Levosimendan is a calcium sensitizer — 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 -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 -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 in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. Some of the Phase III studies in the extensive clinical program including the trials LIDO, RUSSLAN, REVIVE-I, REVIVE-II and SURVIVE. In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind randomized studies. In the SURVIVE study, despite a reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days. However, the drug was proven to be superior to dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they are hospitalized with acute decompensations.
Licensing status
The Orion Corporation originally developed levosimendan and applied for a new drug application in 1998 in the U.S. However the Food and Drug Administration requested further trials be conducted and Orion withdrew the application in November 1999. Initially, Orion obtained the approval to market the drug in Sweden in 2000. Since then 60 countries worldwide have approved the drug but it remains unapproved in North America, where it is currently in Phase III development by Tenax Therapeutics for reduction in morbidity and mortality of cardiac surgery patients at risk of low cardiac output syndrome.
