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The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: a systematic review and meta-analysis

Journal of Anesthesia volume 33, pages 543–550 (2019)Cite this article

Abstract

Prophylactic use of levosimendan in cardiac surgery remains controversial and no meta-analysis has been done exclusively about that in patients undergoing coronary artery bypass graft (CABG) surgery. We conducted this systematic review and meta-analysis of levosimendan in CABG using PubMed, Embase, Scopus, and Cochrane Library (till April 20, 2018). Two-hundred and forty manuscripts were identified and 21 randomized trials (1727 patients in total) investigating the effect of levosimendan on the patients undergoing CABG surgery were finally included in this analysis. We found that levosimendan was an effective, well-tolerated inotropic agent in CABG, which was associated with a significantly reduced mortality rate [odds ratio (OR) 0.43, 95% confidence interval (CI) (0.26, 0.71), p = 0.001, I2 = 0%] and postoperative atrial fibrillation [OR 0.50, 95% CI (0.26, 0.97), p = 0.04, I2 = 76%], but a higher incidence of hypotension [OR 2.26, 95% CI (1.05, 4.85), p = 0.04, I2 = 79%]. Subgroup analyses revealed that such a benefit was mainly observed in the isolated CABG, the preoperative administration, with-bolus and on-pump subgroups. More high-quality and well-designed prospective studies are needed to confirm or disprove our findings in future.

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References

  1. Diodato M, Chedrawy EG. Coronary artery bypass graft surgery: the past, present, and future of myocardial revascularisation. Surg Res Pract. 2014;2014:726158.

    PubMed  PubMed Central  Google Scholar 

  2. Weiss AJ, Elixhauser A. Trends in operating room procedures in US Hospitals, 2001–2011: statistical brief #171. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Agency for Healthcare Research and Quality (US): Rockville; 2006.

    Google Scholar 

  3. Nalysnyk L, Fahrbach K, Reynolds MW, Zhao SZ, Ross S. Adverse events in coronary artery bypass graft (CABG) trials: a systematic review and analysis. Heart. 2003;89(7):767–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mebazaa A, Pitsis AA, Rudiger A, Toller W, Longrois D, Ricksten SE, Bobek I, De Hert S, Wieselthaler G, Schirmer U, von Segesser LK, Sander M, Poldermans D, Ranucci M, Karpati PC, Wouters P, Seeberger M, Schmid ER, Weder W, Follath F. Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery. Crit Care. 2010;14(2):201.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Algarni KD, Maganti M, Yau TM. Predictors of low cardiac output syndrome after isolated coronary artery bypass surgery: trends over 20 years. Ann Thor Surg. 2011;92(5):1678–84.

    Article  Google Scholar 

  6. Landoni G, Bove T, Crivellari M, Poli D, Fochi O, Marchetti C, Romano A, Marino G, Zangrillo A. Acute renal failure after isolated CABG surgery: 6 years of experience. Minerva Anestesiol. 2007;73(11):559–65.

    CAS  PubMed  Google Scholar 

  7. Vela JP, Rivera JJ, Llorente MA, de Marcos BG, Torrado H, Laborda CG, Zamora MF, Fernández FG, Benítez JM. Low cardiac output syndrome in the postoperative period of cardiac surgery. Profile, differences in clinical course and prognosis. The ESBAGA study. Med Intensiva. 2018;42(3):159-6.

  8. Fellahi JL, Parienti JJ, Hanouz JL, Plaud B, Riou B, Ouattara A. Perioperative use of dobutamine in cardiac surgery and adverse cardiac outcome propensity-adjusted analyses. Anesthesiology. 2008;108(6):979–87. https://doi.org/10.1097/ALN.0b013e318173026f.

    Article  CAS  PubMed  Google Scholar 

  9. Nielsen DV, Hansen MK, Johnsen SP, Hansen M, Hindsholm K, Jakobsen CJ. Health outcomes with and without use of inotropic therapy in cardiac surgery: results of a propensity score-matched analysis. Anesthesiology. 2014;120(5):1098–108. https://doi.org/10.1097/ALN.0000000000000224.

    Article  PubMed  Google Scholar 

  10. Levijoki J, Pollesello P, Kaivola J, Tilgmann C, Sorsa T, Annila A, Kilpeläinen I, Haikala H. 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;32(3):479–91.

    Article  CAS  PubMed  Google Scholar 

  11. Lilleberg J, Nieminen MS, Akkila J, Heikkilä L, Kuitunen A, Lehtonen L, Verkkala K, Mattila S, Salmenperä M. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J. 1998;19(4):660–8.

    Article  CAS  PubMed  Google Scholar 

  12. Ukkonen H, Saraste M, Akkila J, Knuuti MJ, Lehikoinen P, Någren K, Lehtonen L, Voipio-Pulkki LM. Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Thera. 1997;61(5):596–607.

    Article  CAS  Google Scholar 

  13. du Toit EF, Genis A, Opie LH, Pollesello P, Lochner A. A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart. Br J Pharmacol. 2008;154(1):41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Levijoki J, Pollesello P, Kaheinen P, Haikala H. Improved survival with simendan after experimental myocardial infarction in rats. Eur J Pharmacol. 2001;419(2–3):243–8.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Belletti A, Castro ML, Silvetti S, Greco T, Biondi-Zoccai G, Pasin L, Zangrillo A, Landoni G. The Effect of inotropes and vasopressors on mortality: a meta-analysis of randomized clinical trials. Br J Anaesth. 2015;115(5):656–75.

    Article  CAS  PubMed  Google Scholar 

  17. Landoni G, Biondi-Zoccai G, Greco M, Greco T, Bignami E, Morelli A, Guarracino F, Zangrillo A. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med. 2012;40(2):634-646.

  18. Harrison RW, Hasselblad V, Mehta RH, Levin R, Harrington RA, Alexander JH. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth. 2013;27(6):1224–322.

    Article  CAS  PubMed  Google Scholar 

  19. Greco T, Calabrò MG, Covello RD, Greco M, Pasin L, Morelli A, Landoni G, Zangrillo A. A Bayesian network meta-analysis on the effect of inodilatory agents on mortality. Br J Anaesth. 2015;114(5):746–56.

    Article  CAS  PubMed  Google Scholar 

  20. Koster G, Wetterslev J, Gluud C, Zijlstra JG, Scheeren TW, van der Horst IC, Keus F. 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.

    Article  CAS  PubMed  Google Scholar 

  21. Putzu A, Clivio S, Belletti A, Cassina T. Perioperative levosimendan in cardiac surgery: A systematic review with meta-analysis and trial sequential analysis. Int J Cardiol. 2018;251:22–31.

    Article  PubMed  Google Scholar 

  22. Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012;17(3):125–30.

    PubMed  PubMed Central  Google Scholar 

  23. Cholley B, Caruba T, Grosjean S, Amour J, Ouattara A, Villacorta J, Miguet B, Guinet P, Lévy F, Squara P, Hamou NA. Effect of levosimendan on low cardiac output syndrome in patients with low ejection fraction undergoing coronary artery bypass grafting with cardiopulmonary bypass: the LICORN randomized clinical trial. JAMA. 2017;318(6):548–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mehta RH, Leimberger JD, van Diepen S, Meza J, Wang A, Jankowich R, Harrison RW, Hay D, Fremes S, Duncan A, Soltesz EG. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med. 2017;376(21):2032–42.

    Article  CAS  PubMed  Google Scholar 

  25. Landoni G, Lomivorotov VV, Alvaro G, Lobreglio R, Pisano A, Guarracino F, Calabrò MG, Grigoryev EV, Likhvantsev VV, Salgado-Filho MF, Bianchi A. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017;376(21):2021–31.

    Article  CAS  PubMed  Google Scholar 

  26. Guarracino F, Heringlake M, Cholley B, Bettex D, Bouchez S, Lomivorotov VV, Rajek A, Kivikko M, Pollesello P. Use of levosimendan in cardiac surgery: an update after the LEVO–CTS, CHEETAH, and LICORN trials in the light of clinical practice. J Cardiovasc Pharmacol. 2018;71(1):1–9. https://doi.org/10.1097/FJC.0000000000000551.

    Article  CAS  PubMed  Google Scholar 

  27. Elbadawi A, Elgendy IY, Saad M, Megaly M, Mentias A, Abuzaid AS, Shahin HI, Goswamy V, Abowali H, London B. Meta-analysis of trials on prophylactic use of levosimendan in patients undergoing cardiac surgery. Ann Thorac Surg. 2018;105(5):1403–10. https://doi.org/10.1016/j.athoracsur.2017.11.027.

    Article  PubMed  Google Scholar 

  28. Pollesello P, Parissis J, Kivikko M, Harjola VP. Levosimendan meta-analyses: is there a pattern in the effect on mortality? Int J Cardiol. 2016;209:77–83.

    Article  CAS  PubMed  Google Scholar 

  29. Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from: www.handbook.cochrane.org.

  30. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Al-Shawaf E, Ayed A, Vislocky I, Radomir B, Dehrab N, Tarazi R. Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery. J Cardiothorac Vasc Anesth. 2006;20(3):353–7.

    Article  CAS  PubMed  Google Scholar 

  32. Desai PM, Sarkar MS, Umbarkar SR. Prophylactic preoperative levosimendan for off-pump coronary artery bypass grafting in patients with left ventricular dysfunction: Single-centered randomized prospective study. Ann Card Anaesth. 2018;21(2):123–8. https://doi.org/10.4103/aca.ACA_178_17.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sahin V, Uyar IS, Gul I, Akpinar MB, Abacilar AF, Uc H, Okur FF, Tavli T, Ates M, Alayunt EA. Evaluation of myocardial contractility determination with tissue tracking echocardiography after levosimendan infusion in patients with poor left ventricular function and hemodynamics. Heart Surg Forum. 2014;17(6):E313–8. https://doi.org/10.1532/HSF98.2014415.

    Article  PubMed  Google Scholar 

  34. Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, Barash PG, Hsu PH, Mangano DT. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA. 2004;291(14):1720–9.

    Article  CAS  PubMed  Google Scholar 

  35. Zangrillo A, Alvaro G, Belletti A, Pisano A, Brazzi L, Calabrò MG, Guarracino F, Bove T, Grigoryev EV, Monaco F, Boboshko VA. Effect of levosimendan on renal outcome in cardiac surgery patients with chronic kidney disease and perioperative cardiovascular dysfunction: a substudy of a multicenter randomized trial. J Cardiothorac Vasc Anesth. 2018;32(5):2152–9.

    Article  CAS  PubMed  Google Scholar 

  36. Abacilar AF, Dogan OF. Levosimendan use decreases atrial fibrillation in patients after coronary artery bypass grafting: a pilot study. Heart Surg Forum. 2013;16(5):E287–94.

    Article  PubMed  Google Scholar 

  37. Pagel PS, Harkin CP, Hettrick DA, Warltier DC. Levosimendan (OR-1259), a myofilament calcium sensitizer, enhances myocardial contractility but does not alter isovolumic relaxation in conscious and anesthetized dogs. Anesthesiology. 1994;81(4):974–87.

    Article  CAS  PubMed  Google Scholar 

  38. Haikala H, Kaheinen P, Levijoki J, Lindén IB. The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res. 1997;34(3):536–46.

    Article  CAS  PubMed  Google Scholar 

  39. Lilleberg J, Laine M, Palkama T, Kivikko M, Pohjanjousi P, Kupari M. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. Eur J Heart Fail. 2007;9(1):75–82.

    Article  CAS  PubMed  Google Scholar 

  40. Slawsky MT, Colucci WS, Gottlieb SS, Greenberg BH, Haeusslein E, Hare J, Hutchins S, Leier CV, LeJemtel TH, Loh E, Nicklas J. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure: study investigators. Circulation. 2000;102(18):2222–7.

    Article  CAS  PubMed  Google Scholar 

  41. Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107(1):81–6.

    Article  CAS  PubMed  Google Scholar 

  42. Toller W, Heringlake M, Guarracino F, Algotsson L, Alvarez J, Argyriadou H, Ben-Gal T, Černý V, Cholley B, Eremenko A, Guerrero-Orriach JL. Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion. Int J Cardiol. 2015;184:323–36.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Wanyu Wang, Xiaoshuang Zhou, Bin Liu & Hai Yu

  2. Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Xinyang Liao

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  1. Wanyu Wang
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  2. Xiaoshuang Zhou
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Cite this article

Wang, W., Zhou, X., Liao, X. et al. The efficacy and safety of prophylactic use of levosimendan on patients undergoing coronary artery bypass graft: a systematic review and meta-analysis. J Anesth 33, 543–550 (2019). https://doi.org/10.1007/s00540-019-02643-3

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  • DOI: https://doi.org/10.1007/s00540-019-02643-3

Keywords

  • Coronary artery bypass graft (CABG)
  • Levosimendan
  • Efficacy
  • Safety
  • Meta-analysis
  • Systematic review