Duration of the haemodynamic action of a 24‐h infusion of levosimendan in patients with congestive heart failure

Abstract

Aims: To determine the duration of haemodynamic and neurohormonal action of a 24-h infusion of levosimendan in heart failure. Methods and results:This was a double-blind, parallel group study in patients with New York Heart Association class II to IV heart failure. Twenty-two patients, with left ventricular ejection fraction < 35% and pulmonary capillary wedge pressure (PCWP) above 12 mmHg, were randomised to receive either levosimendan (12 Ag/kg followed by a continuous infusion of 0.1 -0.2 Ag/min) or placebo. Invasively measured cardiac output (CO) increased from 4.3 l/min to 5.4 l/min in the levosimendan group at 6 h. PCWP decreased from 20 mmHg to 15 mmHg in response to levosimendan. Echocardiographically measured maximal effect on PCWP occurred after 6 h, whereas CO reached its highest value at 24 h. The estimated duration of the decrease in PCWP was 7 -9 days, and in CO was 12 -13 days. Plasma NT-proANP and NTproBNP levels reached their lowest values at days 3 and 2, and the treatment effect was estimated to last 16 and 12 days, respectively. The long-acting haemodynamic responses reflect levels of the active metabolites OR-1896 and OR-1855, maximal metabolite levels occurred at day 3. Conclusions: Levosimendan infusion achieved a rapid improvement in haemodynamic parameters in patients with congestive heart failure with maximal effects occurring 1 -3 days after starting the infusion, effects were sustained for up to at least a week. Levosimendan is a new calcium-sensitizing and vasodilatory agent developed for the short-term treatment of decompensated chronic heart failure. Levosimendan increases myocardial contractility [1], reduces filling pressure [2] and dilates both the peripheral and coronary blood vessels [3,4]. The positive inotropic action of levosimendan is due to the calcium-dependent binding of the drug to cardiac troponin C [5,6], whilst it's vasodilative effect is mainly due to the opening of ATP-dependent K-channels in vascular smooth muscle [7,6].Levosimendan is used in clinical practice for the treatment of acutely decompensated, severe heart failure.To date, clinical studies have demonstrated the efficacy and good tolerability of levosimendan in over 1000 adult patients with decompensated heart failure of both ischaemic and non-ischaemic origin [8,9]. In contrast to earlier inotropic agents, levosimendan does not seem to increase mortality in acute heart failure [8,9]. It is presumed that both levosimendan and its active metabolite, OR-1896, are involved in the cardiovascular effects. However, the exact duration of the haemodynamic effect of a single levosimendan infusion is unclear. There are also no data to indicate how frequently levosimendan may be administered.Due to an active long acting metabolite [10], the haemodynamic effects of a levosimendan infusion seem to continue for several days after stopping the infusion. However, the effects of levosimendan on left ventricular filling pressure and CO have not been evaluated beyond 48 h from the start of the levosimendan infusio...

Use of levosimendan in critically ill patients with severe aortic stenosis and left ventricular dysfunction

“…In addition, the long-lasting pharmacodynamic effects of its metabolite OR-1896 (7-9 days) may help to maintain improved cardiac performance. 15 Our patients were exceedingly ill. Nevertheless, following 24 hours of levosimendan infusion there was a significant clinical and echocardiographic improvement.…”

Efficiency and safety of prolonged levosimendan infusion in patients with acute heart failure

“…Another limitation is the absence of hemodynamic data [19,20], which could support adequately the scope of the study. This could be the goal of a future study in the same way of using alternative infusion patterns.…”

Myocardial ischemia-reperfusion and cardioprotection: a study with microdialysis in a porcine model

“…At high concentrations (>0.3 µM; >100ng/ml) levosimendan probably has a dose-dependent phosphodiesterase-III-inhibitory effect (Toller 2006), with heart rate increase as a consequence. Levosimendan has an active metabolite OR-1896 that can prolong the clinical effects for several days after ending a 24 h infusion (Lehtonen 2007, Lilleberg 2007. Levosimendan has also demonstrated effects on myocardial stunning (Toller 2006).…”