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Literature Review

Levosimendan for Hemodynamic Support After Cardiac Surgery

Landoni G, Lomivorotov VV, Alvaro G, et al. N Engl J Med. 2017;376(21):2021-2031.

Reviewer: Sherif Assaad, MD1

  1. VA Healthcare System, Yale University, New Haven, CT
Background

Acute left ventricular failure is a major complication after cardiac surgery, affecting up to 20% of patients and associated with a high mortality rate. Inotropic support such as catecholamines and phosphodiesterase inhibitors type III have been the cornerstone in hemodynamic support for decades. Recently, a new inotrope has been added to the arena (levosimendan) with the advantage of being a positive inotrope, antioxidant, antiinflammatory with minimal effect on myocardial oxygen consumption. The long-term advantages of levosimendan have been shown in a meta-analysis to be favorable. The aim of this study is to test the hypothesis that levosimendan, in addition to standard care, will result in lower mortality rateS in patients with left ventricular failure after cardiac surgery.

Methods

Study Design:

This is a randomized, double-blinded, placebo-controlled multicenter trial of 14 centers in Italy, Russia, and Brazil.

Inclusion Criteria:

Presence of at least one of the following:

Exclusion Criteria:

Patients included in the study were randomized in a 1:1 ratio to receive either levosimendan or placebo infusion.

Patients received their standard medical care per discretion of the attending physicians. In addition, patients were assigned to receive an infusion of levosimendan at a dose of 0.025 to 0.2 mg per kilogram body weight per minute or a placebo for up to 48 hours after surgery or until intensive care unit (ICU) discharge.

Outcome Measures:

Primary outcome: 30-day mortality.

Secondary outcomes include: acute kidney injury; duration of mechanical ventilation; duration of ICU and hospital stay; need for advanced mechanical circulatory support; myocardial infarction or neurologic damage; sepsis, pneumonia, tracheostomy, or mediastinitis.

Results

Five hundred six patients were enrolled in this study and were randomized to 248 patients in the levosimendan group and 258 patients in the placebo group. There was no significant difference in patients’ characteristics between the two groups.

The study was interrupted early because there was no difference in the 30-day mortality rate between the levosimendan group and the placebo group (12.9% vs 12.8%, P=.97). In addition, there was no difference between the two groups in the secondary outcomes. In a subgroup analysis, levosimendan did not show improvement in primary or secondary outcomes when stratified according to the type of surgery.

Discussion

This trial failed to show 30-day survival benefit in patients receiving levosimendan for left ventricular dysfunction after cardiac surgery compared to placebo. Also, it did not show a benefit in secondary outcomes compared to placebo.

In this trial, levosimendan infusion was started at a low infusion dose without a loading dose compared to other trials. This was used to avoid the hypotension episodes and the prolonged use of vasoactive drugs to counteract the hypotensive effect.

Comments

Levosimendan is a member of a new class of agents, the calcium sensitizers that increase myocardial contractility without increasing intracellular calcium. It shows a dose-dependent positive inotropic and vasodilatory effects without interfering with the diastolic relaxation. This positive lusitropic effect is attributed to its phosphodiesterase III inhibition at higher concentrations. Its continuous infusion also resulted in a decrease in pulmonary vascular resistance and pulmonary artery pressure. In contrast to other positive inotropic agents, it exerts its inotropic effects without increasing myocardial oxygen consumption.1,2 This effect created hope that it will be the drug of choice to treat cardiac dysfunction post–cardiac surgery given its transient nature.

Several studies showed hemodynamic benefits for levosimendan. Interestingly, one of the authors of this trial showed equivalent effect of levosimendan compared to intra-aortic balloon pump support.3 

Although this study is considered pivotal to show no survival benefit of levosimendan over placebo, the dose used in this study was far lower than the recommended dose. Levosimendan has dose-dependent inotropic, lusitropic, and vasodilatory effects. This raises a concern that the no-survival benefit might be secondary to the low dose used. Given that there were no adverse events witnessed, levosimendan with its superior profile still is considered a valid tool in our armamentarium that we cannot afford to dismiss to treat the potential hemodynamic derangements after cardiac surgery.

References

  1. Raja SG, Rayen BS. Levosimendan in cardiac surgery: current best available evidence. Ann Thorac Surg. 2006;81(4):1536-1546.
  2. Milligan DJ, Fields AM. Levosimendan: calcium sensitizer and inodilator. Anesthesiol Clin. 2010;28(4):753-760.
  3. Lomivorotov VV, Cherniavskiy AM et al. Levosimendan vs. intra-aortic balloon pump in high-risk cardiac surgery. Asian Cardiovasc Thorac Ann. 2011;19(2):154-159.

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