Levosimendan Does Not Improve Septic Shock Outcomes

Diana Phillips

October 10, 2016

Adding the calcium sensitizer levosimendan to standard care for patients with septic shock does not lessen the incidence or severity of organ dysfunction in affected adults, a phase 2 randomized controlled trial has shown.

Further, patients who received adjunctive levosimendan therapy were less likely to be weaned from mechanical ventilation than those who received standard care alone, and they had a higher risk for supraventricular tachyarrhythmia.

Anthony C. Gordon, MD, from the Section of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, United Kingdom, and colleagues report their findings in an article published online October 5 in the New England Journal of Medicine.

Primarily indicated for the short-term treatment of acutely decompensated severe chronic heart failure, levosimendan increases myocardial contraction without markedly increasing oxygen demand. Previous small studies have linked the drug to improvements over standard care in hemodynamic variables, microcirculatory flow, and renal and hepatic function in adults with septic shock.

To determine whether these benefits would translate into reduced severity of organ dysfunction, and to assess the drug's safety in this population, the researchers designed the Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) double-blind, placebo-controlled study.

The study included 516 patients who were receiving standard care including clinically indicated inotropic agents. The researchers randomly assigned 259 patients to receive an infusion of levosimendan (0.05 - 0.2 μg/kg of body weight/minute) for 24 hours, and 257 patients to receive a placebo infusion.

The study's primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit (ICU) up to day 28. Secondary outcomes were 28-day mortality, time to weaning from mechanical ventilation, and adverse events.

The SOFA scores during the ICU stay for the patients in the treatment and placebo groups, respectively, were 6.68 ± 3.96 and 6.06 ± 3.89 (mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P = .053). After adjustment for potential confounders, including patient age, ICU, and score on the Acute Physiology and Chronic Health Evaluation II, the mean difference between the two groups was 0.59 (95% CI, −0.02 to 1.20; P = .06).

When the researchers analyzed the components of the SOFA score individually, the treatment group had a higher mean daily cardiovascular SOFA score than the placebo group. The relative increase "reflects the higher doses of norepinephrine that were required to maintain the mean arterial pressure," the authors write.

The treatment group also experienced supraventricular tachyarrhythmia and higher heart rates, "most likely owing to vasodilatation but possible related to the higher rate of infusion (i.e., higher dose) of norepinephrine in the levosimendan group," the authors hypothesize.

In terms of secondary outcomes, 28-day mortality for the treatment and placebo groups, respectively, was 34.5% and 30.9% (mean difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P = .43), the authors report. In addition, "[a]mong patients requiring mechanical ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P = 0.03)."

Patients in the treatment group experienced more serious adverse events than those in the placebo group (32 vs 23).

There were no significant between-group differences over time in the cardiac index, stroke volume, central venous oxygen saturations or pressure, ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, or serum creatinine and bilirubin levels.

In planned subgroup analyses examining the effect of levosimendan in high-risk patients (those with low cardiac output, those with impaired oxygen delivery to the tissues, those receiving high-dose catecholamines), there was no evidence that the agent conferred a benefit in any of the subgroups, the authors write.

This trial was funded by the National Institute for Health Research and Tenax Therapeutics and sponsored by Imperial College London. The authors have disclosed a variety of financial relationships from pharmaceutical companies, therapeutics companies, and medical organizations, including grant support, speaker fees, consulting fees, and personal fees. One author reports a patent related to a novel treatment for acute respiratory distress syndrome. A complete list is available on the journal's website.

N Engl J Med. Published online October 5, 2016. Full text

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