Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. a randomized, placebo-controlled, double-blind study (RUSSLAN)

Moiseyev, V.S.; Põder, Pentti; Andrejevs, N.

doi:10.1016/s1062-1458(03)00060-6

Cited by 130 publications

(202 citation statements)

References 23 publications

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“…Furthermore, positive effects on long-term survival up to 6 months were observed. 6,7 Levosimendan is registered for clinical use in several countries in Europe, South America, and Asia. There are an increasing number of reports on practical experiences and therapeutic successes in different clinical situations.…”

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confidence: 99%

European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Folláth

Franco

Silva-Cardoso

2005

The American Journal of Cardiology

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The novel calcium sensitizer and ATP-dependent potassium channel opener levosimendan has been introduced for routine use in several European countries. Recent reports on clinical experience confirm the positive hemodynamic results and beneficial clinical effects described in the initial dose-finding and randomized comparative therapeutic trials in patients with severe low-output heart failure. In addition, studies in small series of patients with cardiogenic shock after myocardial infarction and/or surgical interventions and postinterventional myocardial dysfunction ( Levosimendan is a new calcium-sensitizing drug that opens adenosine triphosphate-dependent potassium (K ATP ) channels with effects that increase myocardial contraction and cause vasodilation. Compared with other agents for acute heart failure syndromes (AHFS), its main potential advantages are the improvement of myocardial contractility without increasing oxygen requirements, reduction of ventricular preload, and an antistunning, anti-ischemic effect by opening K ATP channels. [1][2][3] This pharmacologic profile of levosimendan offers new therapeutic possibilities in patients with AHFS. In initial dose-finding 4,5 and therapeutic trials, 6 a rapid and prolonged hemodynamic improvement with an increase in cardiac index, reduction of pulmonary capillary wedge pressure (PCWP), and reduction of peripheral vascular resistance without proarrhythmic effects were documented. Furthermore, positive effects on long-term survival up to 6 months were observed. 6,7 Levosimendan is registered for clinical use in several countries in Europe, South America, and Asia. There are an increasing number of reports on practical experiences and therapeutic successes in different clinical situations. In this article, we summarize recent publications on therapeutic indications, dose schedules, outcomes, and tolerance. MethodsClinical reports on levosimendan therapy in patients with severe decompensated acute or chronic heart failure (HF), cardiogenic shock after myocardial infarction (MI), or cardiac interventions and perioperative administration are reviewed. These publications were mostly smaller randomized or observational trials, with good descriptions of patient inclusion criteria, levosimendan administration, and methods of clinical and/or hemodynamic evaluation. Therapeutic Efficacy of Levosimendan in Acute Heart Failure SyndromesDecompensated low-output heart failure: Decompensated low-output HF is the best documented therapeutic indication for levosimendan administered as a single intravenous infusion lasting 6 to 24 hours. Patients included in the dose-finding and comparative clinical trials 4 -6 were characterized by dyspnea (New York Heart Association [NYHA] functional class III to IV) and signs of venous and pulmonary congestion accompanied by peripheral vasoconstriction. Hemodynamic inclusion criteria were reduced cardiac index (Ͻ2.5 L/min per m 2 ) and increased PCWP (Ͼ16 mm Hg). Patients with systolic blood pressure Ͻ90 mm Hg were excluded in these initial ...

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confidence: 99%

European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Folláth

Franco

Silva-Cardoso

2005

The American Journal of Cardiology

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“…23 Safety, efficacy, and effects on mortality of levosimendan in patients with LV failure complicating AMI were investigated in the RUSSLAN study. 24 There were no significant differences among the treatment groups in the proportion of patients who experienced clinically important ischemia in this study. Although levosimendan also produced significantly fewer ischemic adverse effects compared with dobutamine in the LIDO study, 25 it did not aggravate ischemia in patients with stable coronary heart disease as assessed by a 24-hour Holter electrocardiogram.…”

Section: Discussionmentioning

confidence: 57%

Comparison of Ischemic Side Effects of Levosimendan and Dobutamine with Integrated Backscatter Analysis

Duygu

Nalbantgil

Zoghi

et al. 2009

Clinical Cardiology

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Background: Levosimendan improves cardiac contractility without increasing oxygen consumption. However, its effects on ischemia were not supported with the utilization of a noninvasive parameter of myocardial characterization. Hypothesis: The changes observed in integrated backscatter (IBS) may be reflective of change in myocardial ischemia. In this study, the effect of levosimendan on ischemia detected by IBS was evaluated in patients with ischemic heart failure (HF). Methods: Patients who had LVEF <40% and NYHA III-IV symptoms of HF were included in this study. Patients were randomized to levosimendan (n = 21), or to dobutamine (n = 25) groups. The cyclic variation of integrated backscatter (CVIBS) was determined as the difference between the maximal and minimal values in a cardiac cycle, average of three consecutive beats. CVIBS was taken from the mid-anteroseptal, mid-inferior, and mid-posterolateral areas of the parasternal short axis images before the drug administration and at the end of the 24-hour infusion period. Results: Baseline characteristics and concomitant medications were similar in both groups. A significant reduction in CVIBS was detected in anteroseptal (7.6 ± 1.4 dB versus 5.9 ± 0.8 dB, p = 0.01), inferior wall (7.4 ± 0.8 dB versus 6.7 ± 1.5 dB, p = 0.03), and posterolateral wall (9.0 ± 1.2 dB versus 8.2 ± 0.6 dB, p = 0.04) after dobutamine administration, while no significant changes were observed in the levosimendan group in all walls. Conclusions: Unlike dobutamine, levosimendan may not induce myocardial ischemia as shown by CVIBS at commonly used dosages in the setting of decompensated HF without active ischemia.

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“…It is well recognized that, in HF, the positive inotropic effects of cAMP-dependent inotropes are attenuated, but Ca 2ϩ sensitizer-produced myofilament Ca 2ϩ sensitization is preserved. Increased experimental studies and clinical data have shown that levosimendan has some advantages over other positive inotropic agents in the treatment of HF (2,6,14,25,40,46,55).…”

Section: Fig 2 Group Means Of Increasing Hrcaused Percent Changes Omentioning

confidence: 99%

“…Of note, recent demonstrated actions of levosimendan, such as increased activity of the Na ϩ -Ca 2ϩ exchange (20) and anti-ischemia (2,40), may also contribute to the rate-related enhancements of LV contractile performance and relaxation. However, the relative contribution of each of the factors is unclear and awaits further study.…”

Section: Fig 2 Group Means Of Increasing Hrcaused Percent Changes Omentioning

confidence: 99%

Levosimendan restores the positive force-frequency relation in heart failure

Masutani

Cheng

Tachibana

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Masutani S, Cheng HJ, Tachibana H, Little WC, Cheng CP. Levosimendan restores the positive force-frequency relation in heart failure. Am J Physiol Heart Circ Physiol 301: H488 -H496, 2011. First published May 13, 2011; doi:10.1152/ajpheart.01116.2010.-Frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise. In heart failure (HF), this positive force-frequency relation is impaired, and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. A myofilament Ca 2ϩ sensitizer, levosimendan, has been shown to improve exercise tolerance in HF. This may be due to its beneficial actions on the force-frequency relation and LV-arterial coupling (end-systolic elastance/arterial elastance, EES/EA). We assessed the effects of therapeutic doses of levosimendan on the forcefrequency relation and EES/EA in nine conscious dogs after pacinginduced HF using pressure-volume analysis. Before HF, pacing tachycardia increased E ES, shortened , and did not impair EES/EA and mechanical efficiency (stroke work/pressure-volume area, SW/PVA). In contrast, after HF, pacing at 140, 160, 180, and 200 beat/min (bpm) produced smaller a increase of EES or less shortening of , whereas EES/EA (from 0.56 at baseline to 0.42 at 200 bpm) and SW/PVA (from 0.52 at baseline to 0.43 at 200 bpm) progressively decreased. With levosimendan, basal E ES increased 27% (6.2 mmHg/ml), decreased 11% (40.8 ms), EES/EA increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, E ES further increased by 23%, 37%, 68%, and 89%; decreased by 9%, 12%, 15%, and 17%; and EES/EA was augmented by 11%, 16%, 31%, and 33%, incrementally, with pacing rate. SW/PVA was improved (0.61 to 0.64). In conclusion, in HF, treatment with levosimendan restores the normal positive LV systolic and diastolic force-frequency relation and prevents tachycardia-induced adverse effect on LV-arterial coupling and mechanical efficiency.drugs; contractility; diastole; heart rate UNDER NORMAL CONDITIONS, an increase in heart rate (HR) augments myocardial contractility and the rate of relaxation (15,39,44). This force-frequency behavior is determined by both calcium handling and myofilament properties (26). It has been shown that the integrated dynamic balance of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is the primary cellular mechanism responsible for the force-frequency relation (FFR) and is determined by sarcoplasmic reticulum (SR) Ca 2ϩ load and Ca 2ϩ flux through the sarcolemma via L-type Ca 2ϩ channels and the Na ϩ -Ca 2ϩ exchanger (13). The positive FFR and relaxation-frequency relation (RFR) enhance cardiac performance during stress or exercise (7,36,39,44,52). In heart failure (HF), the positive FFR and RFR are impaired (16,24,28,29,44), and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. This contributes to exercise intolerance in HF (44, 52). The altered responses of LV contraction and relaxation to HR in HF may at least partially ...

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Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. a randomized, placebo-controlled, double-blind study (RUSSLAN)

Cited by 130 publications

References 23 publications

European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

European Experience on the Practical Use of Levosimendan in Patients with Acute Heart Failure Syndromes

Comparison of Ischemic Side Effects of Levosimendan and Dobutamine with Integrated Backscatter Analysis

Levosimendan restores the positive force-frequency relation in heart failure

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