Section 2, Chapter 3
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Levosimendan (Simdax, Simendan) in acute heart failure

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Key points

  • Levosimendan alleviates heart failure symptoms, increases cardiac output, and lowers pulmonary artery pressure without increasing myocardial oxygen consumption. The inotropic effect of levosimendan is not affected by the concurrent use of beta-blockers. The vasodilating effect reduces preload and afterload, further reducing myocardial workload.
  • Levosimendan is used in severe acute or chronic heart failure.
  • Consider urgent angiography in patients with unknown etiology for acute severe heart failure.
  • A recent echocardiographic examination should be available or performed urgently to evaluate ventricular and valvular function.
  • Levosimendan drug is generally well-tolerated. Severe adverse effects are less common.
  • Levosimendan may be administered simultaneously with milrinone. The drugs can also be given sequentially.
  • Hypotension can be counteracted with simultaneous administration of norepinephrine.
  • All patients with severe acute heart failure who receive levosimendan should be monitored invasively (e.g. arterial line, PiCCO, central venous catheter).
  • The hemodynamic effects persist for 7–10 days after the end of infusion.
  • Refer to Table 2 for a comparison between levosimendan, milrinone and dobutamine.

Mechanisms of action

Levosimendan exhibits both inotropic and vasodilatory effects. The drug exerts its effects through three pharmacological mechanisms: (1) augmentation of myocardial contractility via calcium sensitization of troponin C; (2) vasodilatory actions; and (3) modulation of sarcolemmal and mitochondrial potassium-ATP channels. Levosimendan alleviates heart failure symptoms, increases cardiac output, and lowers pulmonary artery pressure without increasing myocardial oxygen consumption. The inotropic effect of levosimendan is not affected by the concurrent use of beta-blockers. The vasodilating effect reduces preload and afterload, further reducing myocardial workload.1

The pharmacokinetic profile of levosimendan is modulated by the presence of an active metabolite, which exerts sustained hemodynamic effects for up to 2 weeks. The peak vasodilatory effect is observed between 2-4 days following the infusion. This delayed onset is attributable to its active metabolite, which reaches maximum plasma concentration approximately 48 hours after the infusion has been completed. Furthermore, the blood pressure-lowering effect persists for a duration of 3 to 4 days post-infusion, thereby providing extended therapeutic benefits.2

Infusion of levosimendan can be repeated at 2-6 weeks intervals, or more frequently, as individually appropriate.3

Important study: Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock (N Engl J Med 2021; 385:516-525)

In a randomized, double-blind study involving 192 patients with cardiogenic shock, researchers compared the effectiveness of milrinone and dobutamine. The primary composite outcome included in-hospital mortality, resuscitated cardiac arrest, cardiac transplantation or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke, and initiation of renal replacement therapy. The study found no significant differences between the two treatment groups with respect to either the primary or secondary outcomes. Primary outcome events occurred in 49% of patients in the milrinone group and 54% in the dobutamine group, with a relative risk of 0.90 (95% CI: 0.69 to 1.19; P=0.47). The study suggests that in cardiogenic shock, milrinone and dobutamine offer comparable therapeutic efficacy and safety profiles, and thus the selection between them may be guided by individual patient needs rather than by a distinct advantage of one drug over the other. Mathew et al. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med 2021; 385:516-525

Indications

  • Severe left ventricular failure, acute or chronic.
  • Severe biventricular failure, acute or chronic.
  • Severe left ventricular failure post-myocardial infarction.
  • Low cardiac output states or cardiogenic shock post cardiac surgery or percutaneous coronary or valvular interventions.
  • Cardiogenic shock refractory to high doses of dobutamine (>5 µg/kg/min for >24 h).

Adverse effects

  • 5% of normotensive patients develop hypotension.
  • Premature ventricular beats and short bursts of ventricular tachycardia (VT) are common, particularly when levosimendan is administered at doses exceeding the recommendations.
  • QT interval prolongation, particularly at doses exceeding the recommendations.
  • High doses may cause a drop in hemoglobin concentration.
  • Hypokalemia is common, particularly at higher doses.

Should severe adverse events occur, a decrease in the infusion rate or discontinuation of the infusion may be warranted.

Contraindications

  • Hypersensitivity to levosimendan
  • Severe hypotension (consider initiating norepinephrine infusion in order to continue levosimendan).
  • Severe tachycardia.
  • Severe outflow obstruction (e.g. aortic stenosis, mitral stenosis, LVOT obstruction).
  • History of torsade de pointes (TdP).
  • Renal failure (eGFR <30 ml/min) is a relative contraindication. Levosimendan is considered in urgent scenarios, or when renal failure is a direct consequence of heart failure.
  • Hepatic failure is a relative contraindication.

Caution

  • Hypotension or risk of hypotension.
  • Rapid atrial fibrillation or sinus tachycardia.
  • Ventricular arrhythmias.
  • Hepatic or renal failure may result in elevated plasma concentrations of levosimdenan.
  • Correction of potassium levels (particularly hypokalemia) is warranted before administration of levosimendan.
  • Anemia may be exacerbated by levosimendan, which may aggravate myocardial ischemia.

Monitoring

  • ECG monitoring is required in all patients receiving levosimendan.
  • ST segment monitoring should be used in suspicion of ongoing myocardial ischemia.
  • An arterial line for invasive blood pressure monitoring is recommended for all patients receiving levosimendan due to acute heart failure.
  • Consider a central venous catheter to measure central venous pressure (CVP) or establish a PiCCO for advanced hemodynamic monitoring.

Dosage and administration

  • A loading dose is not required.
  • Levosimendan should be administered over 24 hours. Longer infusions are unlikely to further improve hemodynamic status.
  • No dose adjustment is required in mild to moderate renal failure or during RRT (renal replacement therapy).
  • Hemodynamic responses should be evaluated 30 to 60 minutes following the initiation of the infusion. The starting dosage is set at 0.1 µg/kg/min. If the initial assessment indicates that the dose is excessively high, it can be reduced to 0.05 µg/kg/min. The dosage may be increased to 0.2 µg/kg/min if required.
  • Route: Central route is preferred but a large dedicated peripheral line is accepted.

Administration

  • One vial of levosimendan is adequate for treatment in the majority of cases. Patients >90 kg (>200 lbs) may require a second vial in order to complete the 24 hour infusion.
  • Vials: Levosimendan 2.5 mg/ml in 5 ml vials (12.5 mg per vial).
  • Dilution: 5 ml levosimendan is added to 245 ml glucose 5%; resulting in a concentration of 0.05 mg/ml.

Table 1. Infusion rate for levosimendan 0.05 mg/ml

Body weight (kg / lbs)0.05 µg/kg/min0.1 µg/kg/min0.2 µg/kg/min
Reduced doseNormal doseIncreased dose
40 kg / 90 lbs2 ml/h5 ml/h10 ml/h
50 kg / 110 lbs3 ml/h6 ml/h12 ml/h
60 kg / 132 lbs4 ml/h7 ml/h14 ml/h
70 kg / 155 lbs4 ml/h8 ml/h17 ml/h
80 kg / 180 lbs5 ml/h10 ml/h19 ml/h
90 kg / 200 lbs5 ml/h11 ml/h22 ml/h
100 kg / 220 lbs6 ml/h12 ml/h24 ml/h
110 kg / 240 lbs7 ml/h13 ml/h26 ml/h
120 kg / 260 lbs7 ml/h14 ml/h29 ml/h
Infusion rate in ml/ h.

Table 2. Comparison of levosimendan, dobutamine and milrinone.

LevosimendanDobutamineMilrinone
MechanismCalcium sensitizerBeta-1 adrenergic agonistPhosphodiesterase 3 inhibitor
Effect on intracellular calcium levelNoneIncreased calcium levelIncreased calcium level
InotropeYesYesYes
VasodilatorYes:
– Coronary
– Systemic
– Pulmonary
– Mild systemic vasodilationYes:
– Pulmonary
– Systemic
Myocardial oxygen consumptionNot affected.Increased.Not affected.
Arrhythmogenic potentialRare (less than dobutamine). May be due to QT prolongation.Less than milrinone. Ventricular and supraventricular arrhythmias.Ventricular and supraventricular arrhythmias are common (>10%).
Hemodynamic effectsIncreased contractility, lower preload, lower afterload, blood-pressure lowering.Increases cardiac output by increased contractility and (to some extent) heart rate.Increases cardiac output by improving myocardial contractility and inducing vasodilation.
Compatilibity with beta-blockersYes.Yes, but effects may be attenuated when used alongside beta-blockers.Yes.
Adverse effectsHeadache. Hypotension. Premature ventricular beats, QT prolongation, hypokalemia, hemoglobin drop.Increased heart rate, arrhythmias, increased myocardial oxygen consumption. Hypertension.Headache. Hypotension. Ventricular arrhythmias. Thrombocytopenia
Drug interactionsNone significantNone significantFew significant
Comparison of milrinone, levosimendan and dobutamine.

References

Follath F et al. Dose ranging study and safety with iv levosimendan in low output heart failure:
Experience in three pilot studies and outline of the levosimendan infusion versus dobutamine (LIDO)
trial. Am J Cardiol 1999; 83: 211 – 251.

Summary of product characteristics, Simdax, Orion Pharma. Last updated 03/10/2016 accessed via
www.simdax.com on 26/04/2018

Injectable Medicines Guide Levosimendan monograph accessed via http://www.injguide.nhs.uk
26/04/2018

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