Levosimendan Does Not Reduce Mortality in Cardiac Surgery

LETTERS TO THE EDITOR

Levosimendan Does Not Reduce Mortality in Cardiac Surgery

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in patients undergoing cardiac surgery. To confirm our results, however, a large randomized controlled trial would be needed. Hisato Takagi, MD, PhD Takuya Umemoto, MD, PhD Department of Cardiovascular Surgery Shizuoka Medical Center Shizuoka, Japan

To the Editor: We read with great interest a meta-analysis by Landoni et al1 of 10 randomized controlled trials (representing 440 patients) of levosimendan on mortality in patients undergoing cardiac surgery. Overall analysis showed that the use of levosimendan was associated with a significant reduction in postoperative mortality (4.7% in the levosimendan group v 12.7% in the control arm; odds ratio [OR], 0.35; 95% confidence interval [CI], 0.18-0.71; p ⫽ 0.003). Data of 3 of the 10 trials,2-4 however, were not combined in the meta-analysis, resulting in 361 patients in the remaining 7 trials, because of no events (deaths) in both the groups and inestimable ORs. Furthermore, results of a number of randomized trials have been published since the meta-analysis was conducted. We herein performed an updated meta-analysis of randomized trials of levosimendan in cardiac surgery including the 3 trials2-4 not in the meta-analysis by Landoni et al.1 Our comprehensive search identified 2 additional randomized controlled trials.5,6 A trial by Eriksson et al5 included 60 patients with 3-vessel coronary disease and a left ventricular ejection fraction of less than 0.50. In a trial by Tritapepe et al,6 102 patients undergoing elective coronary artery bypass graft surgery were included. In total, our meta-analysis included data on 602 patients in 12 trials. To combine data of all the trials including zero-events trials (no deaths in both the groups), we generated not ORs but risk differences (RDs) and 95% CIs for each study by the use of data regarding postoperative mortality in both the levosimendan and control groups. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic RDs in both fixed- and random-effects models. Pooled analysis showed no statistically significant difference in postoperative mortality between the levosimendan and control groups in random-effects models (3.5% v 9.8%; RD, ⫺0.03; 95% CI, ⫺0.07 to 0.01; p ⫽ 0.17) (Fig 1). There was little difference in the pooled result from fixed-effects modeling (RD, ⫺0.02; 95% CI, ⫺0.05 to 0.01; p ⫽ 0.23). Despite the results of the meta-analysis by Landoni et al,1 the results of our updated meta-analysis (including zero-events trials) suggest that levosimendan may not reduce postoperative mortality

Fig 1. A forest plot for the RDs of postoperative mortality comparing levosimendan versus control. df, degrees of freedom; IV, inverse variance.

REFERENCES 1. Landoni G, Mizzi A, Biondi-Zoccai G, et al: Reducing mortality in cardiac surgery with levosimendan: A meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 24:51-57, 2010 2. Barisin S, Husedzinovic I, Sonicki Z, et al: Levosimendan in off-pump coronary artery bypass: A four-times masked controlled study. J Cardiovasc Pharmacol 44:703-708, 2004 3. Husedzinovic´ I, Barisin S, Bradic´ N, et al: Levosimendan as a new strategy during off-pump coronary artery bypass grafting: Double-blind randomized placebo-controlled trial. Croat Med J 46:950-956, 2005 4. Tritapepe L, De Santis V, Vitale D, et al: Preconditioning effects of levosimendan in coronary artery bypass grafting—A pilot study. Br J Anaesth 96:694-700, 2006 5. 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 87:448-454, 2009 6. Tritapepe L, De Santis V, Vitale D, et al: Levosimendan pretreatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 102:198-204, 2009 doi:10.1053/j.jvca.2010.06.011

Response: Does Levosimendan Reduce Mortality in Cardiac Surgery? To the Editor: We are grateful to Takagi and Umemoto1 for their letter and updates of our meta-analysis,2 which offer us the possibility to further explain and clarify our paper. We recently suggested that levosimendan significantly reduced perioperative mortality in cardiac surgery from 12.7% to 4.7% in 440 patients from 10 studies2 and from 22.4% to 17.6% in the overall critically ill population in 3,350 patients from 27 studies.3