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LEVO-CTS: Prophylactic levosimendan fails to improve outcomes in surgery population

Issue: May 2017

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WASHINGTON — In the LEVO-CTS trial, prophylactic levosimendan before cardiac surgery in patients with reduced left ventricular function did not have an effect on mortality, dialysis, MI or mechanical-assist device use within specified time points.

However, levosimendan was safe and effective as an inotrope to increase cardiac output in patients at risk for perioperative low cardiac output syndrome, John H. Alexander, MD, MHS, FACC, said during a presentation at the American College of Cardiology Scientific Session.

“Given its effect on cardiac output, low cardiac output syndrome and other inotrope use, and the absence of adverse safety signals, levosimendan is a reasonable option to consider in patients undergoing cardiac surgery where increased cardiac output is the desired objective,” Alexander said here.

Levosimendan is an inotropic agent that increases sensitivity of troponin C to calcium within myocytes. It is approved for treatment of acute HF in more than 60 countries. The drug has been widely used during pericardiac surgery for prevention and treatment of low cardiac output syndrome in Europe, according to Alexander.

The randomized, placebo-controlled, phase 3 LEVO-CTS trial investigated the efficacy and safety of levosimendan vs. placebo in patients with LV ejection fraction 35% (mean age, 65 years; 20% women) who were undergoing cardiac surgery with cardiopulmonary bypass support. The study was conducted at 70 sites in the United States and Canada from September 2014 to November 2016.

Levosimendan was administered via IV infusion at a starting dose of 0.2 mcg/kg of body weight per minute for 1 hour, then reduced to 0.1 mcg/kg per minute for 23 hours.

Isolated CABG was used in 66% of the surgeries. Smaller numbers of patients underwent CABG plus aortic valve surgery, isolated mitral valve surgery or any combination of these procedures. The median time from IV levosimendan or placebo was 0.33 hours in both groups.

Alexander reported results from 849 patients in a modified intent-to-treat population who received levosimendan or placebo.

The study was designed with two co-primary endpoints: a four-component composite of death within 30 days, renal-replacement therapy within 30 days, perioperative MI within 5 days or use of a mechanical-assist device within 5 days and a two-component composite of death within 30 days or use of a mechanical-assist device within 5 days.

The rate of the four-component outcome was 24.5% in both groups (OR = 1.01; 95% CI, 0.66-1.54) and the rate of the two-component outcome was 13.1% in the levosimendan group vs. 11.4% in the placebo group (OR = 1.18; 95% CI, 0.76-1.82).

Low cardiac output syndrome occurs in an estimated 3% to 14% of patients who undergo cardiac surgery with the use of cardiopulmonary bypass. In secondary analyses, levosimendan was associated with increased cardiac output (mean, 2.86 mls/min/m² vs. 2.68 mls/min/m²; P < .0001). This resulted in a reduction in low cardiac output syndrome in the levosimendan group (18.2% vs. 25.7%; OR = 0.62; 95% CI, 0.44-0.88), less secondary inotrope use and no difference in ICU length of stay compared with placebo, Alexander said.

Adverse events were similar between the two groups. At 30 days, hypotension, atrial fibrillation, ventricular tachycardia/fibrillation, stroke and rehospitalization did not differ among patients assigned levosimendan or placebo. At 90 days, the rate of mortality was 4.7% with levosimendan vs. 7.1% with placebo (HR = 0.64; 95% CI, 0.37-1.13). Infusion discontinuation was higher in the levosimendan group (5.8% vs. 3.8%). Thirteen percent of patients assigned the study drug required dose adjustment. Hypotension was cited as the most common cause for discontinuation of levosimendan. – by Katie Kalvaitis

Reference s :

Alexander JH, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.

Mehta RH, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1616218.

Disclosure: The study was funded by Tenax Therapeutics. Alexander reports receiving research support from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Pfizer and Tenax Therapeutics and consulting for Bristol-Myers Squibb, Cempra, CryoLife, CSL Behring, Pfizer and Portola.