American Journal of Cardiovascular Drugs

, Volume 17, Issue 6, pp 453–463 | Cite as

Effects of Levosimendan on Patients with Heart Failure Complicating Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials

  • Guokai Shang
  • Xinyan Yang
  • Daijun Song
  • Yun Ti
  • Yuanyuan Shang
  • Zhihao Wang
  • Mengxiong Tang
  • Yun Zhang
  • Wei Zhang
  • Ming Zhong
Systematic Review



The prognosis for patients with heart failure (HF), including cardiogenic shock (CS), complicating acute coronary syndrome (ACS) remains poor.


This study aimed to review the relevant literature and evaluate whether levosimendan was associated with better clinical outcomes in these patients.


We searched PubMed, EMBASE, and the Cochrane library databases for randomized controlled trials that investigated levosimendan compared with any control in patients with HF/CS complicating ACS.


A total of 1065 patients from nine trials were included in this study. Analysis showed that levosimendan significantly reduced total mortality and the incidence of worsening HF. In patients with HF-ACS, levosimendan was associated with reduced mortality. In patients with CS-ACS, no significant difference was observed between the two groups. Levosimendan contributed to significantly reduced mortality when compared with placebo, but no significant reduction was seen compared with dobutamine. Compared with controls, levosimendan decreased pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac index, with no significant difference observed between the groups in terms of heart rate. Levosimendan non-significantly increased the risk of hypotension but did not increase the risk of ischemic episodes, sinus tachycardia, atrial fibrillation, or ventricular arrhythmias.


Levosimendan appears to be a promising drug to reduce mortality and worsening HF in patients with HF/CS-ACS. It appears to provide hemodynamic benefit and was associated with an increased risk of hypotension.


Compliance with Ethical Standards


This study was funded by research grants from the State Program of National Science Foundation of China for Innovative Research Group (Grant 81321061), the National Natural Science Foundation of China (91439201, 81100605, 81270352, 81270287, 81300168, 81471036, 81470560, and 81570400), the Natural Science Foundation of Shandong Province (ZR2014HQ037), the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP 20130131120065), and Key Research and Development Program of Shandong Province (2015GSF118062).

Conflicts of interest

GS, XY, DS, YT, YS, ZW, MT, YZ, WZ, and MZ have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.


  1. 1.
    Aissaoui N, Puymirat E, Tabone X, Charbonnier B, Schiele F, Lefevre T, et al. Improved outcome of cardiogenic shock at the acute stage of myocardial infarction: a report from the USIK 1995, USIC 2000, and FAST-MI French nationwide registries. Eur Heart J. 2012;33(20):2535–43. doi: 10.1093/eurheartj/ehs264.CrossRefPubMedGoogle Scholar
  2. 2.
    Desta L, Jernberg T, Lofman I, Hofman-Bang C, Hagerman I, Spaak J, et al. Incidence, temporal trends, and prognostic impact of heart failure complicating acute myocardial infarction. The SWEDEHEART Registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies): a study of 199,851 patients admitted with index acute myocardial infarctions, 1996 to 2008. JACC Heart Fail. 2015;3(3):234–42. doi: 10.1016/j.jchf.2014.10.007.CrossRefPubMedGoogle Scholar
  3. 3.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200. doi: 10.1093/eurheartj/ehw128.CrossRefPubMedGoogle Scholar
  4. 4.
    Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725–36. doi: 10.1093/eurheartj/ehl193.CrossRefPubMedGoogle Scholar
  5. 5.
    Tarvasmaki T, Harjola VP, Nieminen MS, Siirila-Waris K, Tolonen J, Tolppanen H, et al. Acute heart failure with and without concomitant acute coronary syndromes: patient characteristics, management, and survival. J Card Fail. 2014;20(10):723–30. doi: 10.1016/j.cardfail.2014.07.008.CrossRefPubMedGoogle Scholar
  6. 6.
    Aronson D, Krum H. Novel therapies in acute and chronic heart failure. Pharmacol Ther. 2012;135(1):1–17. doi: 10.1016/j.pharmthera.2012.03.002.CrossRefPubMedGoogle Scholar
  7. 7.
    Bayram M, De Luca L, Massie MB, Gheorghiade M. Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes. Am J Cardiol. 2005;96(6A):47G–58G. doi: 10.1016/j.amjcard.2005.07.021.CrossRefPubMedGoogle Scholar
  8. 8.
    Pathak A, Lebrin M, Vaccaro A, Senard JM, Despas F. Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects. J Clin Pharm Ther. 2013;38(5):341–9. doi: 10.1111/jcpt.12067.CrossRefPubMedGoogle Scholar
  9. 9.
    Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159(2):82–7. doi: 10.1016/j.ijcard.2011.07.022.CrossRefPubMedGoogle Scholar
  10. 10.
    Moreno N, Tavares-Silva M, Lourenco AP, Oliveira-Pinto J, Henriques-Coelho T, Leite-Moreira AF. Levosimendan: the current situation and new prospects. Rev Port Cardiol. 2014;33(12):795–800. doi: 10.1016/j.repc.2014.05.009.PubMedGoogle Scholar
  11. 11.
    Nieminen MS, Buerke M, Cohen-Solal A, Costa S, Edes I, Erlikh A, et al. The role of levosimendan in acute heart failure complicating acute coronary syndrome: a review and expert consensus opinion. Int J Cardiol. 2016;218:150–7. doi: 10.1016/j.ijcard.2016.05.009.CrossRefPubMedGoogle Scholar
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336–41. doi: 10.1016/j.ijsu.2010.02.007.CrossRefPubMedGoogle Scholar
  13. 13.
    Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011.
  14. 14.
    De Luca L, Proietti P, Celotto A, Bucciarelli-Ducci C, Benedetti G, Di Roma A, et al. Levosimendan improves hemodynamics and coronary flow reserve after percutaneous coronary intervention in patients with acute myocardial infarction and left ventricular dysfunction. Am Heart J. 2005;150(3):563–8. doi: 10.1016/j.ahj.2004.10.013.CrossRefPubMedGoogle Scholar
  15. 15.
    De Luca L, Sardella G, Proietti P, Battagliese A, Benedetti G, Di Roma A, et al. Effects of levosimendan on left ventricular diastolic function after primary angioplasty for acute anterior myocardial infarction: a Doppler echocardiographic study. J Am Soc Echocardiogr. 2006;19(2):172–7. doi: 10.1016/j.echo.2005.08.016.CrossRefPubMedGoogle Scholar
  16. 16.
    Jia Z, Guo M, Zhang YQ, Liang HQ, Zhang LY, Song Y. Efficacy of intravenous levosimendan in patients with heart failure complicated by acute myocardial infarction. Cardiology. 2014;128(2):195–201. doi: 10.1159/000357864.CrossRefPubMedGoogle Scholar
  17. 17.
    Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297(17):1883–91. doi: 10.1001/jama.297.17.1883.CrossRefPubMedGoogle Scholar
  18. 18.
    Moiseyev VS, Poder P, Andrejevs N, Ruda MY, Golikov AP, Lazebnik LB, 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;23(18):1422–32.CrossRefPubMedGoogle Scholar
  19. 19.
    Wu X, Wu J, Yan X, Zhang Y. Enhancement of myocardial function and reduction of injury with levosimendan after percutaneous coronary intervention for acute myocardial infarction: a pilot study. Cardiology. 2014;128(2):202–8. doi: 10.1159/000360933.CrossRefPubMedGoogle Scholar
  20. 20.
    Dominguez-Rodriguez A, Samimi-Fard S, Garcia-Gonzalez MJ, Abreu-Gonzalez P. Effects of levosimendan versus dobutamine on left ventricular diastolic function in patients with cardiogenic shock after primary angioplasty. Int J Cardiol. 2008;128(2):214–7. doi: 10.1016/j.ijcard.2007.05.018.CrossRefPubMedGoogle Scholar
  21. 21.
    Fuhrmann JT, Schmeisser A, Schulze MR, Wunderlich C, Schoen SP, Rauwolf T, et al. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2008;36(8):2257–66. doi: 10.1097/CCM.0b013e3181809846.CrossRefPubMedGoogle Scholar
  22. 22.
    Garcia-Gonzalez MJ, Dominguez-Rodriguez A, Ferrer-Hita JJ, Abreu-Gonzalez P, Munoz MB. Cardiogenic shock after primary percutaneous coronary intervention: effects of levosimendan compared with dobutamine on haemodynamics. Eur J Heart Fail. 2006;8(7):723–8. doi: 10.1016/j.ejheart.2006.01.007.CrossRefPubMedGoogle Scholar
  23. 23.
    Samimi-Fard S, Garcia-Gonzalez MJ, Dominguez-Rodriguez A, Abreu-Gonzalez P. Effects of levosimendan versus dobutamine on long-term survival of patients with cardiogenic shock after primary coronary angioplasty. Int J Cardiol. 2008;127(2):284–7. doi: 10.1016/j.ijcard.2007.04.143.CrossRefPubMedGoogle Scholar
  24. 24.
    Husebye T, Eritsland J, Muller C, Sandvik L, Arnesen H, Seljeflot I, et al. Levosimendan in acute heart failure following primary percutaneous coronary intervention-treated acute ST-elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo-controlled study. Eur J Heart Fail. 2013;15(5):565–72. doi: 10.1093/eurjhf/hfs215.CrossRefPubMedGoogle Scholar
  25. 25.
    Landoni G, Mizzi A, Biondi-Zoccai G, Bignami E, Prati P, Ajello V, et al. Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies. Minerva Anestesiol. 2010;76(4):276–86.PubMedGoogle Scholar
  26. 26.
    Koster G, Wetterslev J, Gluud C, Zijlstra JG, Scheeren TW, van der Horst IC, et al. Effects of levosimendan for low cardiac output syndrome in critically ill patients: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2015;41(2):203–21. doi: 10.1007/s00134-014-3604-1.CrossRefPubMedGoogle Scholar
  27. 27.
    Gong B, Li Z, Yat Wong PC. levosimendan treatment for heart failure: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2015;29(6):1415–25. doi: 10.1016/j.ijcard.2015.08.188.CrossRefPubMedGoogle Scholar
  28. 28.
    Huang X, Lei S, Zhu MF, Jiang RL, Huang LQ, Xia GL, et al. Levosimendan versus dobutamine in critically ill patients: a meta-analysis of randomized controlled trials. J Zhejiang Univ Sci. 2013;14(5):400–15. doi: 10.1631/jzus.B1200290.CrossRefGoogle Scholar
  29. 29.
    Maharaj R, Metaxa V. Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials. Crit Care. 2011;15(3):R140. doi: 10.1186/cc10263.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Delaney A, Bradford C, McCaffrey J, Bagshaw SM, Lee R. Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials. Int J Cardiol. 2010;138(3):281–9. doi: 10.1016/j.ijcard.2008.08.020.CrossRefPubMedGoogle Scholar
  31. 31.
    Ribeiro RA, Rohde LE, Polanczyk CA. Levosimendan in acute decompensated heart failure: systematic review and meta-analysis. Arq Bras Cardiol. 2010;95(2):230–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Michaels AD, McKeown B, Kostal M, Vakharia KT, Jordan MV, Gerber IL, et al. Effects of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circulation. 2005;111(12):1504–9. doi: 10.1161/01.CIR.0000159252.82444.22.CrossRefPubMedGoogle Scholar
  33. 33.
    Sonntag S, Sundberg S, Lehtonen LA, Kleber FX. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol. 2004;43(12):2177–82. doi: 10.1016/j.jacc.2004.02.052.CrossRefPubMedGoogle Scholar
  34. 34.
    Russ MA, Prondzinsky R, Christoph A, Schlitt A, Buerke U, Soffker G, et al. Hemodynamic improvement following levosimendan treatment in patients with acute myocardial infarction and cardiogenic shock. Crit Care Med. 2007;35(12):2732–9. doi: 10.1097/01.ccm.0000287524.17358.48.PubMedGoogle Scholar
  35. 35.
    Christoph A, Prondzinsky R, Russ M, Janusch M, Schlitt A, Lemm H, et al. Early and sustained haemodynamic improvement with levosimendan compared to intraaortic balloon counterpulsation (IABP) in cardiogenic shock complicating acute myocardial infarction. Acute Card Care. 2008;10(1):49–57. doi: 10.1080/17482940701358564.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of CardiologyQilu Hospital of Shandong UniversityJi’nanPeople’s Republic of China
  2. 2.Department of EmergencyDonggang People’s HospitalRizhaoPeople’s Republic of China
  3. 3.Department of GeriatricsQilu Hospital of Shandong UniversityJi’nanPeople’s Republic of China
  4. 4.Department of EmergencyQilu Hospital of Shandong UniversityJi’nanPeople’s Republic of China

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