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Levosimendan: review of recent clinical data

PRACTICAL THERAPEUTICS
Levosimendan is a cardioprotective inodilator, with unique mechanisms of action and a beneficial effect on survival and length of hospital stay for decompensated heart failure patients. A review of the recent clinical data is given

Giovanni Landoni MD
Department of Anaesthesia and
Intensive Care,
San Raffaele Scientific Institute,
Milan, Italy
Levosimendan (Figure 1) is a well-studied cardioprotective inodilator and its pharmacodynamics and pharmacokinetics have recently been reviewed in detail.(1) The inotropic effect is based on the calcium-sensitising effect in the cardiac myofilaments, whereas vasodilation is due to activation of adenosine triphosphate-sensitive sarcolemmal potassium channels of smooth muscle cells. In contrast with other inotropic drugs, levosimendan may have a cardioprotective effect, related to the activation of adenosine triphosphate-sensitive potassium channels in cardiovascular mitochondria. Cardiovascular effects of levosimendan persist for seven-to-nine days after the discontinuation of a 24-hour infusion, because it is metabolised into OR-1896, an active, long-life metabolite with inodilator properties.(2)
Levosimendan is the only inotropic agent that seems to reduce mortality in critically ill patients. A recent meta-analysis pooled all the 45 randomised controlled trials on levosimendan in critically ill patients published to 1 November 2010. Overall analysis showed a significant reduction of mortality: 17.4% in levosimendan group versus 23.3% in the control group (p < 0.001; I2 = 15.4%; number needed to treat (NNT) = 17). Improved survival was evident in cardiac surgery (5.8% versus 12.9; p < 0.001; I2 = 0%; NNT = 14) and cardiology settings (20% versus 25.5%; p = 0.002; I2 = 25.5%; NNT = 18). The same study also highlighted a reduction in length of hospital stay, especially evident in the cardiology setting, with a weighted mean difference of 1.59 days (p < 0.0001; I2 = 54.9%).(3)
A cumulative meta-analysis that is hereby published for the first time shows that the beneficial effect of levosimendan on survival could have been detected since 2002 (Figure 2). Cumulative meta-analysis are performed in order to evaluate the trend in OR and the performance of updated meta-analyses over time. The effect on survival is crucial, as has been underlined in a recent international consensus conference focusing on reduction of perioperative mortality.(4) Levosimendan was among the drugs that might have a beneficial effect on survival in the perioperative period.
Body of literature
In the past ten years, a growing body of literature has been published on levosimendan, showing a constant interest in the effects of this drug. According to Scopus database, more than 150 papers containing levosimendan in the title, abstract or keywords have been published each year since 2006. 
Furthermore, there are 11 ongoing randomised controlled trials registered on www.clinicaltrials.gov. Among these studies, nine register survival as a primary or secondary outcome. The largest ongoing study on levosimendan is HSR-LEVO (NCT00994825). This multicentre study alone plans to enrol 1000 patients in order to demonstrate a survival benefit in high-risk cardiac surgery patients. 
Interestingly, studies have recently compared levosimendan with the intra-aortic balloon pump in high-risk cardiac patients.(5,6) These studies suggested that perioperative infusion of levosimendan might lower cardiac troponin I levels, improve haemodynamics and shorten duration of intensive care stay after cardiac surgery. Particularly, the effect on troponin I release, which has not been documented for other inotropes, has been confirmed by a meta-analysis, pooling the data of five randomised trials performed in cardiac surgery.(7)
Advanced chronic heart failure
A growing body of evidence supports the possibility of using levosimendan in advanced chronic heart failure. Notably, seven studies have recently been published on the use of intermittent levosimendan intravenous administration in patients with advanced chronic heart failure (NYHA class III or IV) with or without pulmonary hypertension.(8-14) The length of infusion ranged between 6 and 24 hours. The interval of administration was weekly for one study, every two or three weeks for two studies, every month for three studies and every two months for one study. In one of these recent randomised controlled trials, Malfatto and colleagues investigate levosimendan intermittent infusion (once a month for three months) versus furosemide infusions on 33 patients. After the first administration, haemodynamics significantly improved (compared with furosemide), cardiac index increased and peripheral resistances decreased.
More interestingly, benefits of this treatment persisted even after a one-month washout period after the fourth infusion. Data showed a significant improvement to baseline in symptoms (NYHA class 3.07±0.36 versus 2.45 ±0.23; p < 0.01), neurohormonal balance (B-type natriuretic peptide 1033±807pg/ml versus 362 ± 210 pg/ml; p < 0.001), and left ventricular function (ejection fraction 25.9±5.1% versus 30.7 ± 4.6%; p < 0.05 – restrictive filling pattern 54% versus 5%; p < 0.05). One-year survival showed a trend favourable for levosimendan but these data were not statistically analysed owing to the small sample size.(9)
Some data on survival are given by Bonios in a recently published randomised controlled trial. A total of 63 patients were allocated to receive weekly intermittent infusion of levosimendan, dobutamine, or both. These patients were in NYHA class IV, refractory to optimal medical therapy, recently hospitalised for cardiac decompensation and stabilised by an intravenous inotrope. At six months, survival free from death or urgent left ventricular device implantation was 80% in the levosimendan group, 48% in the dobutamine group (p = 0.037 versus levosimendan), and 43% in the levosimendan + dobutamine group (p = 0.009 versus levosimendan).(8)
Although most available data on levosimendan concerns patients with decompensated heart failure or undergoing cardiac surgery, its use has been documented in several other settings, such as non-cardiac surgery and sepsis.
Septic shock
The use of levosimendan in septic shock might also be of interest, as long as it does not increase oxygen consumption by the myocardium, does not elicit arrhythmias and improves peripheral perfusion. This last point has been evaluated in a recent randomised controlled trial where Morelli and colleagues compared sublingual microcirculatory blood flow in 40 patients with septic shock, treated with either levosimendan or dobutamine, after receiving fluid resuscitation (central venous pressure 8–12mmHg) and noradrenaline (mean arterial pressure > 65mmHg). Levosimendan at 0.2μg/kg per minute improved sublingual microcirculatory blood flow and this effect was not correlated with changes in systemic flow variables. According to these results, levosimendan improves oxygen delivery at the level of the microcirculation.(15)
A previous study by the same authors showed an improvement in haemodynamics and regional flow in 28 patients with septic shock refractory to dobutamine.(16) Unfortunately, despite the strong physiopathological rationale, the available dataset for sepsis is too small to draw any conclusions on survival in this setting.(3)
Conclusions
In conclusion, levosimendan is a cardioprotective  inodilator, with unique mechanisms of action and a beneficial effect on survival and length of hospital stay that might justify its high costs in critically ill patients with decompensated heart failure. 
Key points
  • Levosimendan is a well-studied cardioprotective inodilator and its pharmacodynamics and pharmacokinetics have recently been reviewed in detail.
  • In contrast with other inotropic drugs, levosimendan may have a cardioprotective effect, related to the activation of adenosine triphosphate-sensitive potassium channels in cardiovascular mitochondria.
  • Levosimendan is the only inotropic agent that seems to reduce mortality in critically ill patients.
  • Studies suggest that perioperative infusion of levosimendan might lower cardiac troponin I levels, improve haemodynamics and shorten duration of intensive care stay after cardiac surgery.
  • A growing body of evidence supports the use of levosimendan in advanced chronic heart failure, cardiac surgery, and other situations when the heart function needs inotropic support.
References
  1. Papp Z et al. Levosimendan: Molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012;23;159:82–7. 
  2. Toller W et al. Perioperative use of levosimendan: Best practice in operative settings. J Cardiothorac Vasc Anesth 2012;[Epub ahead of print].
  3. Landoni G et al. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med 2012;40:634–46.
  4. Landoni G et al. Randomized evidence for reduction of perioperative mortality. J Cardiothorac Vasc Anesth 2012;26:764–72.
  5. Severi L et al. Levosimendan versus intra-aortic balloon pump in high-risk cardiac surgery patients. J Cardiothorac Vasc Anesth 2011;25:632–6.
  6. Lomivorotov VV et al. Levosimendan versus an intra-aortic balloon pump in high-risk cardiac patients. J Cardiothorac Vasc Anesth 2012;26:596–603.
  7. Zangrillo A et al. Levosimendan reduces cardiac troponin release after cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth 2009;23:474–8.
  8. Bonios MJ et al. Comparison of three different regimens of intermittent inotrope infusions for end stage heart failure. International J Cardiol 2012;159:225–9.
  9. Malfatto G et al. Intermittent levosimendan infusions in advanced heart failure: favourable effects on left ventricular function, neurohormonal balance and one-year survival. J Cardiovasc Pharmacol 2012;60:450–5.
  10. Mavrogeni S et al. A 6-month follow-up of intermittent levosimendan administration effect on systolic function, specific activity questionnaire, and arrhythmia in advanced heart failure. J Card Fail 2007;13:556–9.
  11. Berger R et al. Levosimendan and prostaglandin E1 for uptitration of beta- blockade in patients with refractory, advanced chronic heart failure. Eur J Heart Failure 2007;9:202–8.
  12. Kleber FX et al. Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension: results of a pilot study. J Clin Pharmacol 2009;49:109–15.
  13. Levin R et al. The intermittent infusion of levosimendan reduces mortality and re-admisions in patients with advanced heart failure. Circulation 2009;120:S865.
  14. Parissis JT et al. Effects of serial levosimendan infusions on left ventricular performance and plasma biomarkers of myocardial injury and neurohormonal and immune activation in patients with advanced heart failure. Heart 2006;92:1768–72.
  15. Morelli A et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care 2010;14:R232.
  16. Morelli A et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 2005;31:638–44.

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