Advertisement

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

  • Wanyu Wang
  • Xiaoshuang Zhou
  • Xinyang Liao
  • Bin LiuEmail author
  • Hai YuEmail author
Review 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.

Keywords

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

Notes

Compliance with ethical standards

Conflict of interest

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

References

  1. 1.
    Diodato M, Chedrawy EG. Coronary artery bypass graft surgery: the past, present, and future of myocardial revascularisation. Surg Res Pract. 2014;2014:726158.Google Scholar
  2. 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. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.Google Scholar
  7. 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.Google Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.Google Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.Google Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.Google Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. 41.
    Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107(1):81–6.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2019

Authors and Affiliations

  1. 1.Department of AnesthesiologyWest China Hospital, Sichuan UniversityChengduChina
  2. 2.Department of Urology, Institute of UrologyWest China Hospital, Sichuan UniversityChengduChina

Personalised recommendations