Levosimendan is under development in North America for reduction in morbidity and mortality of cardiac surgery patients at risk of low cardiac output syndrome (LCOS). The FDA has granted Fast Track status for levosimendan and has agreed to our Phase 3 clinical trial protocol under a Special Protocol Assessment (SPA).
Outside the US, levosimendan is approved and marketed under the trade name of Simdax (levosimendan i.v.) in over 60 countries for use in Acute Decompensated Heart Failure. Over 1,000,000 patients have been prescribed the drug from its launch in early 2000.
Mechanism of Action
Levosimendan is a novel, first in class calcium sensitizer/K-ATP activator. The therapeutic effects of levosimendan are mediated through:
- increased cardiac contractility by calcium sensitization of troponin C, resulting in a positive inotropic effect which is not associated with substantial increases in oxygen demand (3).
- opening of potassium channels in the vasculature smooth muscle, resulting in a vasodilatory effect on all vascular beds (4).
- opening of mitochondrial potassium channels in cardiomyocytes, resulting in a cardioprotective effect (5)
Low Cardiac Output Syndrome:Definition and Incidence
LCOS is generally defined as a patient’s inability to maintain a cardiac index >2.2 L/min/m2 and hence requiring use of inotropic agents and/or mechanical assist devices such as an intra aortic balloon pump or a left ventricular assistance device. LCOS in the cardiac surgery setting is reported to occur in 5-10% of patients undergoing cardiac surgery and is associated with 10-15 fold higher mortality or severe sequelae as a result of poor organ perfusion (eg. kidney failure, end stage renal disease [ESRD]) (6),(7),(8),(9) (10).
Post-cardiotomy LCOS is associated with poor outcomes including a 10- to 15-fold increase in operative mortality (9).
Unmet Medical Need
Currently no pharmacologic therapies are approved for management or prevention of post-cardiotomy LCOS. While conventional inotropes are used to manage cardiac hemodynamics in the peri-operative setting, none have been shown to improve outcomes.
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- Cohn LH. Cardiac Surgery in the Adult. 3. edition. 2008. p. 621. [Pages available on request].
- Maganti M, Badiwala M, Sheikh A, Scully H, Feindel C, David TE, et al. Predictors of low cardiac output syndrome after isolated mitral valve surgery. J Thorac Cardiovasc Surg. 2010 Oct;140(4):790-6.
- Maganti MD, Rao V, Borger MA, Ivanov J, David TE. Predictors of low cardiac output syndrome after isolated aortic valve surgery. Circulation. 2005 Aug 30;112(9 Suppl):I448-52.
- Rao V, Ivanov J, Weisel RD, Ikonomidis JS, Christakis GT, David TE. Predictors of low cardiac output syndrome after coronary artery bypass. J Thorac Cardiovasc Surg. 1996 Jul;112(1):38-51.
- Bojar RM. Manual of Perioperative Care in Adult Cardiac Surgery, Fourth edition. Blackwell Publishing; 2005.