Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery

N Engl J Med. 2017 May 25;376(21):2032-2042. doi: 10.1056/NEJMoa1616218. Epub 2017 Mar 19.

Abstract

Background: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery.

Methods: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5.

Results: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups.

Conclusions: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Cardiac Output, Low / drug therapy*
  • Cardiac Surgical Procedures*
  • Cardiotonic Agents / adverse effects
  • Cardiotonic Agents / therapeutic use*
  • Double-Blind Method
  • Female
  • Heart-Assist Devices / statistics & numerical data
  • Humans
  • Hydrazones / adverse effects
  • Hydrazones / therapeutic use*
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Mortality*
  • Myocardial Infarction / epidemiology
  • Perioperative Period
  • Postoperative Complications / drug therapy
  • Pyridazines / adverse effects
  • Pyridazines / therapeutic use*
  • Renal Replacement Therapy / statistics & numerical data
  • Simendan
  • Stroke Volume / drug effects
  • Treatment Failure
  • Ventricular Dysfunction, Left / drug therapy*

Substances

  • Cardiotonic Agents
  • Hydrazones
  • Pyridazines
  • Simendan

Associated data

  • ClinicalTrials.gov/NCT02025621
  • ClinicalTrials.gov/NCT02025621