Intermittent levosimendan improves mid-term survival in chronic heart failure patients: meta-analysis of randomised trials

go back to reference Metra M, Ponikoswki P, Dickstein K, McMurray JJ, Gavazzi A, Bergh CH, Fraser AG, Jaarsma T, Pitsis A, Mohacsi P, Böhm M, Anker S, Dargie H, Brutsaert D, Komajda M, for the Heart FailureAssociation of the European Society of Cardiology (2007) Advanced chronic heart failure: a positionstatement from the Study Group on Advanced Heart Failure of the Heart Failure Association ofthe European Society of Cardiology. Eur J Heart Fail 9:684–694PubMedCrossRef Metra M, Ponikoswki P, Dickstein K, McMurray JJ, Gavazzi A, Bergh CH, Fraser AG, Jaarsma T, Pitsis A, Mohacsi P, Böhm M, Anker S, Dargie H, Brutsaert D, Komajda M, for the Heart FailureAssociation of the European Society of Cardiology (2007) Advanced chronic heart failure: a positionstatement from the Study Group on Advanced Heart Failure of the Heart Failure Association ofthe European Society of Cardiology. Eur J Heart Fail 9:684–694PubMedCrossRef

go back to reference Bayram M, De Luca L, Massie MB, Gheorghiade M (2005) Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol 96:47G–58GPubMedCrossRef Bayram M, De Luca L, Massie MB, Gheorghiade M (2005) Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol 96:47G–58GPubMedCrossRef

go back to reference Thackray S, Easthaugh J, Freemantle N, Cleland JG (2002) 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 4:515–529PubMedCrossRef Thackray S, Easthaugh J, Freemantle N, Cleland JG (2002) 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 4:515–529PubMedCrossRef

go back to reference Metra M, Eichhorn E, Abraham WT, Linseman J, Böhm M, Corbalan R, DeMets D, De Marco T, Elkayam U, Gerber M, Komajda M, Liu P, Mareev V, Perrone SV, Poole-Wilson P, Roecker E, Stewart J, Swedberg K, Tendera M, Wiens B, Bristow MR, ESSENTIAL Investigators (2009) Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: The randomized, doubleblind, placebo-controlled, parallel group ESSENTIAL trials. Eur Heart J 30:3015–3026PubMedCentralPubMedCrossRef Metra M, Eichhorn E, Abraham WT, Linseman J, Böhm M, Corbalan R, DeMets D, De Marco T, Elkayam U, Gerber M, Komajda M, Liu P, Mareev V, Perrone SV, Poole-Wilson P, Roecker E, Stewart J, Swedberg K, Tendera M, Wiens B, Bristow MR, ESSENTIAL Investigators (2009) Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: The randomized, doubleblind, placebo-controlled, parallel group ESSENTIAL trials. Eur Heart J 30:3015–3026PubMedCentralPubMedCrossRef

go back to reference Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, Cheng ML, Wynne J, ADHERE Scientific Advisory Committee and Investigators, ADHERE Study Group (2005) In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 46:57–64PubMedCrossRef Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, Cheng ML, Wynne J, ADHERE Scientific Advisory Committee and Investigators, ADHERE Study Group (2005) In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 46:57–64PubMedCrossRef

go back to reference Mebazaa A, Parissis J, Porcher R, Gayat E, Nikolaou M, Boas FV, Delgado JF, Follath F (2011) Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med 37:290–301PubMedCrossRef Mebazaa A, Parissis J, Porcher R, Gayat E, Nikolaou M, Boas FV, Delgado JF, Follath F (2011) Short-term survival by treatment among patients hospitalized with acute heart failure: the global ALARM-HF registry using propensity scoring methods. Intensive Care Med 37:290–301PubMedCrossRef

go back to reference Chatterjee K, Wolfe CL, De Marco T (1994) Nonglycoside inotropes in congestive heart failure: are they beneficial or harmful? Cardiol Clin 12:63–72PubMed Chatterjee K, Wolfe CL, De Marco T (1994) Nonglycoside inotropes in congestive heart failure: are they beneficial or harmful? Cardiol Clin 12:63–72PubMed

go back to reference Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, Colucci WS (2003) Beta-adrenergic receptor stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res 92:136–138PubMedCrossRef Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, Colucci WS (2003) Beta-adrenergic receptor stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res 92:136–138PubMedCrossRef

go back to reference Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, Sollano JA, Shannon J, Tandon PK, DeMets DL, The PROMISE Study Research Group (1991) Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 325:1468–1475PubMedCrossRef Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, Sollano JA, Shannon J, Tandon PK, DeMets DL, The PROMISE Study Research Group (1991) Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 325:1468–1475PubMedCrossRef

go back to reference Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, ESC Committee for Practice Guidelines (CPG) (2008) 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 J Heart Fail 10:933–989PubMedCrossRef Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, ESC Committee for Practice Guidelines (CPG) (2008) 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 J Heart Fail 10:933–989PubMedCrossRef

go back to reference Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW (2009) 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119:e391–e479PubMedCrossRef Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW (2009) 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119:e391–e479PubMedCrossRef

go back to reference Drakos SG, Charitos EI, Nanas SN, Nanas JN (2007) Ventricular-assist devices for the treatment of chronic heart failure. Expert Rev Cardiovasc Ther 5:571–584PubMedCrossRef Drakos SG, Charitos EI, Nanas SN, Nanas JN (2007) Ventricular-assist devices for the treatment of chronic heart failure. Expert Rev Cardiovasc Ther 5:571–584PubMedCrossRef

go back to reference Sorsa T, Pollesello P, Rosevear PR, Drakenberg T, Kilpeläinen I (2004) Stereoselective binding of levosimendan to cardiac troponin C causes Ca2+-sensitization. Eur J Pharmacol 486:1–8PubMedCrossRef Sorsa T, Pollesello P, Rosevear PR, Drakenberg T, Kilpeläinen I (2004) Stereoselective binding of levosimendan to cardiac troponin C causes Ca²⁺-sensitization. Eur J Pharmacol 486:1–8PubMedCrossRef

go back to reference Sorsa T, Heikkinen S, Abbott MB, Abusamhadneh E, Laakso T, Tilgmann C, Serimaa R, Annila A, Rosevear PR, Drakenberg T, Pollesello P, Kilpelainen I (2001) Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem 276:9337–9343PubMedCrossRef Sorsa T, Heikkinen S, Abbott MB, Abusamhadneh E, Laakso T, Tilgmann C, Serimaa R, Annila A, Rosevear PR, Drakenberg T, Pollesello P, Kilpelainen I (2001) Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem 276:9337–9343PubMedCrossRef

go back to reference Avgeropoulou C, Andreadou I, Markantonis-Kyroudis S, Demopoulou M, Missovoulos P, Androulakis A, Kallikazaros I (2005) The Ca(2+)-sensitizer levosimendan improves oxidative damage, BNP and proinflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine. Eur J Heart Fail 7:882–887PubMedCrossRef Avgeropoulou C, Andreadou I, Markantonis-Kyroudis S, Demopoulou M, Missovoulos P, Androulakis A, Kallikazaros I (2005) The Ca⁽²⁺⁾-sensitizer levosimendan improves oxidative damage, BNP and proinflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine. Eur J Heart Fail 7:882–887PubMedCrossRef

go back to reference Moiseyev VS, Põder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, Kobalava ZD, Lehtonen LA, Laine T, Nieminen MS, Lie KI, RUSSLAN Study Investigators (2002) 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, doubleblind study (RUSSLAN). Eur Heart J 23:1422–1432PubMedCrossRef Moiseyev VS, Põder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, Kobalava ZD, Lehtonen LA, Laine T, Nieminen MS, Lie KI, RUSSLAN Study Investigators (2002) 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, doubleblind study (RUSSLAN). Eur Heart J 23:1422–1432PubMedCrossRef

go back to reference Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L, Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360:196–202PubMedCrossRef Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L, Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360:196–202PubMedCrossRef

go back to reference 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 40:634–646PubMedCrossRef 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 40:634–646PubMedCrossRef

go back to reference Biondi-Zoccai GG, Agostoni P, Abbate A, Testa L, Burzotta F (2005) A simple hint to improve Robinson and Dickersin’s highly sensitive PubMed search strategy for controlled clinical trials. Int J Epidemiol 34:224–225PubMedCrossRef Biondi-Zoccai GG, Agostoni P, Abbate A, Testa L, Burzotta F (2005) A simple hint to improve Robinson and Dickersin’s highly sensitive PubMed search strategy for controlled clinical trials. Int J Epidemiol 34:224–225PubMedCrossRef

go back to reference Higgins JPT, Green S (2011) Cochrane handbook for systematic reviews of interventions. Version 5.1.0. http://www.cochranehandbook.org. Accessed March 2011 Higgins JPT, Green S (2011) Cochrane handbook for systematic reviews of interventions. Version 5.1.0. http://​www.​cochranehandbook​.​org. Accessed March 2011

go back to reference Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101PubMedCrossRef Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101PubMedCrossRef

go back to reference Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCentralPubMedCrossRef Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCentralPubMedCrossRef

go back to reference Biondi-Zoccai G, Lotrionte M, Landoni G, Modena MG (2011) The rough guide to systematic reviews and meta-analyses. HSR Proc Intensive Care Cardiovas Anesth 3(3):161–173 Biondi-Zoccai G, Lotrionte M, Landoni G, Modena MG (2011) The rough guide to systematic reviews and meta-analyses. HSR Proc Intensive Care Cardiovas Anesth 3(3):161–173

go back to reference Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700PubMedCentralPubMedCrossRef Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700PubMedCentralPubMedCrossRef

go back to reference Nieminen MS, Cleland JGF, Eha J, Belenkov Y, Kivikko M, Põder P, Sarapohja T (2008) Oral levosimendan in patients with severe chronic heart failure—the PERSIST study. Eur J Heart Fail 10:1246–1254PubMedCrossRef Nieminen MS, Cleland JGF, Eha J, Belenkov Y, Kivikko M, Põder P, Sarapohja T (2008) Oral levosimendan in patients with severe chronic heart failure—the PERSIST study. Eur J Heart Fail 10:1246–1254PubMedCrossRef

go back to reference Harjola VP, Oikarinen L, Toivonen L, Jurkko R, Puttonen J, Sarapohja T, Sundberg S, Nieminen MS (2008) The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA classes II–III heart failure. Int J Clin Pharmacol Ther 8:389–399CrossRef Harjola VP, Oikarinen L, Toivonen L, Jurkko R, Puttonen J, Sarapohja T, Sundberg S, Nieminen MS (2008) The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA classes II–III heart failure. Int J Clin Pharmacol Ther 8:389–399CrossRef

go back to reference Põder P, Eha J, Sundberg S, Antila S, Heinpalu M, Loogna I, Planken U, Rantanen S, Lehtonen L (2004) Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study. J Clin Pharmacol 44:1143–1150PubMedCrossRef Põder P, Eha J, Sundberg S, Antila S, Heinpalu M, Loogna I, Planken U, Rantanen S, Lehtonen L (2004) Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study. J Clin Pharmacol 44:1143–1150PubMedCrossRef

go back to reference Nanas JN, Papazoglou P, Tsagalou EP, Ntalianis A, Tsolakis E, Terrovitis JV, Kanakakis J, Nanas SN, Alexopoulos GP, Anastasiou-Nana MI (2005) Efficacy and safety of intermittent, long-term, concomitant dobutamine and levosimendan infusions in severe heart failure refractory to dobutamine alone. Am J Cardiol 95:768–771PubMedCrossRef Nanas JN, Papazoglou P, Tsagalou EP, Ntalianis A, Tsolakis E, Terrovitis JV, Kanakakis J, Nanas SN, Alexopoulos GP, Anastasiou-Nana MI (2005) Efficacy and safety of intermittent, long-term, concomitant dobutamine and levosimendan infusions in severe heart failure refractory to dobutamine alone. Am J Cardiol 95:768–771PubMedCrossRef

go back to reference Parle NM, Thomas MD, Dembo L, Best M, Driscoll GO (2008) Repeated infusions of levosimendan: well tolerated and improves functional capacity in decompensated heart failure—a single-centre experience. Heart Lung Circ 17:206–210PubMedCrossRef Parle NM, Thomas MD, Dembo L, Best M, Driscoll GO (2008) Repeated infusions of levosimendan: well tolerated and improves functional capacity in decompensated heart failure—a single-centre experience. Heart Lung Circ 17:206–210PubMedCrossRef

go back to reference Tuomainen PO, Magga J, Timonen P, Miettinen K, Kurttila M, Vanninen E, Laitinen T, Timonen K, Punnonen K, Parviainen I, Uusaro A, Vuolteenaho O, Kivikko M, Peuhkurinen K (2013) Intermittent levosimendan treatment in patients with severe congestive heart failure. Clin Res Cardiol 102:485–493PubMedCrossRef Tuomainen PO, Magga J, Timonen P, Miettinen K, Kurttila M, Vanninen E, Laitinen T, Timonen K, Punnonen K, Parviainen I, Uusaro A, Vuolteenaho O, Kivikko M, Peuhkurinen K (2013) Intermittent levosimendan treatment in patients with severe congestive heart failure. Clin Res Cardiol 102:485–493PubMedCrossRef

go back to reference Jalanko M, Kivikko M, Harjola VP, Nieminen MS, Laine M (2011) Oral levosimendan improves filling pressure and systolic function during long-term treatment. Scand Cardiovasc J 45:91–97PubMedCrossRef Jalanko M, Kivikko M, Harjola VP, Nieminen MS, Laine M (2011) Oral levosimendan improves filling pressure and systolic function during long-term treatment. Scand Cardiovasc J 45:91–97PubMedCrossRef

go back to reference Bonios M, Terrovitis J, Drakos J, Pozios I, Tseliou E, Katsaros L, Kaldara E, Alexopoulos G, Kanakakis J, Nanas J (2010) Intermittent inotropic infusions for the treatment of refractory end stage heart failure: a randomized clinical study. Abstract presented at ESC Congress 2010 Bonios M, Terrovitis J, Drakos J, Pozios I, Tseliou E, Katsaros L, Kaldara E, Alexopoulos G, Kanakakis J, Nanas J (2010) Intermittent inotropic infusions for the treatment of refractory end stage heart failure: a randomized clinical study. Abstract presented at ESC Congress 2010

go back to reference Altenberger J, Parissis JT, Ulmer H, Poelzl G, Levo Rep Investigators (2010) Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in out patients with advanced heart failure (Levo Rep Study). Eur J Heart Fail 12:186–192PubMedCrossRef Altenberger J, Parissis JT, Ulmer H, Poelzl G, Levo Rep Investigators (2010) Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in out patients with advanced heart failure (Levo Rep Study). Eur J Heart Fail 12:186–192PubMedCrossRef

go back to reference Zhang YH, Qing EM, Zhang J, Huang Y, Lü R, Zhou Q, Wei BQ, An T, Qing P, Zou CH (2012) Hemodynamic and efficacies of domestic levosimendan versus dobutamine in patients with acute decompensated heart failure. Zhonghua Yi Xue Za Zhi. 92:555–558PubMed Zhang YH, Qing EM, Zhang J, Huang Y, Lü R, Zhou Q, Wei BQ, An T, Qing P, Zou CH (2012) Hemodynamic and efficacies of domestic levosimendan versus dobutamine in patients with acute decompensated heart failure. Zhonghua Yi Xue Za Zhi. 92:555–558PubMed

go back to reference Kleber FX, Bollmann T, Borst MM, Costard-Jäckle A, Ewert R, Kivikko M, Petterson T, Pohjanjousi P, Sonntag S, Wikström G (2009) Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study. J Clin Pharmacol 49:109–115PubMedCrossRef Kleber FX, Bollmann T, Borst MM, Costard-Jäckle A, Ewert R, Kivikko M, Petterson T, Pohjanjousi P, Sonntag S, Wikström G (2009) Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study. J Clin Pharmacol 49:109–115PubMedCrossRef

go back to reference Berger R, Moertl D, Huelsmann M, Bojic A, Ahmadi R, Heissenberger I, Pacher R (2007) Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure. Eur J Heart Fail 9:202–208PubMedCrossRef Berger R, Moertl D, Huelsmann M, Bojic A, Ahmadi R, Heissenberger I, Pacher R (2007) Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure. Eur J Heart Fail 9:202–208PubMedCrossRef

go back to reference Bonios MJ, Terrovitis JV, Drakos SG, Katsaros F, Pantsios C, Nanas SN, Kanakakis J, Alexopoulos G, Toumanidis S, Anastasiou-Nana M, Nanas JN (2012) Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure. Int J Cardiol 159:225–229PubMedCrossRef Bonios MJ, Terrovitis JV, Drakos SG, Katsaros F, Pantsios C, Nanas SN, Kanakakis J, Alexopoulos G, Toumanidis S, Anastasiou-Nana M, Nanas JN (2012) Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure. Int J Cardiol 159:225–229PubMedCrossRef

go back to reference Levin R, Porcile R, Tanus E, Degrange M (2009) Abstract 3815: the intermittent infusion of levosimendan reduces mortality and re-admissions in patients with advanced heart failure. Circulation 120:S865CrossRef Levin R, Porcile R, Tanus E, Degrange M (2009) Abstract 3815: the intermittent infusion of levosimendan reduces mortality and re-admissions in patients with advanced heart failure. Circulation 120:S865CrossRef

go back to reference Malfatto G, Della Rosa F, Villani A, Rella V, Branzi G, Facchini M, Parati G (2012) Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance and one-year survival. J Cardiovasc Pharmacol 60:450–455PubMedCrossRef Malfatto G, Della Rosa F, Villani A, Rella V, Branzi G, Facchini M, Parati G (2012) Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance and one-year survival. J Cardiovasc Pharmacol 60:450–455PubMedCrossRef

go back to reference Mavrogeni S, Giamouzis G, Papadopoulou E, Thomopoulou S, Dritsas A, Athanasopoulos G, Adreanides E, Vassiliadis I, Spargias K, Panagiotakos D, Cokkinos DV (2007) 6-month follow-up of intermittent levosimendan administration effect on systolic function, specific activity questionnaire, and arrhythmia in advanced heart failure. J Card Fail 13:556–559PubMedCrossRef Mavrogeni S, Giamouzis G, Papadopoulou E, Thomopoulou S, Dritsas A, Athanasopoulos G, Adreanides E, Vassiliadis I, Spargias K, Panagiotakos D, Cokkinos DV (2007) 6-month follow-up of intermittent levosimendan administration effect on systolic function, specific activity questionnaire, and arrhythmia in advanced heart failure. J Card Fail 13:556–559PubMedCrossRef

go back to reference Parissis JT, Adamopoulos S, Farmakis D, Filippatos G, Paraskevaidis I, Panou F, Iliodromitis E, Kremastinos DT (2006) Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure. Heart 92:1768–1772PubMedCentralPubMedCrossRef Parissis JT, Adamopoulos S, Farmakis D, Filippatos G, Paraskevaidis I, Panou F, Iliodromitis E, Kremastinos DT (2006) Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure. Heart 92:1768–1772PubMedCentralPubMedCrossRef

go back to reference Landoni G, Mizzi A, Biondi-Zoccai G, Bignami E, Prati P, Ajello V, Marino G, Guarracino F, Zangrillo A (2010) Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies. Minerva Anestesiol 76:276–286PubMed Landoni G, Mizzi A, Biondi-Zoccai G, Bignami E, Prati P, Ajello V, Marino G, Guarracino F, Zangrillo A (2010) Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies. Minerva Anestesiol 76:276–286PubMed

go back to reference Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Põder P, Kivikko M, SURVIVE Investigators (2007) Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA 297:1883–1891PubMedCrossRef Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Põder P, Kivikko M, SURVIVE Investigators (2007) Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA 297:1883–1891PubMedCrossRef

go back to reference 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 11:304–311PubMedCentralPubMedCrossRef 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 11:304–311PubMedCentralPubMedCrossRef

go back to reference Kyrzopoulos S, Adamopoulos S, Parissis JT, Rassias J, Kostakis G, Iliodromitis E, Degiannis D, Kremastinos DT (2005) Levosimendan reduces plasma B-type natriuretic peptide and interleukin-6, and improves central hemodynamics in severe heart failure patients. Int J Cardiol 99:409–413PubMedCrossRef Kyrzopoulos S, Adamopoulos S, Parissis JT, Rassias J, Kostakis G, Iliodromitis E, Degiannis D, Kremastinos DT (2005) Levosimendan reduces plasma B-type natriuretic peptide and interleukin-6, and improves central hemodynamics in severe heart failure patients. Int J Cardiol 99:409–413PubMedCrossRef

go back to reference Erdei N, Papp Z, Pollesello P, Edes I, Bagi Z (2006) The levosimendan metabolite OR-1896 elicits vasodilation by activating the KATP and BKCa channels in rat isolated arterioles. Br J Pharmacol 148:696–702PubMedCentralPubMedCrossRef Erdei N, Papp Z, Pollesello P, Edes I, Bagi Z (2006) The levosimendan metabolite OR-1896 elicits vasodilation by activating the KATP and BKCa channels in rat isolated arterioles. Br J Pharmacol 148:696–702PubMedCentralPubMedCrossRef

go back to reference McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P (2012) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P (2012) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69

go back to reference 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 159:82–87PubMedCrossRef 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 159:82–87PubMedCrossRef

go back to reference Majure DT, Greco T, Greco M, Ponschab M, Biondi-Zoccai G, Zangrillo A, Landoni G (2012) Meta-analysis of randomized trials of effect of milrinone on mortality in cardiac surgery: an update. J Cardiothorac Vasc Anesth. doi:10.1053/j.jvca.2012.08.005 PubMed Majure DT, Greco T, Greco M, Ponschab M, Biondi-Zoccai G, Zangrillo A, Landoni G (2012) Meta-analysis of randomized trials of effect of milrinone on mortality in cardiac surgery: an update. J Cardiothorac Vasc Anesth. doi:10.​1053/​j.​jvca.​2012.​08.​005 PubMed