Levosimendan meta-analyses : Is there a pattern in the effect on mortality?

Background: Levosimendan is an inodilator developed for treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. Levosimendan has been studied in different therapeutic settings including acutely decompensated chronic heart failure, advanced heart failure, right ventricular failure, cardiogenic shock, septic shock, and cardiac and non-cardiac surgery. This variety of data has been re-analysed in 25 meta-analyses from 15 different international research groups, based on different rationales to select the studies included. Methods: We here review all previously published meta-analyses on levosimendan to determine any common denominators for its effects on patient mortality. In addition, we also perform a comparative meta-analysis of the six phase II and III randomized double-blind trials which were taken into consideration by the regulatory authorities for the purpose of introducing levosimendan into the market. Results: Irrespective of clinical setting or comparator, all meta-analyses consistently show benefits for levosimendan, with lower relative risk (or odds ratio) for patient mortality. In 3/25 of the meta-analyses these beneficial trends did not reach statistical significance, while in 22/25 significance was reached. The relative risk is consistent overall, and very similar to that obtained in our own meta-analysis that considered only the 'regulatory' studies. Conclusion: The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of levosimendan, with data from multiple randomized trials and meta-analyses. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.Peer reviewe

Time-course of left ventricle function during mild therapeutic hypothermia in out-of-hospital cardiac arrest patients

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Levosimendan in Acute and Advanced Heart Failure : an Expert Perspective on Posology and Therapeutic Application

Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.Peer reviewe

Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II

Aims International guidelines are frequently not implemented in the elderly population with heart failure (HF). This study determined the management of octogenarians with HF enrolled in Euro Heart Failure Survey II (EHFS II) (2004-05). Methods and results We compared the clinical profile, 12 month outcomes, and management modalities between 741 octogenarians (median age 83.7 years) and 2836 younger patients (median age 68.4 years) hospitalized for acute/decompensated HF. Management modalities were also compared with those observed in EHFS I (2000-01). Female gender, new onset HF (de novo), hypertension, atrial fibrillation, co-morbidities, disabilities, and low quality of life were more common in the elderly (all P < 0.001). Mortality rates during hospital stay and during 12 months after discharge were increased in octogenarians (10.7 vs. 5.6% and 28.4 vs. 18.5%, P < 0.001). Underuse and underdosage of medications recommended for HF were observed in the elderly. However, a significant improvement was observed when compared with EHFS I both in the overall HF octogenarian population and in the subgroup with ejection fraction ≤45% for prescription rates of ACE-I/ARBs, beta-blockers, and aldosterone antagonists at discharge (82 vs. 71%; 56 vs. 29%; 54 vs. 18.5%, respectively, all P < 0.01), as well as for recommended combinations and dosage. Prescription rates remained stable for 12 months after discharge in survivors. Conclusion Our study confirms that the contemporary management of very elderly patients with HF remains suboptimal but that the situation is improvin

2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)

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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

Treatments targeting inotropy

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term

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

Hyponatraemia and changes in natraemia during hospitalization for acute heart failure and associations with in-hospital and long-term outcomes – from the ESC-HFA EORP Heart Failure Long-Term Registry

Aims To comprehensively assess hyponatraemia in acute heart failure (AHF) regarding prevalence, associations, hospital course, and post-discharge outcomes.Methods and results Of 8298 patients in the European Society of Cardiology Heart Failure Long-Term Registry hospitalized for AHF with any ejection fraction, 20% presented with hyponatraemia (serum sodium &lt;135 mmol/L). Independent predictors included lower systolic blood pressure, estimated glomerular filtration rate (eGFR) and haemoglobin, along with diabetes, hepatic disease, use of thiazide diuretics, mineralocorticoid receptor antagonists, digoxin, higher doses of loop diuretics, and non-use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers. In-hospital death occurred in 3.3%. The prevalence of hyponatraemia and in-hospital mortality with different combinations were: 9% hyponatraemia both at admission and discharge (hyponatraemia Yes/Yes, in-hospital mortality 6.9%), 11% Yes/No (in-hospital mortality 4.9%), 8% No/Yes (in-hospital mortality 4.7%), and 72% No/No (in-hospital mortality 2.4%). Correction of hyponatraemia was associated with improvement in eGFR. In-hospital development of hyponatraemia was associated with greater diuretic use and worsening eGFR but also more effective decongestion. Among hospital survivors, 12-month mortality was 19% and adjusted hazard ratios (95% confidence intervals) were for hyponatraemia Yes/Yes 1.60 (1.35- 1.89), Yes/No 1.35 (1.14-1.59), and No/Yes 1.18 (0.96-1.45). For death or heart failure hospitalization they were 1.38 (1.21- 1.58), 1.17 (1.02- 1.33), and 1.09 (0.93-1.27), respectively.Conclusion Among patients with AHF, 20% had hyponatraemia at admission, which was associated with more advanced heart failure and normalized in half of patients during hospitalization. Admission hyponatraemia (possibly dilutional), especially if it did not resolve, was associated with worse in-hospital and post-discharge outcomes. Hyponatraemia developing during hospitalization (possibly depletional) was associated with lower risk