Publicerade studier med Simdax

Landoni G, Mizzi A, Biondi-Zoccai G, et al.

Minerva Anestesiol 2010;76:276-86.

The authors conducted a systematic review and meta-analysis of data pooled from existing trials to determine the impact of levosimendan on mortality in any setting dealing with critically ill patients requiring inotropic drug support. The following inclusion criteria were used for relevant studies: random allocation to treatment, comparison of levosimendan vs. control with no restriction in dose and time of administration, and information on the primary outcome (mortality). Exclusion criteria were non-human experimental studies.

In total, 27 randomised clinical trials comprising 3350 patients (1893 patients treated with levosimendan and 1457 receiving control treatment) were included in the analysis.

The use of levosimendan was associated with a significant reduction in mortality: 17.6% (333/1893) in the levosimendan group compared with 22.4 % (326/1457) in the control group, OR=0.74 (0.62-0.89, p=0.001. Data on myocardial infarction showed a significant difference between the patients receiving levosimendan and the control group: 0.6% (3/493) in the levosimendan group vs. 3.9% (14/356) in the control group, OR=0.20 (0.06-0.64), p=0.007. Hypotension was more common in patients receiving levosimendan (11.1%, 164/1484) compared with the control group (9.7%, 106/1093), p=0.02. The authors conclude that levosimendan has cardioprotective effects that could result in a reduced mortality in critically ill patients.

Bergh C-H, Andersson B, Dahlström U, et al.

Eur J Heart Fail 2010;12:404-10.

The aim of this double-blind, double-dummy phase IVstudy (BEAT-CHF trial) was to compare the effects of a 24-hour infusion of levosimendan with a 48-hour infusion of dobutamine on invasive haemodynamics in patients with acute decompensated heart failure on optimal therapy including a beta-blocker.

Sixty patients were included (29 received levosimendan and 31 received dobutamine) from 13 centres in Sweden, Norway and Iceland. Patients were required to have a LVEF ≤35% within 3 months prior to inclusion, a cardiac index <2.5 L/min/m2 and PCWP >15 mmHg. The planned sample size was 110 patients. Howeverer, due to slow recruitment this was reduced to 60 patients.

The primary objective was to compare the change in cardiac index (CI) and PCWP between the treatment groups from baseline to 24 hours after start of study drug infusion. Both levosimendan and dobutamine infusions induced haemodynamic improvements. At 24 hours, the mean improvement in CI from baseline showed a trend in favour of levosimendan (p=0.066). At 48 hours, the difference in CI between the treatment groups was statistically significant (p=0.037). At 48 hours, the difference between the groups in the mean change of PCWP from baseline was more marked for the levosimendan group compared with the dobutamine group (p=0.015).

The reductions in BNP from baseline was more marked with levosimendan compared with dobutamine and the difference was statistically significant at 48 hours (p=0.03).

The primary objective of this study was not met. However, a trend in favour of levosimendan was seen at 24 hours after start of infusion. Because of slow recruitment the study was terminated before the prespecified number of patients had been included.

Cardoso JS, Ferreira J, Oliveira-Soares A, et al.

Rev Port Cardiol 2009;28:143-154.

The Portuguese authors evaluated the clinical effectiveness and safety of levosimendan in daily clinical practice. The study was prospective, non-randomised with 15 centres and 129 consecutive patients involved (PORTLAND-study). Eligible patients were those admitted to hospital with NYHA-class III-IV, LVEF ≤40 %, and evidence of decompensation which in the opinion of the investigator required treatment of inotropes.

The primary endpoint was a composite consisting of subjective parameters (NYHA-class and patient self-evaluation) and objective parameters (body weight, pulmonary congestion, urine output, serum creatinine, oral or intravenous heart failure medication). Among the secondary endpoints were adverse events, the number and length of hospital readmissions due to heart failure during the 6 months following levosimendan compared with the 6 months prior treatment.

Levosimendan was given with an optional loading dose of 12 µg/kg for 10 minutes followed by a continuous infusion of 0.05 – 0.2 µg/kg/minute. The patients were evaluated at baseline (before starting levosimendan infusion) and at 24 hours, 5 days, 3 months and at 6 months.

The primary combined endpoint was reached by approximately 80% of the patients at 24 hours and at 5 days. There were significant improvements in NYHA-class, urine output and serum creatinine levels at 24 hours and 5 days following levosimendan infusion. The most frequent adverse event was hypotension (n=5).

The number of heart failure hospitalisations (mean ± SD) per patient were 1.3 ± 1.0 6 months before, and 0.4 ± 0.7 6 months after the initiation of levosimendan (p<0.001). The number of days of hospitalisation for heart failure per patients was 14.9 ± 14.6 6 months before compared to 3.1 ± 7.6 6 months after the initiation of levosimendan (p<0.001).

The authors stated that the marked reduction in heart failure hospitalisations during the subsequent 6 months indicates that levosimendan can help decrease the total costs involved in the management of patients with heart failure who need inotropic support.

Landoni G, Mizzi A, Biondi-Zoccai G, et al.

J Cardiothorac Vasc Anesth 2009 Aug 21 [Epub ahead of print].

The authors conducted a systematic review and meta-analysis of data pooled from existing trials to determine the impact of levosimendan on mortality in patients undergoing cardiac surgery. Inclusion criteria for relevant studies were: random allocation to treatment, comparison of levosimendan versus control, studies performed on cardiac surgery patients with no restriction in dose and time of administration, and information on the primary outcome (mortality).

The primary endpoint was postoperative mortality. Among the secondary end-points were in-hospital myocardial infarction, acute renal failure, rate of atrial fibrillation and troponin release. In total, 10 studies comprising 440 randomised patients (235 patients were randomised to levosimendan and 205 patients were randomised to control) were included in the analysis. Eight studies used levosimendan in cardiac surgery with cardiopulmonary bypass and two studies used levosimendan during off-pump coronary artery bypass grafting. In four studies the controlgroup received placebo, in three studies dobutamine, and in three studies the controlgroup received milrinone.

Levosimendan was associated with significant reduction in postoperative mortality (11/235 [4.7%]) compared with 26/205 [12.7%] in the controlgroup. Odds ratio 0.35, 95% CI: 0.18-0.71, p=0.003. Further, the incidence of atrial fibrillation was reduced, and acute myocardial infarction and renal failure were more seldom seen with levosimendan compared with control.

This meta-analysis showed that perioperative use of levosimendan is associated with a reduction in postoperative mortality. However, randomised controlled studies are needed to confirm the clinical advantages of levosimendan in cardiac surgery.

Cohen-Solal A, Logeart D, Huang B, et al

J Am Coll Cardiol 2009;53:2343-2348.

Natriuretic peptides (B-type natriuretic peptide [BNP] or N-terminal pro-B-type natriuretic peptide [NT-proBNP] have rapidly gained popularity as biomarkers of diagnostic and prognostic value in patients with acute and chronic heart failure. BNP values at discharge have been shown to be strong predictors of subsequent outcomes in patients admitted for acute decompensation of heart failure. The authors describe a retrospective analysis of results from patients participated in the SURVIVE (Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support) study.

The purpose of this analysis was to determine whether changes in plasma BNP levels within the first 5 days of hospitalisation could predict short- and long-term mortality for patients with severe acute decompensated heart failure (ADHF).

SURVIVE was a randomised, multicentre, international, double-blind, double-dummy, parallel group, active-controlled study of levosimendan versus dobutamine in patients with severe ADHF.* The primary endpoint of the SURVIVE study was all-cause mortality at 180 days. Among secondary endpoints were BNP concentrations from the initiation of study drug (at baseline) to 24 hours. In addition, BNP concentrations were determined at Day 3 and 5. Mortality was evaluated at Days 1, 5, 14 and Day 31 and 180.

With regard to the percentage change in BNP from baseline to Day 5 the patients were divided into responders (decrease ≥30%) or nonresponders (decrease <30%). Another definition of responders was patients with an absolute BNP level of <800 pg/ml at Day 5. In total, 1038 patients who had BNP samples taken at both baseline and at Day 5 were included in the analysis.

BNP-responders at Day 5 had a 67% risk reduction in 31-day mortality compared with nonresponders (p<0.001). For 180-day mortality, the risk reduction was 47% (p<0.0001). Mortality rate at Day 31 was 4.6% for responders compared with 13.1% for nonresponders. The 180-day mortality rate was 17.9% for responders compared with 30.3% for nonresponders.

Occurrence of cardiogenic shock, cardiac failure and ventricular tachycardia was significantly less in the responder group. Moreover, there was a significant difference between responders and nonresponders regarding overall serious adverse events 22% (119 of 549) of responders, and 32% (158 of 489) of nonresponders had serious events during the study period.

This retrospective analysis of the SURVIVE study showed that a decrease in BNP of ≥30% during the first 5 days of hospitalisation of patients with ADHF was positively associated with improved survival at 31 days and 180 days.

* Mebazaa A. Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure. The SURVIVE randomized trial. JAMA 2007; 297:1883-1891.

Salmenperä M, Eriksson H.

Curr Opin Anaesthesiol 2009;22:496-501.

This review summarises the recent experiences and studies on the pharmacologic profile of levosimendan in the context of surgery, anaesthesia and critical care.

The authors conclude that, evidence is gathering to support the use of levosimendan in cardiac surgery. The cardioprotective ability of levosimendan is now well established in patients undergoing ischemic arrest. In patients resistant to or requiring increasing doses of catecholamines with low output after myocardial infarction or following cardiac surgery, levosimendan should be considered as a treatment option. The use of levosimendan in other perioperative and critical care conditions is attractive but needs to be confirmed by clinical research before any evidence-based recommendations can be made.