Efficacy and Safety of Pulsed Infusions of Levosimendan in Outpatients With Advanced Heart Failure

Study Overview
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Brief Summary
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The purpose of this study is to compare the effects of a pulsed application of Levosimendan versus placebo on the composite end-point functional capacity and quality of life.

Detailed Description
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BACKGROUND Significant advances have been made in the treatment of congestive heart failure (CHF) in the past few years. Neurohumoral therapy with ACE-inhibitors, ß-blockers and aldosterone antagonists has been established to significantly reduce morbidity and mortality. However, despite the advances of modern therapy advanced CHF remains a syndrome with a poor prognosis. Additionally, this syndrome is associated with poor quality of life and leads to progressive debiliation and cardial cachexia. Repeat hospitalizations for acute heart failure are common among severe CHF patients. Besides the discomfort for the patients hospital admissions constitute the lion's share of the health expenditure for the heart failure syndrome. Inotropic support is provided to patients suffering acute heart failure refractory to neurohumoral therapy. This approach is performed according to the AHA/ACC- as well as to ESC Guidelines for therapy of CHF. Inotropic therapy is targeted on hemodynamic stabilization, improvement of functional status, and reduction of rehospitalization. Moreover, in many centres treatment with inotropes such as dobutamine and milrinone are an integral part of the applied bridge to transplant concept in severe heart failure patients. In fact, continuous or pulsed inotropic support in severe heart failure patients has been tested repeatedly in small clinical studies. Intermittent ambulatory low dose administration of dobutamine versus conventional therapy did not improve functional capacity in the DICE-Trial. By contrast, several case series with different dose regimens of dobutamine indicated improvement of functional status. TRIAL RATIONALE Based on its pharmacologic profile Levosimendan appears to be promising in the treatment of severe chronic heart failure functional NYHA class III/IV to improve quality of life and physical activity and to reduce hospital admissions for acute heart failure. Repeat drug administration may be superior over a single shot therapy to maintain beneficial long-term results. For economical reasons and for the sake of the patients comfort drug administration should ideally be managed on an outpatient basis rather than in the hospital. Therefore and for practical reasons, a time period of six hours for drug administration might be reasonable. Dosing of the drug will be based on the experiences in the Russlan Trial and on a small case report by Martys. In the latter study serial administration of levosimendan for 6 hours (bolus of 12 mcg/kg followed by a continuous infusion of 0,1 μg/kg/min for 50min and 0,2 μg/kg/min for the next 5 hours) induced a significant fall of BNP. In an outpatient setting, however, a bolus should be not be given for safety reasons.

Official Title
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Efficacy and Safety of Pulsed Infusions of Levosimendan in Outpatients With Advanced Heart Failure - A Multicenter, Double-blind, Placebo Controlled Prospective Trial With Two Arms

Conditions
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Chronic Stable Heart Failure

Intervention / Treatment
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* Drug: Levosimendan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic stable heart failure NYHA III and IV diagnosed at least 3 months before inclusion 6-min.-walk-test < 350 meters EF < 35 % Age > 20 years Optimized and individualised neurohormonal background therapy according to ESC-guidelines for the treatment of chronic heart failure. Patient has signed informed consent Exclusion Criteria: Hospitalization for decompensated heart failure requiring i.v. diuretics within the last month before randomization History of torsades des pointes Allergy to Levosimendan or any of the excipients Administration of inotropes in the last 4 weeks Potassium <3,5 and >5,5 mmol/l Systolic blood pressure <= 100 mmHg Women at childbearing age without using effective contraceptives ( oral contraceptives, intrauterine contraceptive devices) unless surgical sterilisation has been undertaken. Female patients who are pregnant or nursing Creatinin Clearance < 30ml/min/m2 Severe anemia (Hb < 10 mg /dl) Mechanical obstruction affecting the ventricular filling or the outflow or both Patients with non compliance Severe conditions, which make the patient unsuitable to participate in a study as judged by the investigator Severe liver disease Percutaneous coronary intervention within the last 1 months Coronary bypass surgery within the last 3 months Planned HTX within the next six months Patient involved in another clinical trial De-nove heart failure

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levosimendan<br>Chronic stable heart failure | Drug: Levosimendan<br>* Levosimendan will be infused on an outpatient basis for six hours at a dosage of 0,2 μg/kg/min without a bolus<br>|
| Placebo Comparator: Placebo<br>Chronic Stable Heart Failure | Drug: Placebo<br>* Levosimendan will be infused on an outpatient basis for six hours at a dosage of 0,2 μg/kg/min without a bolus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of patients showing an improvement in the six-minutes walk test and a higher scoring in the Kansas City Cardiomyopathy Questionnaire (KCCQ) |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| effects of a pulsed application of levosimendan on event free survival |  | 8 weeks from randomization | 
| effects of a pulsed application of levosimendan on event free survival |  | 24 weeks from randomization |