Bistola V & Chioncel O. (Attikon University Hospital, National and Kapodistrian University of Athens, Greece). Continuing Cardiology Education 2017 (ePub Nov 17). REVIEW.
A short chapter about levosimendan is included, where the authors refer to the older clinical trials (LIDO, RUSSLAN, REVIVE, SURVIVE and BEAT). They conclude that the role of levosimendan in acute heart failure remains controversial, but that the drug should be preferred to other inotropes in patients with pulmonary arterial hypertension, ischaemic heart disease, acute cardiorenal syndrome, and it may confer a cardioprotective effect in cardiac surgery.
Putzu A et al. (Cardiocentro Ticino, Lugano, Switzerland). Int J Cardiol 2017 (ePub Oct 21). META-ANALYSIS.
Meta-analysis including 40 trials involving a total of 4246 patients, including trials with pre-, intra- and postoperatively administered levosimendan, any control, patients undergoing any type of cardiac surgery with varying degree of preoperative LVEF, as well as various durations of levosimendan infusion. Levosimendan is associated with a significantly lower postoperative mortality (OR 0.56; 95% CI 0.44 to 0.71; trial sequential analysis conclusive), acute kidney injury and need for renal replacement therapy. However, in the 5 low-risk of bias trials involving only 1910 patients, no significant association between levosimendan and these parameters could be shown. There seems still to be place to define the effects on clinical outcome of levosimendan administered preoperatively.
Sellami W et al. (Université El-Manar, Tunis, Tunisie). Méd Intensive Réa 2017 (ePub). (in French with an English summary). CASE REPORT.
Patients presenting with acute fulminant myocarditis with unknown aetiology can have a complete recovery with an appropriate and rapid timing of an aggressive haemodynamic support including levosimendan and extracorporeal membrane oxygenation.
Chen Q-H et al. Subei People's Hospital, Yangzhou University, Jiangsu, People's Republic of China. Critical Care 2017 (ePub Oct 17). META-ANALYSIS.
Meta-analysis of 17 trials involving 2756 patients. Levosimendan therapy significantly reduces the risk of death, but this benefit loses significance when only low bias multicentre trials are considered. However, levosimendan therapy is clearly associated with reduced mortality in patients with preoperative ventricular systolic dysfunction. In these patients, levosimendan therapy resulted in less renal replacement therapy and shorter ICU stays.
Sanfilippo F et al. Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, Palermo, Italy. Critical Care 2017 (ePub Oct 19). META-ANALYSIS.
This meta-analysis tests the efficacy of levosimendan against placebo in high-risk cardiac surgery patients (defined as a preoperative LVEF <35% and/or low cardiac output syndrome). Six randomized clinical trials comprising 1728 patients were included, of which 4 trials included only patients undergoing CABG. Levosimendan was administered mostly preoperatively. Mortality was similar in both levosimendan and placebo groups, but in the subgroup of patients with LVEF <35% it was significantly lower with levosimendan. Need for renal replacement therapy and acute kidney injury were significantly reduced in the levosimendan group.
Roeleveld PP & de Klerk JCA. Leiden University Medical Center, Leiden, The Netherlands. World J Pediatr Congenit Heart Surg 2017 (ePub). REVIEW.
The survey about the postoperative use of inotropes (covering 62 international centres) disclosed that levosimendan was routinely used by 5%. The authors state that levosimendan could be useful in children with congenital heart disease.
Fang M et al. 3rd Hospital of HeBei Medical University, Shi Jiazhuang, China. Medicina Intensiva 2017 (ePub Nov 7). META-ANALYSIS.
By analysing 13 trials with a total of 648 patient, mortality was reduced with levosimendan, but the difference did not reach statistical significance (borderline), RR was 0.82 with 95% CI from 0.65 to 1.01. Levosimendan significantly improved most haemodynamic parameters and cardiac function, but no differences in length of ICU stay was observed.
Ergenekon E et al. Gazi University Hospital, Ankara, Turkey. Curr Pharm Des 2017 (ePub Sept 18). REVIEW.
Based on the results from 22 clinical trials where inotropes or vasoactive drugs were used, the most prevalent pharmacodynamic effects were, not surprisingly, increased blood pressure and heart rate. The present review demonstrates the need for further systematic studies on all the reviewed drugs (including levosimendan).
Janikowski K et al. Medical University Lodz, Poland. Folia Cardiologica 2017; 12: 378-385. CASE REPORT.
A patient with acute heart failure followed by anuria despite standard pharmacotherapy was treated with levosimendan. The patient's clinical status stabilised in the subsequent days. No details or numerical data are given in the abstract.
Thielmann M et al. University Hospital Essen, Essen, Germany. Eur Heart J 2017; 38: 2392-2411. CURRENT OPINION.
In the chapter "General management of peri-operative myocardial injury and type 5 myocardial infarction" it is shortly stated that in cases of overt heart failure, pharmacological haemodynamic optimisation and/or mechanical support may be indicated. Due to safety concerns, inotropes are reserved for patients with inadequate peripheral tissue perfusion or hypotension. The beta-agonist dobutamine, phosphodiesterase inhibitors like milrinone or enoximone, and the calcium sensitizer levosimendan can all be used to treat postoperative refractory low cardiac output syndrome and decompensated heart failure.
Madeira M et al. (Centro Hospitale e Universitario de Coimbra, Hospital Geral, Coimbra, Portugal) Rev Port Cardiol2017;36(9):619–625. RETROSPECTIVE OBSERVATIONAL TRIAL.
108 consecutive patients receiving either levosimendan or dobutamine were included. The levosimendan group had a significantly lower incidence of cardiorenal syndrome than dobutamine, 49% vs 77%, and showed a better recovery of renal function after discharge. Levosimendan had also a lower in-hospital mortality rate than dobutamine.
Jiang R et al. (Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China) Clin Respir J 2017 (ePub Sept 1). OPEN, UNCONTROLLED OBSERVATIONAL TRIAL.
In this small population of 45 patients, WHO Functional Class improved by one class, and also Borg dyspnea score as well as 6 min walk test improved significantly. This study had many limitations, including the small number of patients and the uncontrolled and open nature of the trial.
Chen X et al. (The Second Medical College of Nanchang University, Nanchang, Jiangxi, China) Am J Cardiovasc Drugs 2017 (ePub August 17). META-ANALYSIS.
The present network meta-analysis using Bayesian methodology included 63 articles with a total of 19,520 adult patients. Levosimendan significantly reduced the occurrence of acute kidney injury compared to placebo (Odds Ratio 0.63; 95% CI 0.43–0.88). The most effective therapy was natriuretic peptide (Odds Ratio 0.24). It can further be mentioned that also dexmedetomidine significantly reduced acute kidney injury (Odds Ratio 0.54). However, the methodology used has some limitations, so the results must be interpreted with caution.
Silvetti S et al. (IRCCS San Raffaele Scientific Institute, Milan, Italy) ESC Heart Failure 2017 (ePub Jun 29). META-ANALYSIS.
A total of 319 patients from 6 trials were included, representing very heterogeneous study designs, dosing and comparators. Intermittently administered levosimendan significantly reduced the number of re-hospitalisations at 3 months compared to controls (Risk Ratio 0.40; 95% CI 0.27–0.59). The result was similar when only placebo controlled studies were included.
Qiu J et al. (Henan University of Science and Technology, Luoyang, China) Life Sciences 2017;184:30–36. META-ANALYSIS.
The present meta-analysis of a total of 359 patients with a variety of heart and lung diseases analysed primarily right ventricular function using Doppler echocardiography and right heart catheterisation. Levosimendan was found to improve haemodynamics more than controls; e.g. increased ejection fraction as well as decreased systolic pulmonary artery pressure and pulmonary vascular resistance. Multicentre, randomised, controlled trials with large sample sizes and long follow-up times are needed to establish the role of levosimendan in the treatment of right heart failure.
Tavare-Silva M et al. (Department of Physiology and Cardiothoracic Surgery, University of Porto, Portugal) J.Cardiovasc.Pharmacol. Therapeut. 2017;22(5):485–95. PRECLINICAL.
Despite non clinical, this study shows beneficial acute systolic and diastolic functional effects of LEV in experimental chronic PH and right ventricle afterload compared with DOB and MIL. LEV improves RV VVC and CI without further improvement with the addition of sildenafil, although this combination further decreased PVRI. Overall, they support further clinical trials with LEV in patients with PH, particularly in class 1 PH, in the perioperative and critical care setting.
Pölzl G et al. (Innsbruck University, Austria) Int J Cardiol. May 2017. DOI: 10.1016/j.ijcard.2017.05.081. EXPERT OPINION.
Levosimendan has been suggested as a treatment that reduces re-hospitalisation and improves quality of life in advanced heart failure. However, previous clinical studies were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians met in November 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. The group tested the data from the PERSIST and LEVOREP trials post hoc using the same composite clinical endpoint as the earlier FIGHT trial, and demonstrated superiority of levosimendan treatment vs placebo. The use of this endpoint in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.
Wang X. & Li S. (Daqing Oilfield General Hospital, Daqing, People's Republic of China) Clin Interv Aging 2017; 12: 917-921. RANDOMISED CLINICAL TRIAL.
This was a prospective randomised double-blind clinical trial in 240 Chinese patients over 65 years of age with sepsis. Levosimendan (12.5 mg, infused at 0.1–0.2 μg/kg/min) in addition to standard care reduced the number of days of ICU and hospital stay and improved cardiovascular function compared to standard care alone. However, mortality rate was similar and renal, hepatic and respiratory function were also comparable between the two groups.
Shang G et al. (Qilu Hospital of Shandong University, Ji'nan, People's Republic of China) Am J Cardiovasc Drugs 2017 (ePub June 8). META-ANALYSIS.
A meta-analysis was performed in 1065 patients with heart failure (including cardiogenic shock) and acute coronary syndrome from 9 studies with heterogeneous designs. Mortality at the end of follow-up and incidence of worsening heart failure were significantly reduced in patients receiving levosimendan compared to all controls. No significant reduction was seen when levosimendan was compared to dobutamine. Since not all of the studies reported all outcome parameters, the outcome data was based on relatively small numbers of measurements. More randomised clinical trials are required for more reliable conclusions.
Kandasamy et al. (SRM University, Kattankulathur, Chennai, Tamil Nadu, India) Ann Cardiac Anaesth 2017; 20: 200-206. RANDOMISED CLINICAL TRIAL.
The trial comprised 80 patients, randomly assigned to receive either levosimendan at 0.1 μg/kg/min or dobutamine at 5 μg/kg/min. Blood pressure, filling pressure, and systemic vascular resistance were significantly lower in the levosimendan group than in the dobutamine group. Cardiac index and cardiac contractility parameters increased significantly with levosimendan. Furthermore, the levosimendan group showed a lower incidence of atrial fibrillation, as well as shorter length of ICU and hospital stay. The results indicate that levosimendan is superior to dobutamine in terms of myocardial performance and some outcome parameters in this surgical setting.
Husebye T et al. (University Hospital Ullevål, Oslo, Norway) Eur Heart J Acute Cardiovasc Care 2017 (ePub Jan 1). RETROSPECTIVE OBSERVATIONAL STUDY.
This article reports results of a sub-analysis of the LEAF trial in which 61 patients with acute heart failure following a myocardial infarction received levosimendan or placebo. Tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) were used to measure left ventricular function. Systolic mitral annulus velocity (S’) measured with TDI was a sensitive and feasible marker of the inotropic effect of levosimendan. S’ increased significantly more with levosimendan than with placebo (30% vs. 3% increase from baseline to day 5, p<0.0005), indicating improved left ventricular systolic function.
Ortis O, et al. J Int Med Res 2017;45:361-71. RETROSPECTIVE NON-RANDOMISED CONTROLLED STUDY.
The analyses were based on 25 patients receiving levosimendan intermittently for 6–12 months and 25 non-randomised control patients. At 6 months, the number of hospitalisations and length of stay in hospital were significantly reduced in the levosimendan group. A subset of the levosimendan group were ‘super-responders’ with >20% improvement in LVEF and reduced hospitalisation rate compared to the rest of the levosimendan group. The number of patients was too small to draw any conclusions on mortality. Intermittent levosimendan may represent an option for patients whose disease is rapidly worsening despite optimal treatment.