Perioperative use of levosimendan in patients undergoing cardiac surgery: systematic review and meta-analysis
Keywords:
Meta-analysis, Mortality, Cardiac Output, Low, Acute Kidney Injury, Dialysis, Atrial fibrillation
Abstract
Introduction:
Patients undergoing cardiac surgery frequently develop low cardiac output syndrome (LCOS). Multiple interventions including levosimendan have been used in the prevention and treatment of LCOS. Preliminary studies reported lower mortality respect to placebo or other inotropes, however, recently, 3 clinical trials found no benefit against this outcome.
Objective:
Our objective was to evaluate the evidence of levosimendan on mortality and secondary outcomes in patients undergoing cardiac surgery, and to determine the sources of heterogeneity.
Methods:
We conducted a systematic review and meta-analysis of the clinical trials that evaluated the efficacy of levosimendan in patients undergoing cardiac surgery. We obtained the odds ratio (OR) of mortality and other outcomes such as kidney injury with dialysis requirement and LCOS, using fixed and random effects models. The risk of bias was assessed and the sources of heterogeneity were explored.
Results:
Of 47 studies identified, 14 studies were selected (n=2752). Regarding the mortality outcome and use of levosimendan, only a decrease was found in the studies of low quality (OR 0,30; CI 95%, 0,18 to 0,51). While high-quality studies, there was no protective effect (OR 0.99,95% CI 0.70-1.40) with an I2 = 0%. The quality of the studies and ejection fraction were the main sources of heterogeneity.
Conclusion:
In high-quality studies, the use of levosimendan in patients undergoing cardiovascular surgery has no effect on 30-day mortality. There was a protective effect on postoperative renal failure with dialysis.
References
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7. Pilarczyk K, Boening A, Jakob H, et al. Preoperative intra-aortic counterpulsation in high-risk patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. Eur J Cardiothorac Surg 2016;49:5-17.
8. Deppe AC, Weber C, Liakopoulos OJ, et al. Preoperative intra-aortic balloon pump use in high-risk patients prior to coronary artery bypass graft surgery decreases the risk for morbidity and mortality-a meta-analysis of 9,212 patients. J Card Surg 2017;32:177-185.
9. Gaudard P, Mourad M, Eliet J, et al. Management and outcome of patients supported with Impelía 5.0 for refractory cardiogenic shock. Crit Care 2015;19:1-12.
10. Griffith BP, Anderson MB, Samuels LE, et al. The recover I: a multicenter prospective study of Impella 5.0/LD for postcardiotomy circulatory support. J Thorac Cardiovasc Surg 2013;145:548-554.
11. Burkhoff D, Cohen H, Brunckhorst C, et al. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:469.e1-469.e8.
12. Thiagarajan RR, Barbaro RP, Rycus PT, et al. Extracorporeal Life Support Organization Registry International Report 2016. ASAIO J 2017;63:60-67.
13. Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012;159:82-87.
14. McBride BF, White CM. Levosimendan: implications for clinicians. J Clin Pharmacol 2003;43:1071-1081.
15. Faisal SA, Apatov DA, Ramakrishna H, et al. Levosimendan in cardiac surgery: evaluating the evidence. J Cardiothorac Vasc Anesth 2019;33:1146-1158.
16. Harrison RW, Hasselblad V, Mehta RH, et al. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2013;27:1224-1232.
17. Mehta RH, Leimberger JD, van Diepen S, et al. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med 2017;376:2032-2042.
18. Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med 2017;376:2021-2031.
19. Cholley B, Caruba T, Grosjean S, et al. Effect of levosimendan on low cardiac output syndrome in patients with low ejection fraction undergoing coronary artery bypass grafting with cardio-pulmonary bypass-the LICORN randomized clinical trial. JAMA 2017;318:548-556.
20. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1-e34.
21. Cochrane Collaboration Cochrane Manual of Systematic Reviews of Interventions, Version 5.1.0. 2011;1-639, Cochrane Iberoamerican Centre, translators; available at: https://es.cochrane.org/sites/es.cochrane.org/files/public/uploads/Manual_Cochrane_510_reduit.pdf. [Quoted March 21, 2019].
22. Baysal A, Yanartas M, Dogukan M, et al. Levosimendan improves renal outcome in cardiac surgery: a randomized trial. J Cardio-thorac Vasc Anesth 2014;28:586-594.
23. Erb J, Beutlhauser T, Feldheiser A, et al. Influence of levosimendan on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery. J Int Med Res 2014;42:750-764.
24. Sharma P, Malhotra A, Gandhi S, et al. Preoperative levosimendan in ischemic mitral valve repair. Asian Cardiovasc Thorac Ann 2014;22:539-545.
25. Shastri N, Patel J, Malhotra A, et al. Study of levosimendan during off-pump coronary artery bypass grafting in patients with LV dysfunction: a double-blind randomized study. Indian J Pharmacol 2014;46:29.
26. Al-Shawaf E, Ayed A, Vislocky I, et al. Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery. J Cardiothorac Vasc Anesth 2006;20:353-357.
27. De Hert SG, Lorsomradee S, Cromheecke S, et al. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg 2007;104:766-773.
28. Levin RL, Degrange MA, Porcile R, et al. The calcium sensitizer levosimendan gives superior results to dobutamine in postoperative low cardiac output syndrome. Rev Esp Cardiol 2008;61:471-479.
29. Eriksson HI, Jalonen JR, Heikkinen LO, et al. Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann Thorac Surg 2009;87:448-454.
30. Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 2009;102:198-204.
31. Lahtinen P, Pitkänen O, Pölönen P, et al. Levosimendan reduces heart failure after cardiac surgery: a prospective, randomized, placebo-controlled trial. Crit Care Med 2011;39:2263-2270.
32. Levin R, Degrange M, Del Mazo C, et al. 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;17:125-130.
33. Lomivorotov VV, Efremov SM, Kirov MY, et al. Low-cardiac-output after cardiac syndrome surgery. J Cardiothorac Vasc Anesth 2017;31:291-308.
34. Maharaj R, Metaxa V. Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials. Crit Care 2011;15:R140.
35. Lim JY, Deo SV, Rababa’h HA, et al. Levosimendan reduces mortality in adults with left ventricular dysfunction undergoing cardiac surgery: a systematic review and meta-analysis. J Card Surg 2015;30:547-554.
36. Elbadawi A, Elgendy IY, Saad M, et al. Meta-analysis of trials on prophylactic use of levosimendan in patients undergoing cardiac surgery. Ann Thorac Surg 2018;105:1403-1410.
37. Guarracino F, Heringlake M, Cholley B, et al. 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;71:1-9.
38. Sanfilippo F, Knight JB, Scolletta S, et al. Levosimendan for patients with severely reduced left ventricular systolic function and/or low cardiac output syndrome undergoing cardiac surgery: a systematic review and meta-analysis. Crit Care 2017;21:1-10.
39. Glasziou PP, Sanders SL. Investigating causes of heterogeneity in systematic reviews. Stat Med 2002;21:1503-1511.
40. Zhou C, Gong J, Chen D, et al. Levosimendan for prevention of acute kidney injury after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2016;67:408-416.
41. García-González MJ, Jorge-Pérez P, Jiménez-Sosa A, et al. Levosimendan improves hemodynamic status in critically ill patients with severe aortic stenosis and left ventricular dysfunction: an interventional study. Cardiovasc Ther 2015;33:193-199.
42. Yilmaz MB, Grossini E, Silva Cardoso JC, et al. Renal effects of levosimendan: a consensus report. Cardiovasc Drugs Ther 2013; 27:581-590.
43. Alvarez J, Bouzada M, Fernández AL, et al. Hemodynamic effects of levosimendan compared with dobutamine in patients with low cardiac output after cardiac surgery. Rev Esp Cardiol 2006;59:338-345.
44. Leppikangas H, Jrvelä K, Sisto T, et al. Preoperative levosimendan infusion in combined aortic valve and coronary bypass surgery. Br J Anaesth 2011;106:298-304.
2. Mehta R, Grab J, O’Brien S. Clinical characteristics and in-hospital outcomes of patients with cardiogenic shock undergoing coronary artery bypass surgery: insights from the Society of Thoracic Surgeons National Cardiac Database. Circulation 2008;117:876-885.
3. Algarni KD, Maganti M, Yau TM. Predictors of low cardiac output syndrome after isolated coronary artery bypass surgery: trends over 20 years. Ann Thorac Surg 2011;92:1678-1684.
4. Fellahi JL, Parienti JJ, Hanouz JL, et al. Perioperative use of dobutamine in cardiac surgery and adverse cardiac outcome. Anesthesiology 2008;108:979-987.
5. Zangrillo A, Biondi-Zoccai G, Ponschab M, et al. Milrinone and mortality in adult cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2012;26:70-77.
6. Nielsen DV, Torp-Pedersen C, Skals RK, et al. Intraoperative milrinone versus dobutamine in cardiac surgery patients: a retrospective cohort study on mortality. Crit Care 2018;22:1-11.
7. Pilarczyk K, Boening A, Jakob H, et al. Preoperative intra-aortic counterpulsation in high-risk patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. Eur J Cardiothorac Surg 2016;49:5-17.
8. Deppe AC, Weber C, Liakopoulos OJ, et al. Preoperative intra-aortic balloon pump use in high-risk patients prior to coronary artery bypass graft surgery decreases the risk for morbidity and mortality-a meta-analysis of 9,212 patients. J Card Surg 2017;32:177-185.
9. Gaudard P, Mourad M, Eliet J, et al. Management and outcome of patients supported with Impelía 5.0 for refractory cardiogenic shock. Crit Care 2015;19:1-12.
10. Griffith BP, Anderson MB, Samuels LE, et al. The recover I: a multicenter prospective study of Impella 5.0/LD for postcardiotomy circulatory support. J Thorac Cardiovasc Surg 2013;145:548-554.
11. Burkhoff D, Cohen H, Brunckhorst C, et al. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:469.e1-469.e8.
12. Thiagarajan RR, Barbaro RP, Rycus PT, et al. Extracorporeal Life Support Organization Registry International Report 2016. ASAIO J 2017;63:60-67.
13. Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012;159:82-87.
14. McBride BF, White CM. Levosimendan: implications for clinicians. J Clin Pharmacol 2003;43:1071-1081.
15. Faisal SA, Apatov DA, Ramakrishna H, et al. Levosimendan in cardiac surgery: evaluating the evidence. J Cardiothorac Vasc Anesth 2019;33:1146-1158.
16. Harrison RW, Hasselblad V, Mehta RH, et al. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2013;27:1224-1232.
17. Mehta RH, Leimberger JD, van Diepen S, et al. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med 2017;376:2032-2042.
18. Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med 2017;376:2021-2031.
19. Cholley B, Caruba T, Grosjean S, et al. Effect of levosimendan on low cardiac output syndrome in patients with low ejection fraction undergoing coronary artery bypass grafting with cardio-pulmonary bypass-the LICORN randomized clinical trial. JAMA 2017;318:548-556.
20. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1-e34.
21. Cochrane Collaboration Cochrane Manual of Systematic Reviews of Interventions, Version 5.1.0. 2011;1-639, Cochrane Iberoamerican Centre, translators; available at: https://es.cochrane.org/sites/es.cochrane.org/files/public/uploads/Manual_Cochrane_510_reduit.pdf. [Quoted March 21, 2019].
22. Baysal A, Yanartas M, Dogukan M, et al. Levosimendan improves renal outcome in cardiac surgery: a randomized trial. J Cardio-thorac Vasc Anesth 2014;28:586-594.
23. Erb J, Beutlhauser T, Feldheiser A, et al. Influence of levosimendan on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery. J Int Med Res 2014;42:750-764.
24. Sharma P, Malhotra A, Gandhi S, et al. Preoperative levosimendan in ischemic mitral valve repair. Asian Cardiovasc Thorac Ann 2014;22:539-545.
25. Shastri N, Patel J, Malhotra A, et al. Study of levosimendan during off-pump coronary artery bypass grafting in patients with LV dysfunction: a double-blind randomized study. Indian J Pharmacol 2014;46:29.
26. Al-Shawaf E, Ayed A, Vislocky I, et al. Levosimendan or milrinone in the type 2 diabetic patient with low ejection fraction undergoing elective coronary artery surgery. J Cardiothorac Vasc Anesth 2006;20:353-357.
27. De Hert SG, Lorsomradee S, Cromheecke S, et al. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg 2007;104:766-773.
28. Levin RL, Degrange MA, Porcile R, et al. The calcium sensitizer levosimendan gives superior results to dobutamine in postoperative low cardiac output syndrome. Rev Esp Cardiol 2008;61:471-479.
29. Eriksson HI, Jalonen JR, Heikkinen LO, et al. Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann Thorac Surg 2009;87:448-454.
30. Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 2009;102:198-204.
31. Lahtinen P, Pitkänen O, Pölönen P, et al. Levosimendan reduces heart failure after cardiac surgery: a prospective, randomized, placebo-controlled trial. Crit Care Med 2011;39:2263-2270.
32. Levin R, Degrange M, Del Mazo C, et al. 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;17:125-130.
33. Lomivorotov VV, Efremov SM, Kirov MY, et al. Low-cardiac-output after cardiac syndrome surgery. J Cardiothorac Vasc Anesth 2017;31:291-308.
34. Maharaj R, Metaxa V. Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials. Crit Care 2011;15:R140.
35. Lim JY, Deo SV, Rababa’h HA, et al. Levosimendan reduces mortality in adults with left ventricular dysfunction undergoing cardiac surgery: a systematic review and meta-analysis. J Card Surg 2015;30:547-554.
36. Elbadawi A, Elgendy IY, Saad M, et al. Meta-analysis of trials on prophylactic use of levosimendan in patients undergoing cardiac surgery. Ann Thorac Surg 2018;105:1403-1410.
37. Guarracino F, Heringlake M, Cholley B, et al. 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;71:1-9.
38. Sanfilippo F, Knight JB, Scolletta S, et al. Levosimendan for patients with severely reduced left ventricular systolic function and/or low cardiac output syndrome undergoing cardiac surgery: a systematic review and meta-analysis. Crit Care 2017;21:1-10.
39. Glasziou PP, Sanders SL. Investigating causes of heterogeneity in systematic reviews. Stat Med 2002;21:1503-1511.
40. Zhou C, Gong J, Chen D, et al. Levosimendan for prevention of acute kidney injury after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2016;67:408-416.
41. García-González MJ, Jorge-Pérez P, Jiménez-Sosa A, et al. Levosimendan improves hemodynamic status in critically ill patients with severe aortic stenosis and left ventricular dysfunction: an interventional study. Cardiovasc Ther 2015;33:193-199.
42. Yilmaz MB, Grossini E, Silva Cardoso JC, et al. Renal effects of levosimendan: a consensus report. Cardiovasc Drugs Ther 2013; 27:581-590.
43. Alvarez J, Bouzada M, Fernández AL, et al. Hemodynamic effects of levosimendan compared with dobutamine in patients with low cardiac output after cardiac surgery. Rev Esp Cardiol 2006;59:338-345.
44. Leppikangas H, Jrvelä K, Sisto T, et al. Preoperative levosimendan infusion in combined aortic valve and coronary bypass surgery. Br J Anaesth 2011;106:298-304.
How to Cite
1.
Oliveros H, García H, Rubio C, Navarrete J. Perioperative use of levosimendan in patients undergoing cardiac surgery: systematic review and meta-analysis. Colomb. J. Anesthesiol. [Internet]. 2019 Jul. 1 [cited 2024 Apr. 26];47(3):142-53. Available from: https://www.revcolanest.com.co/index.php/rca/article/view/58
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2019-07-01
How to Cite
1.
Oliveros H, García H, Rubio C, Navarrete J. Perioperative use of levosimendan in patients undergoing cardiac surgery: systematic review and meta-analysis. Colomb. J. Anesthesiol. [Internet]. 2019 Jul. 1 [cited 2024 Apr. 26];47(3):142-53. Available from: https://www.revcolanest.com.co/index.php/rca/article/view/58
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