Effect of Levosimendan on Low Cardiac Output Syndrome

Study Questions:

Does preoperative levosimendan prevent postoperative low cardiac output syndrome?


Thirteen cardiac surgery centers conducted this randomized, double-blind, two-arm, parallel group, placebo-controlled trial in patients with left ventricular ejection fraction (LVEF) ≤40% who were scheduled for coronary artery bypass grafting (CABG) with cardiopulmonary bypass. The patients were assigned to a 24-hour infusion of levosimendan 0.1 µ/kg/min (n = 167) or placebo (n = 168) after induction of anesthesia in a 1:1 ratio with a deterministic dynamic allocation. They were followed during 6 months after enrollment. The study investigators hypothesized that levosimendan would reduce the composite endpoint by 15% when compared to placebo. The composite endpoint included low cardiac output syndrome with need for an inotrope infusion (i.e., dobutamine, epinephrine, norepinephrine, or milrinone) 48 hours after study drug initiation, need for an LV assist device (LVAD) or failure to wean from it at 96 hours after study drug initiation when the device was inserted preoperatively, or need for renal replacement therapy at any time postoperatively. The primary analysis was performed by the investigators on an intention-to-treat basis for all patients included in the trial except three (one withdrew consent and two refused surgery, declined further participation, and had no criteria of judgment available).


In this study, 336 patients (mean age, 68 years; 16% women) were randomized, of whom 333 completed the trial. The primary endpoint occurred in 52% of the patients (n = 87) in the levosimendan group and 61% of the patients (n = 101) in the placebo group (absolute risk difference taking into account center effect, −7% [95% CI, −17% to 3%]; p = 0.15). Among the three components of the primary endpoint, the need for catecholamine infusion beyond 48 hours of study drug initiation was the most frequent (n = 180; 54%), but was not significantly affected by levosimendan administration, with an absolute risk difference of −8% (95% CI, −18% to 1%; p = 0.09). The investigators found no interaction with EF <30%, type of surgery, and preoperative use of beta-blockers, intra-aortic balloon pump, or catecholamines in a predefined subgroup analysis. The prevalence of hypotension (57% vs. 48%), atrial fibrillation (50% vs. 40%), and other adverse events did not significantly differ between levosimendan and placebo. There was no difference in postoperative myocardial infarction between the two groups.


The authors concluded that levosimendan when compared with placebo did not result in a significant difference in the composite endpoint of prolonged catecholamine infusion, use of LV mechanical assist device, or renal replacement therapy in patients with low EF who were undergoing CABG with cardiopulmonary bypass.


This is an important study because it attempted to reduce the burden of perioperative low cardiac output in patients with low ejection undergoing CABG. These results are consistent with a recent report (the LEVO-CTS study [Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass]) in a similar cohort of patients in whom levosimendan infusion was started at anesthetic induction, a lack of significant reduction in their primary endpoint, composed of mortality at day 30; the need for mechanical assist device at day 5; the need for renal replacement therapy through day 30; and myocardial infarction through day 5. Together, these studies suggest that ‘prophylactic’ inotropes have no role in preventing postoperative low cardiac output syndrome.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Mechanical Circulatory Support

Keywords: Anesthesia, Atrial Fibrillation, Cardiac Output, Low, Cardiopulmonary Bypass, Cardiac Surgical Procedures, Catecholamines, Coronary Artery Bypass, Dobutamine, Epinephrine, Heart-Assist Devices, Heart Failure, Hypotension, Myocardial Infarction, Norepinephrine, Renal Replacement Therapy, Secondary Prevention, Stroke Volume

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