Levosimendan
Encyclopedia
Levosimendan (icon) is a calcium
sensitiser used in the management of acutely decompensated congestive heart failure
. It is marketed under the trade name
Simdax (Orion Corporation
).
effect by increasing calcium sensitivity of myocyte
s 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.
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. 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 (Mebazaa et al. Eur J Heart Fail 2009 11:304-11)
In a meta-analysis of randomized controlled studies by Zangrillo et al. levosimendan is shown to reduce cardiac troponin
release after cardiac surgery when used pre- and peri-operatively.
The drug has a marketing authorization in 48 countries.
, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension
and tachycardia
, and/or history of torsades de pointes
.
s (≥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).
5% solution before infusion.
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
sensitiser used in the management of acutely decompensated congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
. It is marketed under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
Simdax (Orion Corporation
Orion Corporation
Orion Corporation, founded in 1917 and headquartered at Espoo, Finland, is a Finnish company, which develops, manufactures and markets pharmaceuticals, active pharmaceutical ingredients and diagnostic tests for global markets...
).
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 inotropicInotrope
An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions...
effect by increasing calcium sensitivity of myocyte
Myocyte
A myocyte is the type of cell found in muscles. They arise from myoblasts.Each myocyte contains myofibrils, which are long, long chains of sarcomeres, the contractile units of the cell....
s by binding to cardiac troponin C
Troponin
400px|thumb|right|alt = Colored dice with checkered background|Ribbon representation of the human cardiac troponin core complex in the calcium-saturated form...
in a calcium-dependent manner. It also has a vasodilatory
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
effect, by opening adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP)-sensitive potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
channels in vascular smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload
Afterload
Afterload is the tension or stress developed in the wall of the left ventricle during ejection. Following Laplace's law, the tension upon the muscle fibers in the heart wall is the product of the pressure within the ventricle, multiplied by the volume within the ventricle, divided by the wall...
. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.
Indications
Levosimendan is indicated for inotropic support in acutely-decompensatedDecompensation
In medicine, decompensation is the functional deterioration of a previously working structure or system. Decompensation may occur due to fatigue, stress, illness, or old age. When a system is "compensated," it is able to function despite stressors or defects. Decompensation describes an inability...
severe congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...
.
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
Dobutamine
Dobutamine is a sympathomimetic drug used in the treatment of heart failure and cardiogenic shock. Its primary mechanism is direct stimulation of β1 receptors of the sympathetic nervous system. Dobutamine was developed by a laboratory led by Drs...
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. 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 (Mebazaa et al. Eur J Heart Fail 2009 11:304-11)
In a meta-analysis of randomized controlled studies by Zangrillo et al. levosimendan is shown to reduce cardiac troponin
Troponin
400px|thumb|right|alt = Colored dice with checkered background|Ribbon representation of the human cardiac troponin core complex in the calcium-saturated form...
release after cardiac surgery when used pre- and peri-operatively.
The drug has a marketing authorization in 48 countries.
Contraindications
The use of levosimendan is contraindicated in patients with: moderate-to-severe renal impairmentChronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
and tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, and/or history of torsades de pointes
Torsades de pointes
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
.
Adverse effects
Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
, extrasystoles
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
, atrial
Atrium (anatomy)
In anatomy, the atrium , sometimes called auricle , refers to a chamber or space. For example, the term is used for a portion of the lateral ventricle in the brain and the blood collection chamber of the heart...
tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
), 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 glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
5% solution before infusion.