NIHR DC Discover

NIHR Signal The heart failure drug levosimendan doesn’t improve outcomes in adults with severe infections

Published on 13 December 2016

doi: 10.3310/signal-000347

Septic shock is a life-threatening condition resulting from serious infection.

Adding levosimendan to the usual care of adults with septic shock did not reduce the risk of death up to 28 days, nor the degree of damage to essential body organs. It probably also increased patients’ risk of abnormally fast heart rate and increased the time they needed mechanical ventilation.

This large NIHR-supported trial included adults in UK intensive care units. It is the largest to date and presents the best evidence currently available on use of levosimendan in this group. Early smaller studies had shown promising effects on markers of heart function and blood supply in patients with septic shock.

Levosimendan is licensed in several countries to treat heart failure, but does not currently have approval from the US Food and Drug Administration.

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Why was this study needed?

There are 150,000 cases of severe sepsis in the UK every year, with 44,000 deaths. Mortality is very high, 30 to 40% even with the best available treatment.

Severe infections can lead to septic shock with failure of the heart, kidneys and other essential body systems.  Intensive care is directed at supporting these systems while the infection is brought under control.

Drugs similar to adrenaline are commonly used to increase the power of the heart and to improve blood flow around the body. Levosimendan works in slightly different ways to improve heart function and also relaxes blood vessels to improve the circulation.

Smaller studies in severe sepsis have shown that levosimendan improves measurements of the circulation, kidney and liver function. These studies were not large enough to find whether important outcomes such as survival or kidney failure were improved.

There was a need for a larger study to determine whether levosimendan has a place in the management of adults with septic shock.

What did this study do?

This study recruited 516 adult patients from 34 intensive care units in the UK who had septic shock and been treated with vasopressors for at least four hours previously. These criteria may mean that the study included patients who were less severely ill than in some of the earlier studies.  Adults were randomized to receive levosimendan or placebo in addition to usual intensive care management by the local clinicians, according to the “Surviving Sepsis Campaign” guidelines. The trial was double-blind, with neither patients nor assessors aware of treatment given.

The main outcome was the daily change in a composite organ failure score (SOFA: Sequential Organ Failure Assessment) over the subsequent stay in intensive care up to a maximum of 28 days. The score has a top score of 20. Other outcomes included 28-day mortality, kidney function, time to weaning from mechanical ventilation, and adverse events.

What did it find?

  • There was no difference in mean SOFA score between the levosimendan and placebo groups (6.68 vs. 6.06; mean difference, 0.61; 95% confidence interval [CI] −0.07 to 1.29).
  • There was no difference in mortality at 28 days, which was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference 3.6%; 95% CI −4.5 to 11.7).
  • Levosimendan did not reduce the number of acute kidney events, 57.4% in the levosimendan group and 54.3% in the placebo group (absolute difference 3.1%, 95% CI -5.5 to 11.6).
  • Successful weaning from mechanical ventilation was less likely in the levosimendan group over the period of 28 days (hazard ratio 0.77, 95% CI 0.60 to 0.97). Differences between the groups before inclusion in the study may have accounted for this.
  • More patients in the levosimendan group had abnormal fast heart rhythms (3.1% vs. 0.4%; absolute difference 2.7 percentage points, 95% CI 0.1 to 5.3). Again, there were differences between the groups before inclusion in the study which may have accounted for this.

What does current guidance say on this issue?

There is no current NICE guidance on the use of levosimendan in acute sepsis.  It was evaluated in 2003 but not recommended as it was not marketed in the UK at that time.

The current Society of Critical Care Medicine’s Surviving Sepsis Campaign guidelines do not include the use of levosimendan.

Levosimendan has marketing authorisation in a large number of countries, including the UK, but does not currently have US FDA approval.

What are the implications?

Levosimendan did not reduce mortality or major organ failure in this large well conducted study. On this basis, levosimendan cannot be recommended in the usual management of patients with septic shock. 

There were more fast heart rhythms and mechanical ventilation was longer in those who received the drug, but some caution is needed in interpretation as there were differences between the study groups which could explain these findings.

Earlier smaller studies showed potential improvements in measurements of kidney, liver and lung function but this larger study does not show improved outcomes in organ function or mortality.

Citation and Funding

Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med. 2016. [Epub ahead of print].

This project was funded by the National Institute for Health Research / Medical Research Council Efficacy and Mechanism Evaluation Programme (project number 11/14/08) and by Tenax Therapeutics, Inc.

The National Institute for Health Research also provided funding through a fellowship and the NIHR Comprehensive Biomedical Research Centre based at Imperial College London.

The U.K. Intensive Care Foundation provided general research support.

Bibliography

Morelli A, De Castro S, Teboul J-L, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31(5):638-44.

Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.

Zangrillo A, Putzu A, Monaco F, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Crit Care. 2015;30(5): 908-13.

Why was this study needed?

There are 150,000 cases of severe sepsis in the UK every year, with 44,000 deaths. Mortality is very high, 30 to 40% even with the best available treatment.

Severe infections can lead to septic shock with failure of the heart, kidneys and other essential body systems.  Intensive care is directed at supporting these systems while the infection is brought under control.

Drugs similar to adrenaline are commonly used to increase the power of the heart and to improve blood flow around the body. Levosimendan works in slightly different ways to improve heart function and also relaxes blood vessels to improve the circulation.

Smaller studies in severe sepsis have shown that levosimendan improves measurements of the circulation, kidney and liver function. These studies were not large enough to find whether important outcomes such as survival or kidney failure were improved.

There was a need for a larger study to determine whether levosimendan has a place in the management of adults with septic shock.

What did this study do?

This study recruited 516 adult patients from 34 intensive care units in the UK who had septic shock and been treated with vasopressors for at least four hours previously. These criteria may mean that the study included patients who were less severely ill than in some of the earlier studies.  Adults were randomized to receive levosimendan or placebo in addition to usual intensive care management by the local clinicians, according to the “Surviving Sepsis Campaign” guidelines. The trial was double-blind, with neither patients nor assessors aware of treatment given.

The main outcome was the daily change in a composite organ failure score (SOFA: Sequential Organ Failure Assessment) over the subsequent stay in intensive care up to a maximum of 28 days. The score has a top score of 20. Other outcomes included 28-day mortality, kidney function, time to weaning from mechanical ventilation, and adverse events.

What did it find?

  • There was no difference in mean SOFA score between the levosimendan and placebo groups (6.68 vs. 6.06; mean difference, 0.61; 95% confidence interval [CI] −0.07 to 1.29).
  • There was no difference in mortality at 28 days, which was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference 3.6%; 95% CI −4.5 to 11.7).
  • Levosimendan did not reduce the number of acute kidney events, 57.4% in the levosimendan group and 54.3% in the placebo group (absolute difference 3.1%, 95% CI -5.5 to 11.6).
  • Successful weaning from mechanical ventilation was less likely in the levosimendan group over the period of 28 days (hazard ratio 0.77, 95% CI 0.60 to 0.97). Differences between the groups before inclusion in the study may have accounted for this.
  • More patients in the levosimendan group had abnormal fast heart rhythms (3.1% vs. 0.4%; absolute difference 2.7 percentage points, 95% CI 0.1 to 5.3). Again, there were differences between the groups before inclusion in the study which may have accounted for this.

What does current guidance say on this issue?

There is no current NICE guidance on the use of levosimendan in acute sepsis.  It was evaluated in 2003 but not recommended as it was not marketed in the UK at that time.

The current Society of Critical Care Medicine’s Surviving Sepsis Campaign guidelines do not include the use of levosimendan.

Levosimendan has marketing authorisation in a large number of countries, including the UK, but does not currently have US FDA approval.

What are the implications?

Levosimendan did not reduce mortality or major organ failure in this large well conducted study. On this basis, levosimendan cannot be recommended in the usual management of patients with septic shock. 

There were more fast heart rhythms and mechanical ventilation was longer in those who received the drug, but some caution is needed in interpretation as there were differences between the study groups which could explain these findings.

Earlier smaller studies showed potential improvements in measurements of kidney, liver and lung function but this larger study does not show improved outcomes in organ function or mortality.

Citation and Funding

Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med. 2016. [Epub ahead of print].

This project was funded by the National Institute for Health Research / Medical Research Council Efficacy and Mechanism Evaluation Programme (project number 11/14/08) and by Tenax Therapeutics, Inc.

The National Institute for Health Research also provided funding through a fellowship and the NIHR Comprehensive Biomedical Research Centre based at Imperial College London.

The U.K. Intensive Care Foundation provided general research support.

Bibliography

Morelli A, De Castro S, Teboul J-L, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31(5):638-44.

Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.

Zangrillo A, Putzu A, Monaco F, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Crit Care. 2015;30(5): 908-13.

Levosimendan for the prevention of acute organ dysfunction in sepsis

Published on 5 October 2016

A C Gordon; G D Perkins; M Singer; D F McAuley; R M L’E Orme MB; S Santhakumaran; A J Mason; M Cross; F Al-Beidh; J Best-Lane; D Brealey; C L Nutt; J J McNamee; H Reschreiter; A Breen; K D Liu MD; D Ashby;

New England Journal of Medicine , 2016

BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. METHODS We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. RESULTS The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). CONCLUSIONS The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS

Sequential Organ Failure Assessment (SOFA) score. Calculated daily on the basis of five organ systems: cardiovascular, respiratory, kidney, liver and clotting.

Each system is scored between 0 and 4, with higher score indicating more severe organ damage. The maximum score is 20.

Expert commentary

Use of levosimendan in unselected patients with septic shock is not supported, as there is no benefit in survival, reducing renal support or length of admission. The reported complications may or may not be clinically significant. The role of levosimendan in severely septic patients has yet to be fully investigated, but there is not enough evidence to recommend its widespread use.

It is possible that there may be certain groups of patients who may benefit, such as those with significantly impaired heart function.

Dr David Sparkes, Consultant in Intensive Care, University Hospitals, Southampton

Expert commentary

A therapeutic agent showing promise in sepsis again fails on clinical efficacy in a clinical trial. Does LeoPARDS mean Levosimendan has no place? I suspect not. I rather think that it highlights the inadequacy of sepsis studies resulting from heterogeneity in source, pathogen, host response, time of presentation and quality of basic care. We might be looking at this the wrong way.

Until we narrow our recruitment net, until we reduce variation in time to presentation to hospital and delivery of basic care, it’s unlikely we will reap reward. One size doesn’t yet fit all in ITU management of sepsis.

Dr Ron Daniels, CEO of UK Sepsis Trust and Global Sepsis Alliance, Clinical Adviser to NHS England