ELEVATE Early LEvosimendan Vs Usual Care in Advanced Chronic hearT failurE

NCT ID: NCT01290146

Last Updated: 2017-04-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-28
• Study Completion Date: 2017-03-31

Brief Summary

The purpose of this study is to compare in patients with Advanced Chronic Heart Failure the effects of Levosimendan versus diuretic (single 24-hour infusion) applied at the early detection of impending destabilization on hospitalization-free survival during 12 months.

Patients with advanced chronic heart failure (ACHF) have a short term reduced life expectancy with recurrent hospital admissions for clinical exacerbations. Levosimendan improves contractility by calcium-dependent binding to troponin C, determines vasodilation of the coronary arteries and systemic resistance vessels, thus decreasing preload and afterload, while exerting a protective effect on the myocardium against ischemia-reperfusion damage. In randomized clinical trials of acute heart failure patients, levosimendan improved hemodynamics and patients' quality of life and decreased natriuretic peptide plasma levels, with no excess mortality The study will assess whether the administration of levosimendan (single 24-hour infusion) at the early detection of deterioration may reduce frequency and duration of hospital admissions, improve functional status and quality of life in ACHF patients, with respect to diuretic infusion.

Detailed Description

BACKGROUND Patients with advanced chronic heart failure (ACHF) have a short term reduced life expectancy with recurrent hospital admissions for clinical exacerbations. ACHF poses a heavy burden to cardiology departments, where these patients are referred for the severity of their clinical condition, which require a specialist approach, and results in high health care costs due to frequent rehospitalizations.

Patients with ACHF ≥ 2 hospital admissions in 6 months are at high risk of recurrent exacerbations. The benefits of strict outpatient follow-up at specialised HF vs standard community care in ACHF patients have been consistently demonstrated. The standard approach at HF clinics is based on flexible diuretic dose and outpatient iv diuretics as bolus or infusion at early signs of decompensation. Although this strategy results in symptomatic benefit and prevents approximately one third of hospital admission for acute exacerbations, a relevant proportion of patients will still need hospitalization. Predictors of lack of benefit are low systolic blood pressure, prior increase in oral diuretics and beta-blocker use, which taken together represent markers of severe disease susceptible to evolve in a low output state.

In the HF clinic setting, a novel strategy for these patients, to include early support to myocardial contractility, i.e. before compelling criteria for hospital admission become manifest, might prevent further prolonged hospitalizations, myocardial damage and impairment in renal function TRIAL RATIONALE Levosimendan improved hemodynamics and patients' quality of life and decreased natriuretic peptide plasma levels, with no excess mortality, in randomized clinical trials of acute heart failure. In SURVIVE an early larger treatment effect of levosimendan was apparent in patients with acute worsening of chronic HF treatment than in those with de novo disease, possibly because a greater proportion of these patients may be on beta-blockers, that are known to interfere with dobutamine or may potentiate the circulatory actions of levosimendan. Thus levosimendan may be unattractive first-line agent in destabilized ACHF patients on beta-blockers.

Based on the drug cardioprotective properties, hemodynamic and neurohormonal effects, we propose a novel therapeutic approach for the clinically-driven use of levosimendan in recurrent acute exacerbations of ACHF.

Dosing of the drug will omit the bolus to increase tolerability in this severely ill patient population.

Conditions

Advanced Chronic Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Diuretics

Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h

Group Type: ACTIVE_COMPARATOR

Diuretics

Intervention Type: DRUG

Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h

Levosimendan

Patients randomized to Levosimendan receive a 24-hour levosimendan infusion with NO prior bolus injection.

Starting doses will be based on baseline SBP levels

• SBP ≥ 85-99mmHg: 0.05 mcg/kg/min
• SBP ≥100 mmHg: 0.1 mcg/kg/min

Group Type: EXPERIMENTAL

Levosimendan

Intervention Type: DRUG

Patients randomized to Levosimendan receive a 24-hour levosimendan infusion with NO prior bolus injection.

Starting doses will be based on baseline SBP levels

• SBP ≥ 85-99mmHg: 0.05 mcg/kg/min
• SBP ≥100 mmHg: 0.1 mcg/kg/min

Interventions

Diuretics

Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h

Intervention Type: DRUG

Levosimendan

Patients randomized to Levosimendan receive a 24-hour levosimendan infusion with NO prior bolus injection.

Starting doses will be based on baseline SBP levels

• SBP ≥ 85-99mmHg: 0.05 mcg/kg/min
• SBP ≥100 mmHg: 0.1 mcg/kg/min

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Written informed consent
• Systolic dysfunction (LVEF ≤ 35% by echo assessment within 6 months before enrolment)
• No requirement for hospital admission for diagnostic work up or elective treatment to define etiology and/or treatment plan
• Already on optimal standard HF treatment based on individual tolerance, including cardiac resynchronization therapy (CRT)/ICD device according to current guidelines
• At least 2 hospital admissions for HF in the 6 months before enrolment, the most recent one within 30-90 days before enrolment with requirement for inotrope administration

Exclusion Criteria

• Participant in other studies in the last 30 days
• Life expectancy < 1 year for comorbid conditions other than HF
• Pregnancy, lactation, childbearing potential unless on adequate contraception
• Acute coronary syndromes, percutaneous or surgical revascularization, valve surgery performed within 8 weeks before enrolment
• Planned percutaneous or surgical procedures (except for heart transplantation)
• CRT within 6 months before enrolment
• Cardiogenic shock
• Supine systolic BP < 85 mmHg
• Severe liver insufficiency (>three-fold increase in AST-ALT )
• Sever chronic kidney dysfunction (estimated GFR < 30 ml/min)
• Sustained ventricular tachycardia
• Severe chronic or current acute infection (temperature >38 C, WBC >15,000/mm3)
• Severe chronic obstructive pulmonary disease (FEV1 <30% predicted or on oxygen therapy)
• Severe persistent anemia (Hb < 10 g/l))
• ACHF exacerbation due to conditions requiring specific treatment (e.g. anemia, atrial fibrillation, supraventricular tachycardia ) Documented low compliance or unavailable for programmed follow-up visits and phone contact

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Orion Corporation, Orion Pharma

INDUSTRY

Sponsor Role: collaborator

Niguarda Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Fabrizio Oliva, MD

Role: STUDY_CHAIR

Heart Failure Heart Transplant Program, Cardiovascular Department, Niguarda Hospital, Milan, Italy

Michele Senni, MD

Role: STUDY_CHAIR

Cardiovascular Medicine Ospedali Riuniti, Bergamo, Italy

Locations

Ospedali Riuniti di Ancona Cardiology Presidio Lancisi

Ancona, Ancona, Italy

Azienda Ospedaliero-Universitaria, Consorziale Policlinico di Bari, U.O. Cardiologia Universitaria, Dipartimento Emergenza e Trapianti di Organi

Bari, Bari, Italy

Fondazione S. Maugeri. IRCCS Istituto di Cassano Murge

Cassano Murge, Bari, Italy

Ospedali Riuniti di Bergamo Cardiovascular Medicine

Bergamo, Bergamo, Italy

Ospedale Brotzu Cardiology

Cagliari, Cagliari, Italy

Ospedale Sant'Anna Cardiology

Como, Como, Italy

Ospedale SS Annunziata Cardiology

Cosenza, Cosenza, Italy

Istituti Ospitalieri di Cremona Cardiology

Cremona, Cremona, Italy

Ospedale Santa Maria Nuova Cardiology

Florence, Firenze, Italy

Ospedale Vito Fazzi

Lecce, Lecce, Italy

Istituto Auxologico Italiano - IRCCS Clinical Cardiology Cardiovascular Department

Milan, Milan, Italy

Azienda Ospedaliera Niguarda Heart Failure and Heart Transplant Program

Milan, Milan, Italy

Azienda Ospedaliera S. Gerardo Hear Failure and Cardiomyopathy Clinic

Monza, Monza, Italy

Gruppo Policlinico di Monza Clinical Cardiology and Heart Failure Unit Cardiology Department

Monza, Monza, Italy

Ospedale Santa Maria della Misericordia Cardiology

Perugia, Perugia, Italy

Ospedale Guglielmo da Saliceto Cardiology Department

Piacenza, Piacenza, Italy

Azienda Ospedaliera San Camillo-Forlanini, Cardiology, Heart Failure Clinic

Roma, Roma, Italy

Università di Roma Sapienza Dipartimento di Scienze Cardiovascolari e Respiratorie

Roma, Roma, Italy

Azienda Ospedaliera San Giovanni- Addolorata 1st Cardiology Unit

Roma, Roma, Italy

Ospedale Santo Spirito, Cardiology

Roma, Roma, Italy

Azienda Ospedaliero-Universitaria, Ospedale di Cattinara Cardiology

Trieste, Trieste, Italy

Ospedale di Circolo e Fondazione Macchi Cardiology

Varese, Varese, Italy

Countries

Italy

Other Identifiers

FO002

Identifier Type: REGISTRY

Identifier Source: secondary_id

EudraCT code 2009-016958-41

Identifier Type: -

Identifier Source: org_study_id