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Literature Review

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery

Mehta RH, Leimberger JD, van Diepen S, et. al. N Engl J Med. 2017;376(21)2032-2042.

Reviewer: Igor Zhukov, MD1

  1. Emory University, Atlanta, GA
Background

Levosimendan is the newest addition to the inotropic armamentarium for treatment of patients with cardiac dysfunction. Its early use in Europe stimulated research interest in the United States as well as clinicians’ anticipation of its approval for clinical use. Low cardiac output is a significant obstacle to survival and recovery, the area in which levosimendan is postulated to provide maximal benefits as a calcium-sensitizing inotrope. Multiple ongoing trials are aiming to define the niche for levosimendan in the cardiac OR and to illustrate its potential superiority in conventional care.

Methods

This is a multicenter, randomized, placebo-controlled, double-blind study on the effect of levosimendan infusion on incidence of low cardiac output syndrome after cardiac surgery. The cohort was composed of patients undergoing coronary artery bypass grafting (CABG), CABG and aortic valve replacement, mitral valve replacement, or a combination of these in a setting of left ventricular ejection fraction <35% preoperatively. Endpoints were defined as a 4-part composite of mortality or use of renal replacement therapy within 30 days and perioperative myocardial infarction or use of mechanical assist device within 5 days of operation. In addition, 30-day mortality and mechanical assist device use composite endpoint was assessed within 5 days of operation.

Secondary endpoints were the incidence of low cardiac output syndrome, use of inotropes beyond first 24 hours, and the length of intensive care unit (ICU) stay. Low cardiac output syndrome definition included use of the mechanical assist device, two consecutive cardiac index measures <= 2 L/min/m2, or one low cardiac output measure in a setting of two or more inotropes administered.

Authors predicted the four-composite outcome incidence to be at 32%, with an estimated 35% risk reduction in treatment group powered the study with 760 patients; the patient number was increased to 880 due to lower-than-expected occurrence of outcome variables.

Results

Of 882 patients, 442 were randomized to levosimendan and 440 to placebo. Four hundred twenty-eight and 421 patients were analyzed in the intention to treat groups due to loss of 14 and 19 patients, respectively, because of miscellaneous contraindications and protocol variances. 

Four-component endpoint incidences were 25.4% in both groups, while the two-component endpoint occurred 13.1% and 11.4% (P=.45) in the treatment and control group, respectively.

Secondary endpoints demonstrated no difference in ICU stay at 2.8 vs. 2.9 days (P=.25). Incidence of low cardiac output syndrome was 18.2% and 25.7% in treatment and control groups, respectively (P=.007). Of patients in whom cardiac output assessment was available postprocedure, mean cardiac index was 2.86 +/- 0.61 and 2.68 +/- 0.65 in treatment and control groups (P<.001).

Other safety endpoints were surveyed, such as hypotension, rate of atrial fibrillation, ventricular tachycardia and/or fibrillation, cardiac arrest, and stroke; all were not statistically significant between the two groups.

Discussion

Prophylactic levosimendan administration did not reduce the incidence of the composite outcomes of this study. There were statistically significant differences in the incidence of low cardiac output syndrome, which may or may not be clinically important given its relatively broad definition and heterogeneity of the surgical procedures in this trial. The finding of higher cardiac index in the treatment group is hard to interpret given physiologically normal cardiac index in both groups.

Given the rarity of the primary outcomes, a composite measure had to be used to power this study. Authors indicated that if only mortality was used as an endpoint, 3000 patients or more would be needed to achieve statistical power.

Prophylactic use of levosimendan did not produce the anticipated benefit, though complication rates also were not different among the 2 groups. This study was underpowered to allow the expansion of the conclusion of this clinical trial into clinical practice.

Authors argue that the proper role of levosimendan is undefined as a preventative measure of low cardiac output syndrome, and may be different between varying surgical practices. Another trial investigating levosimendan in the cohort with preserved ejection fraction was terminated early due to no benefit demonstrated.1

References

1. Landoni G, Lomivortov VV, Alvaro G. et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. DOI: 10.1056/NEJMoa1616325

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