Sandy Liu, Mercer University College of Pharmacy
Utilizing a heart-lung machine, cardiopulmonary bypass replaces the heart’s pumping action and adds oxygen to blood, allowing the heart and lungs to be still prior to cardiac surgeries.  Morbidity and mortality have demonstrated to be associated with this surgery, as is low cardiac output syndrome.  Despite being managed with inotropic agents and mechanical cardiac assist devices, it has been suggested that short-term mortality is higher compared to patients without this syndrome.  Some available inotropic agents may still have unknown safety profiles or known adverse effects. 
Levosimendan is a calcium-sensitizing inotrope and an adenosine triphosphate (ATP) sensitive potassium channel opener used to enhance cardiac contractility and vasodilation. This medication increases the sensitivity of cardiac myofilament to calcium, rather than increasing intracellular concentrations of free calcium. By binding to cardiac troponin C in a calcium-dependent manner, levosimendan stabilizes troponin C and the kinetics of actin-myosin cross-bridges without increasing myocardial consumption of ATP. 
|Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery |
|Design||Multicenter, randomized, double-blind, placebo-controlled, phase 3;
|Objective||To evaluate the safety and efficacy of prophylactic levosimendan in patients undergoing cardiac surgery with cardiopulmonary bypass|
|Study Groups||Levosimendan (n= 428); placebo (n= 421)|
|Methods||Patients received either intravenous levosimendan (at a dose of 0.2 µg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 µg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery, with no stratification.
Eligible patients were scheduled to undergo cardiac surgery with the use of cardiopulmonary bypass and had a left ventricular ejection fraction of 35% or less as assessed within 60 days before surgery. The cardiac surgical procedures included coronary artery bypass graft (CABG), CABG plus aortic valve surgery, isolated mitral valve surgery, or any combination of these procedures. The use of concomitant medications, including other inotropes and vasopressors, were not controlled.
Blood samples for the analysis of creatine kinase (CK) and CK-MB isoenzyme levels were obtained and analyzed within 8 hours before surgery and at 3 and 5 days after surgery. Electrocardiograms were recorded at baseline and after surgery on days 0, 1, 2, 3, and 5 as well as on the day of and the day after any suspected ischemic event through 30 days.
Renal-replacement therapy (RRT) included hemodialysis (HD), peritoneal dialysis, or continuous venovenous HD. Perioperative myocardial infarction (MI) was defined as a CK-MB level of more than 100 ng per milliliter or a level that was more than 10 times the upper limit of the normal range, or a level more than 50 ng per milliliter or a level that was more than 5 times the upper limit of the normal range, with new Q waves that were more than 30 msec in duration in two contiguous leads or new left bundle branch block. Use of a mechanical cardiac assist device included the use of an intraaortic balloon pump, extracorporeal membrane oxygenator, or ventricular assist device.
|Duration||July 2014 to November 2016|
|Primary Outcome Measure||1) Four-component composite of death through day 30, RRT through day 30, perioperative MI through day 5, or use of a mechanical cardiac assist device through day 5
2) Two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5
|Adverse Events||Common Adverse Events: hypotension (36.2%); atrial fibrillation (38.1%); ventricular tachycardia or fibrillation (10.7%)|
|Serious Adverse Events: stroke (3.5%); deep venous thrombosis (0.7%); congestive heart failure (10.7%)|
|Percentage that Discontinued due to Adverse Events: 1.4%|
|Study Author Conclusions||Prophylactic levosimendan did not decrease short-term composite end point compared with placebo.|
Although levosimendan has been associated with higher rates of weaning from cardiopulmonary bypass and lower rates of inotrope use, it may only benefit patients who have severe left ventricular dysfunction at baseline. Due to its multiple mechanisms of actions, levosimendan’s effects may differ between patients who have left ventricular function due to ischemic heart disease versus those with pressure or volume overload. Unlike other inotropic agents, levosimendan is able to exerts its effects for up several days due to its long-acting metabolites. Not only can this lead to an increase in adverse effects, but it can also harm cardiac patients requiring the use of these medications. With limited data available to suggest levosimendan is superior to other available agents, it is critical for healthcare providers to be cautious with its use, as long-term safety has yet to be established.
 National Heart, Lung, and Blood Institute: Heart Surgery. https://www.nhlbi.nih.gov/health/health-topics/topics/hs/during. Accessed on April 3, 2017.
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