Effects of levosimendan on cardiac arrhythmia: electrophysiologic and ambulatory electrocardiographic findings in phase II and phase III clinical studies in cardiac failure

Abstract

Levosimendan is a novel inotropic and vasodilating agent that enhances the calcium sensitivity of myofilaments by binding to troponin C. Unlike other calcium sensitizers, it is highly dependent on the intracellular concentration of calcium. As a result of this unique property, levosimendan might be expected to increase cardiac contractile force without significantly impairing ventricular relaxation. The electrophysiologic effects of intravenously infused levosimendan were examined in healthy volunteers, and its effects on the surface electrocardiogram and on arrhythmia were recorded on 24-hour Holter recorders in patients with heart failure. Levosimendan had no significant effects on heart rate when data were pooled from the 24-hour electrocardiograms of patients receiving various dose levels, although increases were noted at high doses. The uncorrected QT interval remained unchanged, but the rate-corrected QT interval (QT c) was modestly prolonged at doses several-fold higher than that required for therapeutic effect. Atrial and ventricular effective refractory periods in patients with normal heart function were slightly shortened, although the average effect on the ventricles was only 2–5 msec at different pacing rates. No increase in the frequency of nonsustained ventricular tachycardia (VT) was found from the analysis of ambulatory electrocardiograph data from a total of 792 1-day recordings pooled from 10 studies, which included data from 386 heart failure patients. There was no evidence of any increase in the development of new supraventricular or ventricular tachyarrhythmias, including torsade de pointes, in patients who did not exhibit these abnormalities at baseline. The electrophysiologic actions of levosimendan in healthy volunteers and the effects of the drug on the QT interval of the electrocardiogram and on arrhythmia recorded during its intravenous use in patients with severe heart failure demonstrated little potential for the drug to provoke life-threatening proarrhythmic reactions.