Skip to main content
SpringerLink
Log in

Impact of Perioperative Levosimendan Administration on Risk of Bleeding After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials

  • Systematic Review
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background

Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen consumption and to show protective effects in other organs. Recently, a prospective, randomized controlled trial (RCT) revealed an association between levosimendan use and a possible increased risk of bleeding postoperatively. Levosimendan’s anti-platelet effects have been shown in in vitro studies. Current studies do not provide sufficient data to support a relation between perioperative levosimendan administration and increased bleeding risk.

Purpose

Our goal was to investigate the relation between perioperative levosimendan administration and increased bleeding risk using a meta-analysis study design.

Methods

The PubMed, Ovid, EMBASE and Cochrane Library databases were searched for relevant RCTs before July 1, 2019. The outcome parameters included reoperation secondary to increased bleeding in the postoperative period, the amount of postoperative recorded blood loss, and the need for transfusion of packed red blood cells (RBCs) and other blood products.

Results

A total of 1160 patients in nine RCTs (576 in the levosimendan group and 584 in the control group) were included according to our inclusion criteria. Analysis showed that perioperative levosimendan administration neither increased the rate of reoperation secondary to bleeding nor increased the amount of postoperative chest tube drainage when compared with the control group. In terms of blood product transfusion, levosimendan did not influence the requirement for RBC transfusion, platelet transfusion nor fresh frozen plasma (FFP) transfusion. Levosimendan also did not shorten or prolong the aortic cross-clamp time or the cardiopulmonary bypass time.

Conclusion

The analyzed parameters, including reoperations due to bleeding, postoperative chest drainage and the requirement for blood products, revealed that levosimendan did not increase postoperative bleeding risk. More studies with a larger sample size are needed to address a more reliable conclusion due to study limitations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. 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. https://doi.org/10.1016/j.ijcard.2011.07.022.

    Article  PubMed  Google Scholar 

  2. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. 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;42(1):43–51.

    Article  CAS  PubMed  Google Scholar 

  3. Gödény I, Pollesello P, Édes I, Papp Z, Bagi Z. Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo. Pharmacol Rep. 2013;65(5):1304–10.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kandasamy A, Simon HA, Murthy P, Annadurai M, Ali MM, Ramanathan G. Comparison of levosimendan versus dobutamine in patients with moderate to severe left ventricular dysfunction undergoing off-pump coronary artery bypass grafting: a randomized prospective study. Ann Cardiac Anaesth. 2017;20(2):200–6. https://doi.org/10.4103/aca.ACA_195_16.

    Article  Google Scholar 

  5. Lahtinen P, Pitkanen O, Musialowicz T. Levosimendan increases bleeding risk after heart valve surgery: a retrospective analysis of a randomized trial. J Cardiothorac Vasc Anesth. 2014;28(5):1238–42. https://doi.org/10.1053/j.jvca.2014.04.022.

    Article  CAS  PubMed  Google Scholar 

  6. Vivacqua A, Koch CG, Yousuf AM, Nowicki ER, Houghtaling PL, Blackstone EH, et al. Morbidity of bleeding after cardiac surgery: is it blood transfusion, reoperation for bleeding, or both? Ann Thorac Surg. 2011;91(6):1780–90. https://doi.org/10.1016/j.athoracsur.2011.03.105.

    Article  PubMed  Google Scholar 

  7. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018;27(6):1785–805. https://doi.org/10.1177/0962280216669183.

    Article  PubMed  Google Scholar 

  8. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. https://doi.org/10.1186/1471-2288-14-135.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sahu MK, Das A, Malik V, Subramanian A, Singh SP, Hote M. Comparison of levosimendan and nitroglycerine in patients undergoing coronary artery bypass graft surgery. Ann Cardiac Anaesth. 2016;19(1):52–8. https://doi.org/10.4103/0971-9784.173020.

    Article  Google Scholar 

  10. Anastasiadis K, Antonitsis P, Vranis K, Kleontas A, Asteriou C, Grosomanidis V, et al. Effectiveness of prophylactic levosimendan in patients with impaired left ventricular function undergoing coronary artery bypass grafting: a randomized pilot study. Interact Cardiovasc Thorac Surg. 2016;23(5):740–7. https://doi.org/10.1093/icvts/ivw213.

    Article  PubMed  Google Scholar 

  11. Landoni G, Lomivorotov VV, Alvaro G, Lobreglio R, Pisano A, Guarracino F, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017;376(21):2021–31. https://doi.org/10.1056/NEJMoa1616325.

    Article  CAS  PubMed  Google Scholar 

  12. Baysal A, Yanartas M, Dogukan M, Gundogus N, Kocak T, Koksal C. Levosimendan improves renal outcome in cardiac surgery: a randomized trial. J Cardiothorac Vasc Anesth. 2014;28(3):586–94. https://doi.org/10.1053/j.jvca.2013.09.004.

    Article  CAS  PubMed  Google Scholar 

  13. Tritapepe L, De Santis V, Vitale D, Guarracino F, Pellegrini F, Pietropaoli P, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth. 2009;102(2):198–204. https://doi.org/10.1093/bja/aen367.

    Article  CAS  PubMed  Google Scholar 

  14. Lomivorotov VV, Boboshko VA, Efremov SM, Kornilov IA, Chernyavskiy AM, Lomivorotov VN, et al. Levosimendan versus an intra-aortic balloon pump in high-risk cardiac patients. J Cardiothorac Vasc Anesth. 2012;26(4):596–603. https://doi.org/10.1053/j.jvca.2011.09.006.

    Article  CAS  PubMed  Google Scholar 

  15. Malik V, Subramanian A, Hote M, Kiran U. Effect of levosimendan on diastolic function in patients undergoing coronary artery bypass grafting: a comparative study. J Cardiovasc Pharmacol. 2015;66(2):141–7. https://doi.org/10.1097/fjc.0000000000000256.

    Article  CAS  PubMed  Google Scholar 

  16. Kaptan K, Erinc K, Ifran A, Yildirim V, Uzun M, Beyan C, et al. Levosimendan has an inhibitory effect on platelet function. Am J Hematol. 2008;83(1):46–9.

    Article  CAS  PubMed  Google Scholar 

  17. Ambrus N, Szolnoky JA, Pollesello P, Kun A, Varró A, Papp JG, et al. Prolonged antispasmodic effect in isolated radial artery graft and pronounced platelet inhibition induced by the inodilator drug, levosimendan. Basic Clin Pharmacol Toxicol. 2012;110(3):269–74. https://doi.org/10.1111/j.1742-7843.2011.00801.x.

    Article  CAS  PubMed  Google Scholar 

  18. Plaschke K, Bent F, Rosenhagen C, Wagner S, Hofer S, Kopitz J. The inhibitory in vitro effect of high-dose levosimendan on platelet function may be mediated through its action as a phosphodiesterase inhibitor. Coron Artery Dis. 2012;23(3):215–20. https://doi.org/10.1097/MCA.0b013e32835167cc.

    Article  PubMed  Google Scholar 

  19. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Executive summary: heart disease and stroke statistics–2016 Update: a report from the American Heart Association. Circulation. 2016;133(4):447–54. https://doi.org/10.1161/CIR.0000000000000366.

    Article  PubMed  Google Scholar 

  20. Emeklibas N, Kammerer I, Bach J, Sack F-U, Hellstern P. Preoperative hemostasis and its association with bleeding and blood component transfusion requirements in cardiopulmonary bypass surgery. Transfusion. 2013;53(6):1226–34. https://doi.org/10.1111/j.1537-2995.2012.03885.x.

    Article  PubMed  Google Scholar 

  21. Desborough M, Sandu R, Brunskill SJ, Doree C, Trivella M, Montedori A, et al. Fresh frozen plasma for cardiovascular surgery. Cochrane Database Syst Rev. 2015;7:cd007614. https://doi.org/10.1002/14651858.cd007614.pub2.

    Article  Google Scholar 

  22. Koch CG, Li L, Duncan AI, Mihaljevic T, Loop FD, Starr NJ, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg. 2006;81(5):1650–7.

    Article  PubMed  Google Scholar 

  23. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229–39. https://doi.org/10.1056/NEJMoa070403.

    Article  CAS  PubMed  Google Scholar 

  24. Dorneles CDC, Bodanese LC, Guaragna JCVDC, Macagnan FE, Coelho JC, Borges AP, et al. The impact of blood transfusion on morbidity and mortality after cardiac surgery. Rev Bras Cirurg Cardiovasc. 2011;26(2):222–9.

    Article  Google Scholar 

  25. Biancari F, Mikkola R, Heikkinen J, Lahtinen J, Airaksinen KE, Juvonen T. Estimating the risk of complications related to re-exploration for bleeding after adult cardiac surgery: a systematic review and meta-analysis. Eur J Cardiothorac Surg. 2012;41(1):50–5. https://doi.org/10.1016/j.ejcts.2011.04.023.

    Article  PubMed  Google Scholar 

  26. Kristensen KL, Rauer LJ, Mortensen PE, Kjeldsen BJ. Reoperation for bleeding in cardiac surgery. Interact Cardiovasc Thorac Surg. 2012;14(6):709–13. https://doi.org/10.1093/icvts/ivs050.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Frojd V, Jeppsson A. Reexploration for bleeding and its association with mortality after cardiac surgery. Ann Thorac Surg. 2016;102(1):109–17. https://doi.org/10.1016/j.athoracsur.

    Article  PubMed  Google Scholar 

  28. Ruel M, Chan V, Boodhwani M, McDonald B, Ni X, Gill G, et al. How detrimental is reexploration for bleeding after cardiac surgery? J Thorac Cardiovasc Surg. 2017;154(3):927–35. https://doi.org/10.1016/j.jtcvs.2016.04.097.

    Article  PubMed  Google Scholar 

  29. Salis S, Mazzanti VV, Merli G, Salvi L, Tedesco CC, Veglia F, et al. Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth. 2008;22(6):814–22. https://doi.org/10.1053/j.jvca.2008.08.004.

    Article  PubMed  Google Scholar 

  30. Iino K, Miyata H, Motomura N, Watanabe G, Tomita S, Takemura H, et al. prolonged cross-clamping during aortic valve replacement is an independent predictor of postoperative morbidity and mortality: analysis of the Japan Cardiovascular Surgery Database. Ann Thorac Surg. 2017;103(2):602–9. https://doi.org/10.1016/j.athoracsur.2016.06.060.

    Article  PubMed  Google Scholar 

  31. Haithcock BE, Shepard AD, Raman SB, Conrad MF, Pandurangi K, Fanous NH. Activation of fibrinolytic pathways is associated with duration of supraceliac aortic cross-clamping. J Vasc Surg. 2004;40(2):325–33. https://doi.org/10.1016/j.jvs.2004.04.015.

    Article  PubMed  Google Scholar 

  32. Zangrillo A, Biondi-Zoccai G, Mizzi A, Bruno G, Bignami E, Gerli C, et al. Levosimendan reduces cardiac troponin release after cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth. 2009;23(4):474–8. https://doi.org/10.1053/j.jvca.2008.11.013.

    Article  CAS  PubMed  Google Scholar 

  33. Kivikko M, Kuoppamäki M, Soinne L, Sundberg S, Pohjanjousi P, Ellmen J, et al. Oral levosimendan increases cerebral blood flow velocities in patients with a history of stroke or transient ischemic attack: a pilot safety study. Curr Therap Res. 2015;77:46–51. https://doi.org/10.1016/j.curtheres.2015.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, No.107, Wen Hua Xi Road, Jinan, 250012, China

    Sen-bo Yan, Guo-kai Shang, Zhi-hao Wang, Qi-ming Deng, Jia-wen Song, Wen-wen Sai, Ming Song, Ming Zhong & Wei Zhang

  2. Department of Pharmacy, Qilu Children’s Hospital of Shandong University, Children’s Hospital of Jinan, Jinan, Shandong, China

    Xiao-yan Wang

  3. Department of Geriatric Medicine, Qilu Hospital of Shandong University, Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, Shandong, China

    Zhi-hao Wang

Authors
  1. Sen-bo Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guo-kai Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi-ming Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jia-wen Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-wen Sai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ming Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ming Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Zhang.

Ethics declarations

Funding

This study was funded by the Integrated Thinking Research Fund of Cardiology (CIMF-Z-2016-23-1823), the National Natural Science Foundation of China (81873534, 81702194, 81600633, 81670411, 81570400, 81470560, 81471036), the key research and development program of Shandong Province (2018GSF118002, 2018GSF118017, 2017GSF18156), and the Natural Science Foundation of Shandong Province (ZR2017BH023).

Conflict of interest

Sen-bo Yan, Xiao-yan Wang, Guo-kai Shang, Zhi-hao Wang, Qi-ming Deng, Jia-wen Song, Wen-wen Sai, Ming Song, Ming Zhong and Wei Zhang declare that they have no potential conflicts of interest that might be relevant to the contents of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 22 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, Sb., Wang, Xy., Shang, Gk. et al. Impact of Perioperative Levosimendan Administration on Risk of Bleeding After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials. Am J Cardiovasc Drugs 20, 149–160 (2020). https://doi.org/10.1007/s40256-019-00372-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-019-00372-2

Search

Navigation