Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Use of Levosimendan in Cardiac Surgery: An Update After the LEVO-CTS, CHEETAH, and LICORN Trials in the Light of Clinical Practice.

Levosimendan is a calcium sensitizer and adenosine triphosphate-dependent potassium channel opener, which exerts sustained hemodynamic, symptomatic, and organ-protective effects. It is registered for the treatment of acute heart failure, and when inotropic support is considered appropriate. In the past 15 years, levosimendan has been widely used in clinical practice and has also been tested in clinical trials to stabilize at-risk patients undergoing cardiac surgery. Recently, 3 randomized, placebo-controlled, multicenter studies (LICORN, CHEETAH, and LEVO-CTS) have been published reporting on the perioperative use of levosimendan in patients with compromised cardiac ventricular function. Taken together, many smaller trials conducted in the past suggested beneficial outcomes with levosimendan in perioperative settings. By contrast, the latest 3 studies were neutral or inconclusive. To understand the reasons for such dissimilarity, a group of experts from Austria, Belgium, Finland, France, Germany, Italy, Switzerland, and Russia, including investigators from the 3 most recent studies, met to discuss the study results in the light of both the previous literature and current clinical practice. Despite the fact that the null hypothesis could not be ruled out in the recent multicenter trials, we conclude that levosimendan can still be viewed as a safe and effective inodilator in cardiac surgery.

Levosimendan in Acute and Advanced Heart Failure: An Appraisal of the Clinical Database and Evaluation of Its Therapeutic Applications.

The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. However, negative or insufficient data have been collected regarding the effects of cardiac glycosides, catecholamines, and phosphodiesterase inhibitors on quality of life and survival. More recently, the calcium sensitizer and potassium channel-opener levosimendan has been proposed as a safer inodilator than traditional agents in some heart failure settings, such as advanced heart failure. At the 2017 annual congress of the Heart Failure Association of the European Society of Cardiology (Paris, April 30-May 2), a series of tutorials delivered by lecturers from 8 European countries examined how to use levosimendan safely and effectively in acute and advanced heart failure. The proceedings of those tutorials have been collated in this review to provide an expert perspective on the optimized use of levosimendan in those settings.

Repetitive levosimendan treatment in the management of advanced heart failure.

Inotropes may be an appropriate treatment for patients with advanced heart failure (AdHF) who remain highly symptomatic despite optimized standard therapies. Objectives for inotrope use in these situations include relief of symptoms and improvement of quality of life, and reduction in unplanned hospitalizations and the costs associated with such episodes. All of these goals must be attained without compromising survival. Encouraging findings with intermittent cycles of intravenous levosimendan have emerged from a range of exploratory studies and from three larger controlled trials (LevoRep, LION-HEART, and LAICA) which offered some evidence of clinical advantage. In these settings, however, obtaining statistically robust data may prove elusive due to the difficulties of endpoint assessment in a complex medical condition with varying presentation and trajectory. Adoption of a composite clinical endpoint evaluated in a hierarchical manner may offer a workable solution to this problem. Such an instrument can explore the proposition that repetitive administration of levosimendan early in the period after discharge from an acute episode of worsening heart failure may be associated with greater subsequent clinical stability vis-à-vis standard therapy. The use of this methodology to develop a 'stability score' for each patient means that all participants in such a trial contribute to the overall outcome analysis through one or more of the hierarchical endpoints; this has helpful practical implications for the number of patients needed and the length of follow-up required to generate endpoint data. The LeoDOR study (NCT03437226), outlined in this review, has been designed to explore this new approach to outcome assessment in AdHF.

Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

BACKGROUND: Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models. OBJECTIVE: We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0.125 to 2.0 mg daily for 18-day intervals of each dose; 5 patients received placebo. Twenty-four-hour ambulatory ECG and cerebral blood flow velocities using transcranial Doppler ultrasound were recorded at baseline and at the end of each dosing period. Vasomotor reactivity was assessed via the breath holding index. In addition, plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and the metabolites of levosimendan were determined. RESULTS: Levosimendan induced an increase in cerebral blood flow velocities and a decrease in NT-pro-BNP compared with placebo. There was no significant effect on breath holding index. Doses ≥0.5 mg increased heart rate by 5 to 9 beats/min. The dose level of 2.0 mg exceeded the preset safety margin of ventricular extrasystoles per hour (ie, upper 90% CI of the ratio of levosimendan to placebo above 2) with an estimate of 3.10 (90% CI, 0.95-10.07). CONCLUSIONS: Oral levosimendan increases cerebral blood flow velocities and diminishes NT-pro-BNP levels in patients with earlier ischemic cerebrovascular event. Daily doses up to 1.0 mg were well tolerated, whereas the 2.0 mg dose level induced an increase in ventricular extrasystoles. ClinicalTrials.gov identifier: NCT00698763.

Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure.

AIMS: The aim of this study was to assess the prevalence of abnormal liver function tests (LFTs) and the associated clinical profile and outcome(s) in acute decompensated heart failure (ADHF) patients. Alteration in LFTs is a recognized feature of ADHF, but prevalence and outcomes data from a broad contemporary cohort of ADHF are scarce and the mechanism(s) of ADHF-induced cholestasis is unknown. METHODS AND RESULTS: We conducted a post hoc analysis of SURVIVE, a large clinical trial including ADHF patients treated with levosimendan or dobutamine. All LFTs were available in 1134 patients at baseline. Abnormal LFTs were seen in 46% of ADHF patients: isolated abnormal alkaline phosphatase (AP) was noted in 11%, isolated abnormal transaminases in 26%, and a combination of abnormal AP and transaminases in 9%. Abnormal AP was associated with marked signs of systemic congestion and elevated right-sided filling pressure. Abnormal AP had no relationship with 31-day mortality but was associated with worse 180-day mortality (23.5 vs. 34.9%, P = 0.001 vs. patients with normal AP). Abnormal transaminases were associated with clinical signs of hypoperfusion and with greater 31-day and 180-day mortality compared with normal transaminase profiles (17.6 vs. 8.4% and 31.6 vs. 22.4%, respectively; both P < 0.001). There was no additive value of abnormal AP plus abnormal transaminase on a long-term outcome. CONCLUSION: Abnormal LFTs were present in about a half of patients presenting with ADHF treated with inotropes. Abnormal AP and abnormal transaminases were associated with specific clinical, biological, and prognostic features, including a short-term overmortality with increased transaminases but not with biological signs of cholestasis, in ADHF patients.

Renal effects of levosimendan: a consensus report.

Renal dysfunction is common in clinical settings in which cardiac function is compromised such as heart failure, cardiac surgery or sepsis, and is associated with high morbidity and mortality. Levosimendan is a calcium sensitizer and potassium channel opener used in the treatment of acute heart failure. This review describes the effects of the inodilator levosimendan on renal function. A panel of 25 scientists and clinicians from 15 European countries (Austria, Finland, France, Hungary, Germany, Greece, Italy, Portugal, the Netherlands, Slovenia, Spain, Sweden, Turkey, the United Kingdom, and Ukraine) convened and reached a consensus on the current interpretation of the renal effects of levosimendan described both in non-clinical research and in clinical study reports. Most reports on the effect of levosimendan indicate an improvement of renal function in heart failure, sepsis and cardiac surgery settings. However, caution should be applied as study designs differed from randomized, controlled studies to uncontrolled ones. Importantly, in the largest HF study (REVIVE I and II) no significant changes in the renal function were detected. As it regards the mechanism of action, the opening of mitochondrial KATP channels by levosimendan is involved through a preconditioning effect. There is a strong rationale for randomized controlled trials seeking beneficial renal effects of levosimendan. As an example, a study is shortly to commence to assess the role of levosimendan for the prevention of acute organ dysfunction in sepsis (LeoPARDS).

The clinical effects of levosimendan are not attenuated by sulfonylureas.

OBJECTIVES: Levosimendan is an inodilator indicated for acute heart failure (AHF). Its vasodilatory and anti-ischemic effects are mediated by the opening of ATP-dependent potassium channels (K(ATP) channels). Diabetes mellitus is common in AHF patients and sulfonylureas are often prescribed. Sulfonylureas act by blocking the K(ATP) channels. An interaction between levosimendan and sulfonylureas has been shown in preclinical models and could be hypothesized in clinical practice. DESIGN: We produced a pooled analysis of six randomized levosimendan trials (in total of 3004 patients of which 1700 were treated with levosimendan and 226 both with levosimendan and sulfonylureas) with the aim to study the influence of concurrent sulfonylurea treatment to the levosimendan effects. Invasive and non-invasive hemodynamics, biomarkers (BNP), adverse events related to myocardial ischemia, and survival were evaluated. RESULTS: In our relatively small data set, we could not detect any clinically relevant interactions between the sulfonylureas and levosimendan. Similar decreases in systolic and diastolic blood pressure, pulmonary capillary wedge pressure and BNP, and similar survival and adverse event profiles were seen in sulfonylurea users and non-users exposed to levosimendan. CONCLUSIONS: Concomitant use of sulfonylureas with levosimendan does not attenuate the hemodynamic or other effects of levosimendan.

Beneficial association of ß-blocker therapy on recovery from severe acute heart failure treatment: data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial.

OBJECTIVES: Beta-blocker therapy is recommended for most patients with chronic heart failure, although such therapy may be discontinued or reduced during hospitalizations. The aim is to determine whether ß-blocker use at study entry and/or at discharge has an impact on 31- and 180-day survival. DESIGN: Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support study was designed as a randomized, double-blind, active-controlled, multi-center study. SETTING: Multinational. PATIENTS: A total of 1,327 critically ill patients hospitalized with low-output heart failure in need of inotropic therapy. INTERVENTION: Levosimendan versus dobutamine. MEASUREMENTS: All-cause mortality at 31 and 180 days in patients who survived initial hospitalization with/without ß-blocker use at entry and/or at discharge. RESULTS: Patients on ß-blockers at entry and at discharge had significantly lower 31-day (p < .0001) and 180-day (p < .0001) mortality compared to patients without ß-blockers use at both time points. The association was robust when adjusted for age and co-morbidities (p = .006 at 31 days; p = .003 at 180 days). CONCLUSIONS: Those results strongly suggest, in severe acutely decompensated heart failure patients, admitted on ß-blockers, to continue on them at discharge.

Oral levosimendan improves filling pressure and systolic function during long-term treatment.

OBJECTIVES: Oral levosimendan improves ventricular function in short-term clinical trials. The effects of long-term treatment with oral levosimendan were investigated on echocardiographic parameters of left ventricular function in patients with chronic heart failure. DESIGN: Twenty-nine patients with NYHA III-IV congestive chronic HF were prospectively enrolled in a randomised, double-blind, placebo controlled study. Oral levosimendan was administered on top of existing medication over a treatment period of at least 180 days. Echocardiographic measurements estimating pulmonary capillary wedge pressure (PCWP) and tissue Doppler mitral basal myocardial velocities (Sm, Em) were performed at baseline and 90 and 180 days after randomisation. RESULTS: Estimated PCWP at baseline was elevated in both groups and decreased by 13% in the levosimendan group compared to an increase of 9% in the placebo group (p = 0.035). Sm was decreased in both groups at baseline and improved by 0.9 cm/s in the levosimendan group and decreased by 0.1 cm/s in the placebo group (p = 0.035). Levosimendan did not significantly alter heart rate or systolic blood pressure. CONCLUSIONS: Oral levosimendan improved hemodynamic function in chronic heart failure patients and the effect was sustained over the 180-day follow-up period.

Acetylation status does not affect levosimendan's hemodynamic effects in heart failure patients.

OBJECTIVE: Levosimendan is indicated for acute heart failure. The formation of levosimendan's active metabolite OR-1896 is dependent on the acetylator status. We evaluated whether acetylator status affects the hemodynamic responses after levosimendan infusion. METHODS: Forty-one NYHA III to IV heart failure patients were divided into rapid and slow acetylators by population kinetic modeling. Invasive hemodynamics and plasma concentrations of levosimendan and its metabolites were followed serially. RESULTS: Fifty-six percent of the patients were rapid and 44% slow acetylators. Levosimendan induced increases in heart rate and cardiac output, and decreases in pulmonary capillary wedge pressure (PCWP) and blood pressure, which were sustained at 24 hours after stopping the infusion. At this time, levosimendan levels were undetectable, and OR-1896 levels were about two-fold higher in rapid acetylators. However, hemodynamic effects were similar; mean(SEM) change from baseline in cardiac output was +2.0(0.3) vs. +1.6(0.3) l/min (p = 0.309), and in PCWP -8(2) vs. -7(1) mmHg (p = 0.536), in rapid and slow acetylators, respectively. CONCLUSION: The sustained hemodynamic effects of levosimendan are similar irrespective of acetylator status.

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: An expert panel consensus.

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure.

Oral levosimendan in patients with severe chronic heart failure --the PERSIST study.

BACKGROUND: Intravenous levosimendan improves symptoms in acutely decompensated heart failure. AIMS: To evaluate the effects of oral levosimendan in severe chronic heart failure (CHF). METHODS: 307 patients with NYHA IIIB-IV CHF were randomly assigned, double-blind, to levosimendan 1 mg once or twice daily or placebo for at least 180 days. An exploratory primary end-point, the Patient Journey, a composite consisting of repeated symptom assessments, worsening heart failure and mortality during 60 days was used. Minnesota Living with Heart Failure quality of life score (MLHFQoL) and NT-proBNP were assessed repeatedly. RESULTS: Patients assigned to a lower dose of levosimendan had more severe CHF at baseline. No differences in symptoms emerged and worsening heart failure events and death were similar resulting in a similar Patient Journey score with levosimendan and placebo (p=0.567). Compared to placebo, a net improvement of 3-4 points in MLHFQoL at several time-points in favour of the combined levosimendan groups was observed (p<0.001) which was accompanied by a substantial and persistent reduction in NT-proBNP (-30-40%) (p<0.001). CONCLUSION: Levosimendan improved QoL and decreased NT-proBNP but did not improve the Patient Journey composite in patients with severe CHF. Further research with this compound is warranted to clarify safety and efficacy.

Pharmacokinetics of intravenous levosimendan and its metabolites in subjects with hepatic impairment.

Levosimendan is a vasodilator used in the treatment of acute heart failure. In the present study, the effect of hepatic impairment on the pharmacokinetics of levosimendan and its 2 metabolites, OR-1855 and OR-1896 (pharmacologically active), was investigated in 12 healthy subjects and 12 subjects with moderate hepatic impairment due to alcoholic cirrhosis of the liver but with no heart failure. In addition, the effect of acetylator status on the pharmacokinetics of levosimendan, OR-1855, and OR-1896 was evaluated. Safety and tolerability of levosimendan were also assessed. Levosimendan was given as an intravenous infusion of 0.1 microg/kg/min for 24 hours. Levosimendan showed similar C(max), AUC, and elimination half-life (t(1/2)), with a mean (+/-SEM) t(1/2) of 0.9 +/- 0.0 hours in healthy subjects and 0.8 +/- 0.1 hours in hepatically impaired subjects, respectively (not significant). The t(1/2) of OR-1855 was 61 +/- 5 hours in healthy subjects and 82 +/- 3 hours (P < .01) in subjects with hepatic impairment. The t(1/2) of OR-1896 was 62 +/- 5 hours and 91 +/- 5 hours (P < .01), respectively. However, the AUCs of OR-1855 and OR-1896 were similar in healthy volunteers and hepatically impaired subjects. The effect of acetylator status was seen as higher C(max) and AUC of OR-1855 in slow acetylators. Correspondingly, higher C(max) and AUC of OR-1896 were observed in rapid acetylators. Levosimendan was well tolerated in both study groups. In conclusion, the pharmacokinetics of the parent drug levosimendan was unaltered in subjects with moderate hepatic impairment, whereas the elimination of the metabolites was prolonged. However, because the maximum duration of levosimendan infusion is 24 hours, dosing adjustments of levosimendan may not be required in subjects with impaired hepatic function.

Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites.

BACKGROUND AND OBJECTIVES: Levosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896. STUDY DESIGN: This study was an open-label, nonrandomised, phase I pharmacokinetic study. Levosimendan was administered as a single-dose infusion of 0.1 microg/kg/minute for 24 hours. The follow-up period lasted 3 weeks. STUDY SETTING: Twenty-fivepatients were included:12 patients with severe chronic renal failure (CRF) with creatinine clearance of < 30 mL/minute/1.73 m(2) and 13 patients with end-stage renal disease (ESRD) undergoing haemodialysis. A group of 12 healthy subjects served as controls. RESULTS: Levosimendan, the parent drug, was eliminated rapidly from the plasma after discontinuation of its infusion, with an elimination half-life (t(1/2)) [mean +/- standard error of mean] of 1.5 +/- 0.09 hours in ESRD patients undergoing haemodialysis, 1.0 +/- 0.2 hours in patients with severe CRF and 0.91 +/- 0.03 hours in healthy subjects. The t(1/2) of levosimendan was significantly longer (p < 0.001) in ESRD patients undergoing haemodialysis than in healthy subjects. The t(1/2) of OR-1855 and OR-1896 were 94.0 +/- 20.4 hours and 96.5 +/- 19.5 hours, respectively, in ESRD patients undergoing haemodialysis compared with 60.8 +/- 5.2 and 61.6 +/- 5.2 hours, respectively, in healthy subjects (p = not significant). The t(1/2) of OR-1855 was significantly longer (85.0 +/- 13.6 hours) in patients with severe CRF than in healthy subjects (60.8 +/- 5.2 hours, p < 0.05). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C(max)) of the metabolites were approximately 2-fold in patients with ESRD undergoing haemodialysis and patients with severe CRF compared with healthy subjects. The mean unbound fraction (f(u)) of levosimendan in plasma was approximately 2% in each study group, whereas the f(u) of the metabolites was considerably higher (63-70%). In contrast to levosimendan, the metabolites were dialysable, with dialysis clearance of approximately 100 mL/minute. The haemodynamic responses and adverse event profiles were similar in the study groups, with headache, palpitations and dizziness being the most frequently recorded adverse events. CONCLUSION: The t(1/2) of the levosimendan metabolites was prolonged 1.5-fold and their AUC and C(max) were 2-fold in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.

Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial.

CONTEXT: Because acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival. OBJECTIVE: To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. DESIGN, SETTING, AND PATIENTS: The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004. INTERVENTIONS: Intravenous levosimendan (n = 664) or intravenous dobutamine (n = 663). MAIN OUTCOME MEASURE: All-cause mortality at 180 days. RESULTS: All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P = .40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group. CONCLUSION: Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00348504.

Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy.

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.

Effect of baseline characteristics on mortality in the SURVIVE trial on the effect of levosimendan vs dobutamine in acute heart failure: Sub-analysis of the Finnish patients.

BACKGROUND: In the SURVIVE trial, including 1327 acute heart failure patients, no statistically significant difference between levosimendan and dobutamine in the 180-day all-cause mortality was seen. Country-specific differences in outcome were, however, present. In the Finnish sub-population in fact, mortality was significantly lower in levosimendan treated patients. We aim to understand the reasons for this disparity. METHODS: The risk factors for all-cause mortality were identified in the whole study population using multivariate Cox proportional hazards regression analysis. Those factors were evaluated in the 95 patients of the Finnish sub-population. RESULTS: The treatment by country interaction for mortality in Finland vs. other countries was significant, p=0.029. Levosimendan treated patients had a lower 180-day mortality compared to dobutamine treated (17% vs. 40%, p=0.023) in the Finnish sub-population. Baseline variables predicting survival in the whole SURVIVE trial population included age, systolic blood pressure, heart rate, myocardial infarction during admission, levels of NT-pro-BNP, glucose, creatinine, and alanine transferase, use of ACE inhibitors and ß-blockers, oliguria, time from hospital admission to randomization, history of cardiac arrest, and left ventricular ejection fraction. Finnish patients were more frequently treated with ß-blockers (88% vs. 52%, p<0.0001), their study treatment was started earlier (mean±SD 41±40h vs. 81±154; p<0.0001), and they had more often acute myocardial infarction at admission (39% vs. 16%, p<0.0001). CONCLUSION: The lower mortality in the Finnish patients treated with levosimendan was associated with higher use of ß-blockers, higher frequency of myocardial infarction at admission, and shorter delay between randomization and start of treatment.