Cardiovasc Pharmacol 2000 Apr; 35 (4): 664-9
59. Du Toit EF, Muller CA, McCarthy J, et al. Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart. J Pharmacol Exp Ther 1999; 290 (2): 505-14
60. Leprán I, Papp JG. Effect of long-term oral pretreatment with levosimendan on cardiac arrhythmias during coronary artery occlusion in conscious rats. Eur J Pharmacol 2003 Mar 19; 464 (2-3): 171-6
61. Binkley PF, Nunziata E, Hatton PS, et al. The positive inotropic agent levosimendan mediates increased cardiac output without progression of sympathovagal imbalance in patients with heart failure [abstract no. 3483]. Circulation 2000 Oct 31; 102 Suppl.: II-720
62. Antila S, Eha J, Heinpalu M, et al. Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril. Eur J Clin Pharmacol 1996; 49 (6): 451-8
63. Lehtonen L, Antila S, Eha J, et al. No pharmacodynamic interactions between a new calcium sensitizing agent levosimendan and a calcium antagonist drug felodipine [abstract no. 415]. Eur J Clin Pharmacol 1997; 52 Suppl.: 136
64. Lehtonen L, Sundberg S. The contractility enhancing effect of the calcium sensitiser levosimendan is not attenuated by carvedilol in healthy subjects. Eur J Clin Pharmacol 2002 Oct; 58 (7): 449-52
65. Antila S, Järvinen A, Honkanen T, et al. Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitiser levosimendan and warfarin. Eur J Clin Pharmacol 2000 Dec; 56 (9-10): 705-10
66. Antila S, Järvinen A, Akkila J, et al. Studies on psychomotoric effects and pharmacokinetic interactions of the new calcium sensitizing drug levosimendan and ethanol. Arzneimittelforschung 1997 Jul; 47 (7): 816-20
67. Follath F, Cleland JGF. Comparison of the effect of beta-blockade on the haemodynamic responses to levosimendan and dobutamine in patients with severe low-output heart failure [abstract no. 414]. Eur J Heart Fail 2002; 1 Suppl.: 95
68. Lilleberg J, Antila S, Karlsson M, et al. Pharmacokinetics and pharmacodynamics of simendan, a novel calcium sensitizer, in healthy volunteers. Clin Pharmacol Ther 1994 Nov; 56 (5): 554-63
69. Kivikko M, Antila S, Eha J, et al. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther 2002 Oct; 40 (10): 465-71
70. Põder P, Eha J, Sundberg S, et al. Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure. Int J Clin Pharmacol Ther 2003; 41 (8): 365-73
71. Jonsson EN, Antila S, McFadyen L, et al. Population pharmacokinetics of levosimendan in patients with congestive heart failure. Br J Clin Pharmacol 2003 Jun; 55: 544-51
72. Sandell E-P, Häyhä M, Antila S, et al. Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure. J Cardiovasc Pharmacol 1995; 26 Suppl. 1: S57-62
73. Sandell EP, Aalto T, Antila S, et al. The effects of severe congestive heart failure on the pharmacokinetics of levosimendan [abstract no. 102]. Eur J Clin Pharmacol 1997; 52 Suppl.: A55
74. Swedish Medical Products Agency. Simdax (levosimendan): summary of the product characteristics [online]. Available from URL: http://www.mpa.se/eng/spc/ spc_o-z/ Simdax_ENG.pdf [Accessed 2003 Sep 10]
75. Antila S, Honkanen T, Lehtonen L, et al. The CYP3A4 inhibitor itraconazole does not affect the pharmacokinetics of a new calcium-sensitizing drug levosimendan. Int J Clin Pharmacol Ther 1998 Aug; 36 (8): 446-9
76. Sandell EP, Antila S, Koistinen H. The effects of renal failure on the pharmacokinetics of levosimendan [abstract no. 495]. Thérapie 1995; 80 Suppl.
77. 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
78. Folláth F, Hinkka S. Jäger D, et al. Dose-ranging and safety with intravenous levosimendan in low-output heart failure: experience in three pilot studies and outline of the Levosimendan Infusion versus Dobutamine (LIDO) trial. Am J Cardiol 1999 Jun 24; 83: 21-5
79. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 2000 Nov 15; 36(6): 1903-12
80. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. Am Heart J 2003 Feb; 145 (2 Suppl.): S26-33
81. Cleland JG, Takala A, Apajasalo M, et al. Intravenous levosimendan treatment is cost-effective compared with dobutamine in severe low-output heart failure: an analysis based on the international LIDO trial. Eur J Heart Fail 2003 Jan; 5 (1): 101-8
82. Swedberg K, Kjekshus J, Snapinn S, et al. Long-term survival in severe heart failure in patients treated with enalapril: ten year follow-up of CONSENSUS I. Eur Heart J 1999; 20: 136-9
83. Lehtonen L, Mills-Owens P, Akkila J. Safety of levosimendan and other calcium sensitizers. J Cardiovasc Pharmacol 1995; 26 Suppl. 1: S70-6.
84. Singh BN, Lilleberg J, Sandell E-P, et al. Effects of levosimendan on cardiac arrhythmia: electrophysiologic and ambulatory electrocardiographic findings in phase II and phase III clinical studies in cardiac failure. Am J Cardiol 1999; 83: 16(I)-20(I)
85. International Society for Heart and Lung Transplantation (endorsed by the Heart Failure Society of America). ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). Circulation 2001 Dec 11; 104: 2996-3007
86. Thackray S, Easthaugh J, Freemantle N, et al. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure - a meta-regression analysis. Eur J Heart Fail 2002; 4: 515-29
87. Sanofi-Synthelabo Inc.. Milrinone lactate injection (Primacor®) US prescribing information [online]. Available from URL: http://sanofi- synthelabous.com [Accessed 2003 Oct 23]