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PubMed2003

Levosimendan compared with dobutamine in low output patients.

There are 2 studies which have investigated the hemodynamic efficacy of levosimendan compared to dobutamine in congestive heart failure patients. The first is a dose finding comparative 24-h infusion trial which included 95 NYHA II-III patients to different doses of levosimendan and 20 patients to dobutamine administered as a continuous, open-label infusion of 6 microg/kg/min. Efficacy and safety of levosimendan in severe low-output heart failure a randomized, double-blind comparison to dobutamine study compared the short- and long-term efficacy and safety of a single 24-hour infusion of levosimendan (n=103) with dobutamine (n=100) in hospitalised patients in acute heart failure. This double-blind, parallel-group, randomised trial showed that, irrespective of the aetiology of the heart failure, levosimendan produced significantly greater improvement in major determinants of cardiac function in heart failure patients compared to dobutamine. Levosimendan produced significantly greater haemodynamic improvements than dobutamine by significantly reduced mortality at 31 days compared with dobutamine; this reduction was maintained at 180 days. Levosimendan significantly increased the number of days alive and out of hospital, compared with dobutamine. It was better tolerated than dobutamine and fewer patients receiving levosimendan experienced arrhythmias and myocardial ischaemia, compared with dobutamine. Levosimendan produced haemodynamic responses that were unaffected by concomitant use of beta blockers.

Cardiac Output, Low↗
PubMed2003

Levosimendan: a new dual-action drug in the treatment of acute heart failure.

Levosimendan is a new agent for the treatment of acute heart failure. Levosimendan acts via complementary mechanisms; it enhances contractility by sensitising cardiac myofilaments to calcium and dilates blood vessels by opening ATP-dependent potassium channels. In contrast to traditional inotropes (beta-agonists or phosphodiesterase inhibitors), levosimendan does not raise myocyte calcium levels and is therefore less likely to elicit arrhythmias or to impair diastolic relaxation. The clinical efficacy of levosimendan is supported by four key clinical studies, including more than 900 patients hospitalised for cardiac decompensation due to acutely worsened chronic heart failure or to heart failure following myocardial infarction. When given as short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. At 31 days post-treatment, mortality rates were halved in decompensated chronic heart failure patients who received levosimendan, compared with those on dobutamine--an advantage sustained at 180 days. Similar survival gains were observed among acute failure patients treated with levosimendan following myocardial infarction. With its substantial haemodynamic and survival benefits, levosimendan is well suited to be part of routine management for patients with acutely decompensated heart failure.

Acute Disease↗
PubMed2003

Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure.

OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). METHODS: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.

Administration, Oral↗
PubMedDate not supplied

Levosimendan: a new approach for the treatment of patients with severe heart failure. A brief summary based on a clinical case.

Looking at the clinical report of a single patients admitted with severely decompensated heart failure and successfully managed with levosimendan, the authors review the current knowledge about this new drug. The treatment of severely decompensated heart failure is currently based on classical catecholamines (dopamine and dobutamine). The various new positive inotropics investigated in the past have failed to improve survival. In spite of some symptomatic improvement an increase in long-term mortality was noticed in different trials testing different drugs. More recently a new concept has been introduced regarding a new way to improve myocardial contractility and vasodilation based on calcium-sensitizing properties with additional action on adenosine triphosphate-sensitive potassium channels. Levosimendan is a representative of this new class recently launched in the Portuguese market.

Cardiotonic Agents↗
PubMed2003

Is calcium sensitization the best strategy to improve myocardial contractility in acute heart failure?

The finely-tuned increases and decreases in the intracellular calcium levels in myocytes ultimately regulate the contraction and relaxation of the heart. Therapeutic agents can improve or interfere with this delicate balance. Calcium sensitizers enhance cardiac contraction by improving the use of calcium that is available, rather than by inundating the cell with excessive calcium, as is the case with traditional inotropes. With the sensitizing mechanism, the energy cost of contraction is maintained at a near-normal level, and the threat of arrhythmias and sudden death is low. Levosimendan is the first calcium sensitizer to become available for the treatment of patients with acute heart failure. In recent clinical studies, levosimendan increased cardiac output and stroke volume without significantly increasing oxygen demand. By its additional action as a vasodilator (via potassium channel opening), levosimendan also corrects the hemodynamic decompensation, thus lowering the pulmonary capillary wedge pressure and systemic vascular resistance. Furthermore, levosimendan increases the coronary circulation thus leading to an improved function of the stunned myocardium and lessened ischemia. Taken together, levosimendan's primary calcium-sensitizing action, along with its complementary vasodilator properties, make this new drug a highly promising agent for the treatment of patients with acute heart failure.

Acute Disease↗
PubMed2003

Levosimendan in patients with low-output heart failure: lessons from the LIDO trial.

The novel calcium sensitizer levosimendan improves myocardial contractility without causing an increase in intracellular calcium and cyclic adenosine monophosphate concentrations. It also has a vasodilator action due to an opening of the adenosine triphosphate-sensitive potassium channels. In a double-blind clinical trial levosimendan was compared with dobutamine in 203 patients with severe low-output congestive heart failure. A 24-hour infusion of these inotropic drugs was administered to increase the cardiac output by at least 30% together with a decrease in the pulmonary capillary wedge pressure by > or = 25%. The pre-defined hemodynamic improvement was achieved in 28% of patients receiving levosimendan compared to only 15% with dobutamine (p = 0.022). Levosimendan also reduced the 1- and 6-month mortality more than dobutamine (7.8 vs 17%, p = 0.045 and 26 vs 38%, p = 0.029, respectively). Levosimendan produced less myocardial ischemia and cardiac arrhythmias than dobutamine. Calcium sensitizers offer a new therapeutic possibility in patients with decompensated low-output heart failure.

Adrenergic beta-Agonists↗
PubMed2003

Considerations on the efficacy and safety of levosimendan in ischemic heart failure.

Levosimendan is a new vasodilator agent with properties which improve cardiac contractility by calcium sensitization. Its dose-related efficacy and prolonged action have been documented in several major studies both against placebo and dobutamine. Out of 997 patients, 837 (84%) had acute or stable heart failure due to coronary heart disease. Therefore, it would be most interesting to analyze the efficacy and safety of levosimendan in heart failure due to ischemic heart disease. The dose-finding study included 98 patients who were given intravenous levosimendan at different doses and 20 patients treated with dobutamine. All patients had heart failure due to coronary heart disease. The other major trial included 500 acute myocardial infarction patients with heart failure and was placebo-controlled. In other levosimendan vs placebo or dobutamine comparative trials 50-60% of patients had ischemic heart disease and severe heart failure. Levosimendan significantly improves the cardiac index by 30-39% at bolus doses of 6-24 micrograms/kg/min followed by infusion doses of 0.05-0.2 microgram/kg/min and reduces the wedge pressure by 20-25% to optimal levels (from 15-20 mmHg). There is a lesser blood pressure reduction and some heart rate increase. However in patients with an acute myocardial infarction the rate of ischemia or hypotension were similar in levosimendan- and placebo-treated patients and in the dobutamine controlled trials no major adverse effects were seen or they were more frequent in dobutamine patients. There is no increase in mortality either compared to placebo or to dobutamine. Rather, the opposite seems to be true. No increase in arrhythmias is seen. The hemodynamic effects of levosimendan are dose-dependent and the current recommended doses are safe. No increase in mortality or any life-threatening arrhythmias have been observed.

Calcium Channels, L-Type↗
PubMed2003

Preliminary clinical experience with the repetitive administration of levosimendan in patients with end-stage heart failure.

We present our preliminary clinical experience with the initial and repetitive administration of the novel inotropic agent levosimendan in a cohort of 20 patients with end-stage heart failure who were acutely decompensated or whose symptoms were refractory to the usual pharmacological treatments thus necessitating hospitalization. Repetitive levosimendan infusions were administered to 9 patients (minimum 2, maximum 8 pulses). The effects of this therapy on the symptomatic status, vital signs, hemodynamic performance and clinical outcomes are discussed.

Adolescent↗
PubMed2003

The clinical experience with levosimendan in anesthesiology and in the intensive care unit.

In the present review striking data showing that intensive care unit patients with acute heart failure and high-risk surgical patients may markedly benefit from the use of levosimendan are presented. Indeed, levosimendan is an effective new agent that acts via two complementary mechanisms. It enhances cardiac contractility by improving the response of the myofilaments to intracellular calcium, and it reduces the cardiac workload by opening the adenosine triphosphate-dependent potassium channels for the dilation of blood vessels. Because the therapeutic levels of levosimendan do not increase the intracellular calcium concentrations, levosimendan is less likely than traditional inotropes (beta-agonist inotropes or phosphodiesterase inhibitors) to elicit arrhythmias or impair diastolic relaxation. In fact, the results of recent clinical studies indicate that levosimendan offers significant hemodynamic and survival benefits when given to patients who are hospitalized for acute heart failure. Indeed, in the near future, it is likely that levosimendan may also prove effective for the treatment of patients with diastolic heart failure or for those with a low cardiac output following coronary artery bypass grafting. In addition, levosimendan has the potential of supporting the cardiac function during the initiation of beta-blocker therapy, for weaning patients from cardiopulmonary bypass, for individuals with valvular abnormalities and for those with myocarditis. Preliminary results also suggest that levosimendan may be beneficial for the treatment of patients with right ventricular heart failure. Although the use of levosimendan has been fully validated for the most common causes of acute heart failure, additional clinical trials are needed to safety broaden its therapeutic indications.

Adrenergic beta-Antagonists↗
PubMed2003

The cardiotonic effects of levosimendan in guinea pig hearts are modulated by beta-adrenergic stimulation.

The effects of the Ca2+-sensitiser levosimendan alone or in combination with beta-adrenergic stimulation on the contractile function were studied in various guinea pig cardiac preparations. Echocardiography in narcotised animals indicated that a maximal dose of levosimendan (50 microg x kg(-1)) increased the left ventricular posterior wall movement velocity during systoles and diastoles by 25 +/- 3% (mean +/- S.E.M.) and 17 +/- 2%, respectively. In Langendorff hearts, a saturating concentration of levosimendan (0.3 micromol x l(-1) for 5 min) increased +dP/dt(max) and dP/dt(max) by 28 +/- 3% and 14 +/- 2%, respectively. Further, the Ca2+-sensitising potential of levosimendan in Triton-skinned cardiomyocytes (EC50: 5 +/- 3 nmol x l(-1)) was illustrated by a maximal increase in the isometric force production by 51 +/- 5% (at pCa 6.2). However, following stimulation by isoproterenol, when the level of troponin I phosphorylation was elevated, no significant additional increase in the contractile parameters could be demonstrated upon levosimendan administration. Moreover, the levosimendan-induced increase in force production in isolated skinned myocytes could be prevented by incubation with the catalytic subunit of protein kinase A (100 U x ml(-1) for 40 min). These data indicate that thin filament-targeted Ca2+-sensitisation by levosimendan is modulated by phosphorylation of the contractile filaments, an effect that should be considered during combination therapy with levosimendan.

Adrenergic beta-Agonists↗
PubMed2004

New positive inotropic agents in the treatment of left ventricular dysfunction.

Three major classes of inotropic agents have been clinically evaluated in patients with left ventricular dysfunction: a) agents that increase the intracellular concentration of cyclic adenosine monophosphate by stimulating the beta-adrenergic receptor or inhibiting phosphodiesterase; b) drugs that increase the intracellular sodium concentration; c) the new calcium-sensitizing drugs. This review will focus on the newest drug for each of the above-mentioned classes of inotropic agents. Moreover, we present a new protocol which provides the use of levosimendan in patients with post-ischemic left ventricular dysfunction.

Cardiotonic Agents↗
PubMed2004

Levosimendan in patients with cardiogenic shock undergoing surgical revascularization: a case series.

BACKGROUND: Levosimendan is a new calcium sensitizer, which enhances myocardial contractility while simultaneously having vasodilatory and cardioprotective effects. These properties could be advantageous in patients with myocardial ischemia requiring inotropic support. MATERIAL/METHODS: 10 patients with acute myocardial ischemia, cardiogenic shock, and/or cardiopulmonary resuscitation undergoing emergency surgical revascularization were treated with levosimendan (bolus 6 microg.kg(-1), continuous infusion 0.2 microg.kg(-1).min(-1)) in addition to catecholamines. RESULTS: All patients treated with levosimendan and catecholamines were weaned successfully from CPB on the 1st attempt. All patients needed additional norepinephrine because of vasodilation. In 4 patients, levosimendan was stopped in the early postoperative period. 2 patients died, 8 patients survived without any multiorgan failure. Only 2 patients needed an additional intra-aortic balloon pump. In the surviving patients, postoperative ventilation lasted for 8-72 hours. CONCLUSIONS: Levosimendan may have exerted positive inotropic and cardioprotective effects in these high risk patients with acute myocardial ischemia. However, these preliminary results supporting the use of levosimendan as an inoprotective drug need to be confirmed by a large randomized prospective trial.

Adult↗
PubMedDate not supplied

[Levosimendan in heart failure].

Clinical trials investigating traditional inotropic agents in patients with heart failure demonstrated an increased mortality rate (odds ratio 1.50; IC=0.51-3.92), high incidence of discontinuation of infusion therapy (odds ratio 0.46; IC=0.083-2.29) due to major side effects and, most of all, a limited clinical benefit (odds ratio 0.75; IC=1.42-0.08). On this background a new class of inotropic drugs, the calcium-sensitisers, have been developed. The safety and efficacy of levosimendan (Simdax) has been recently demonstrated in trials (LIDO e RUSSLAN) in patients with heart failure due to ischemic and not ischemic disease. Twenty-six patients with decompensated heart failure of different etiology have been treated with 24 hour infusion of levosimendan. In this experience the levosimendan improved the clinical status and the left ventricular ejection fraction.

Calcium Channel Agonists↗
PubMed2004

Medical therapy in heart failure--is polypharmacy necessary?

The concept of heart failure has undergone several paradigm shifts in the past few decades. Therapeutic targets directed at the heart pump have shifted to circulatory haemodynamics to the current neurohormonal model. Consequently, therapeutic modalities have similarly evolved alongside clinical trials. Successive trials have tested newer drugs in addition to established therapies, resulting in evidence-based treatments necessitating polypharmacy. Optimal heart failure therapy has therefore become increasingly complex. It is only after understanding the precise modes of drug action, as well as the relevance of the design of clinical trials, will physicians hopefully be able to tailor the medical therapy optimally towards the individual patient with heart failure.

Adrenergic beta-Antagonists↗
PubMed2004

Levosimendan in daily intensive care practice--the experience of 15 centers. Background, methods and organization of the PORTLAND study.

INTRODUCTION: The LIDO and RUSSLAN trials showed that levosimendan was well tolerated and had a stronger hemodynamic effect than dobutamine and a positive impact on prognosis. There are, however, few data regarding its effectiveness and safety when used in an everyday clinical setting. OBJECTIVE: To test the hypothesis that in day-to-day practice conditions levosimendan is both effective and safe for the treatment of decompensated heart failure (HF). This primary combined endpoint of effectiveness and safety was evaluated at 24 hours and 5 days after the beginning of the treatment. DESIGN: Prospective, multicenter, nonrandomized clinical trial with evaluations at baseline, 24 hours, 5 days, and 3 and 6 months. Follow-up for 6 months. SETTING: The intensive care units of 15 cardiology or internal medicine departments. PATIENTS: 129 consecutive patients requiring inotropes due to decompensated systolic HF despite maximally tolerated oral therapy. INTERVENTION: 24-hour infusion of levosimendan via a central or peripheral vein. MEASUREMENTS AND EVALUATION OF RESULTS: 1. Monitoring: Continuous ECG monitoring, non-invasive blood pressure, urinary output, oximetry. Invasive monitoring was not required. 2. Follow-up. Baseline evaluation: history, physical examination, ECG, 2D echocardiogram, hemogram, ionogram, liver and kidney function. 24-hour and 5-day evaluations: symptoms, physical examination, recording of medical therapy and previous 24-hour urinary output, ECG, hemogram, ionogram, liver and kidney function, and evaluation of arrhythmic episodes and heart rate and blood pressure trends in previous 24 hours. 3- and 6-month evaluations: number of hospital admissions and length of hospital stay due to HF, and mortality. 3. Evaluation of primary endpoint. EFFECTIVENESS: assessed by a clinical score including 2 subjective parameters (1. NYHA functional class, 2. patient self-evaluation symptom class) and 6 objective parameters (3. body weight, 4. pulmonary congestion, 5. previous 24-hour diuresis, 6. serum creatinine, 7. oral HF medication, 8. intravenous HF medication). Definition of clinical effectiveness: improvement in > or = 1 subjective parameters plus improvement in > or = 1 objective parameters, with all other parameters unchanged. SAFETY: The therapy was judged safe in the absence of any serious adverse event with a probable or undetermined causal relationship with levosimendan. Primary endpoint evaluation: Patients reached the primary endpoint when levosimendan was both effective and safe according to the above definitions.

Critical Care↗
PubMedDate not supplied

[Usefulness of Levosimendan in patients with ventricular dysfunction before surgery].

UNLABELLED: The purpose of this work was to observe the hemodynamic stability on the first 24 hours in 4 patients with ventricular dysfunction (Ejected Fraction < 40 %), considered of high surgical risk, in which 24 at 48 hr before the surgery received an infusion of Levosimendan for 24 hours. This 4 patients was male, with age 55.5+/-7.9 years old, a left ventricle ejection of fraction (LVEF) of 31+/-5.47%; Two of them was underwent to valve replacement, another one to coronary artery bypass graft and the last one patient underwent combined procedure (coronary artery bypass graft surgery and valve replacement). The behavior of the hemodynamic parameters was stable, without necessity of uses high dose of the inotropios and classic vasopresores in the postoperative. CONCLUSION: the Levosimendan could be an inotropic of great application in this group of patient due to its novel action mechanism and to its sustained hemodynamic effects after having finished its infusion.

Cardiac Surgical Procedures↗