Levosimendan (INN) is a calcium sensitiser used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax (Abbott).

Mode of action

Levosimendan is a calcium sensitiser – it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.

Clinical use

Indications

Levosimendan is indicated for inotropic support in acutely-decompensated severe congestive heart failure.

Some of the Phase-III studies in the extensive clinical program were the trials LIDO (200 patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and finally SURVIVE (1350), a head-to-head trial between levosimendan and dobutamine in acute decompensated heart failure. In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind studies, which is the highest number ever in testing a drug for acute decompensated heart failure.

Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group in a head to head comparison study, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes.

The drug has a marketing authorization in 48 countries.

Contraindications

The use of levosimendan is contraindicated in patients with: moderate-to-severe renal impairment, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension and tachycardia, and/or history of torsades de pointes.

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea (Rossi, 2006).

Formulations

Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution before infusion.

References