Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery on Cardiopulmonary Bypass: Rationale and Study Design of the LEVO-CTS Trial

Background Low cardiac output syndrome (LCOS) is associated with increased mortality and occurs in 3–14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of LCOS and related adverse outcomes in patients undergoing cardiac surgery on CPB. Methods LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (LVEF ≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 mcg/kg/min for 1st hour followed by 0.1 mcg/kg for 23 hours) or matching placebo initiated within 8 hours of surgery. The co-primary endpoints are (1) the composite of death or renal replacement therapy through day 30 or perioperative MI, or mechanical assist device use through day 5 (quad endpoint tested at α < 0.01); and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual endpoint tested at α < 0.04). Safety endpoints include new atrial fibrillation and death through 90 days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017. Conclusion LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB. Clinical Trial Registration: ClinicalTrials.gov ( NCT02025621 ).