Levosimendan – another inotropic drug about to disappoint in “failure”?

Implications:  

Implications:

• Acute decompensated heart failure remains an important medical challenge.

• Inotropic drugs which stimulate the heart to contract more strongly and work harder are commonly used to treat this condition.

• While these drugs do improve cardiac function and symptoms over the very short-term, they also produce serious cardiac arrhythmias and have been associated with increased mortality.

• Levosimendan is a new inotropic agent that acts through a unique mechanism postulated to be safer than other similar drugs.

• The present results suggest that levosimendan is not really different from these other drugs.

• Thus, levosimendan, which has also not been clinically effective in large trials, may be domed to “failure” along with the other inotropic drugs.

Analysis:  

Flevari P, Parissis JT, Leftheriotis D, Panou F, Kourea K, Kremastinos DT. Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy. Am J Cardiol. 2006 Dec 15;98:1641-5. Epub 2006 Oct 25

http://www.ajconline.org/article/PIIS000291490601719X/abstract

Levosimendan (Simdax®, Abbott)is a novel inotropic-vasodilator drug that acts as a calcium sensitizer and might be safer than prior similar drugs that act through different mechanisms and have been harmful in heart failure (HF). In this study levosimendan or placebo was given intravenously for 24 hours to patients with advanced refractory HF and cardiac function and electrocardiograms were monitored. As expected, measures of cardiac function improved more on levosimendan than placebo. However, the incidence and severity of ventricular arrhythmias were greater in the levosimendan group. Four patients ultimately died, and 3 of these had received levosimendan and experienced ventricular arrhythmias. Thus, despite the claimed different mechanism of action and potential safety advantage of levosimendan, this experience suggests that this agent has the same adverse event profile of other similar agents that have been associated with increased mortality in HF.

Treatment of decompensated HF remains a clinical challenge. Numerous inotropic-vasodilator drugs, e.g., amrinone and milrinone, have been used to treat this condition and these agents have improved cardiac function and symptoms over the short term, but these agents have also produced cardiac arrhythmias and excess deaths in these patients such that inotropic drugs are a last resort intended only for very short-term use in HF. Levosimendan is a new member of this group and its novel mechanism of action was thought to be unlikely to produce the arrhythmias and undesirable outcomes associated with other drugs of this class. Unfortunately, the present study suggests that levosimendan may be as bad as the other drugs in this class. This finding along with its failure to show clinical benefits in large clinical trials, i.e. SURVIVE, raise considerable doubts about the future of levosimendan in particular and the whole class of inotropic drugs in general, regardless of their specific mechanisms of action.