Clinical trial NCT01290146: ELEVATE Early LEvosimendan Vs Usual Care in Advanced Chronic hearT failurE
Official title: Early Use of Levosimendan Compared to Usual Care in Advanced Chronic Heart Failure (ACHF)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Advanced Chronic Heart Failure
Keywords: Heart Failure
Levosimendan
Inotropic agents
Phosphodiesterase Inhibitors
Vasodilators
Diuretics
Lead sponsor: Niguarda Hospital
Sponsor class: OTHER
Collaborators: name: Orion Corporation, Orion Pharma
First posted: 2011-02-04
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of days alive free of Transplant and out-of-hospital (DAOH)
timeFrame: Measured at 12 months
Secondary outcomes:
measure: Incidence of acute renal dysfunction
timeFrame: Measured at at 24 hours since inception of randomized treatment for acute worsening HF
measure: All cause mortality, hospital readmission and unscheduled office and emergency department visits for ADCHF
timeFrame: Measured at 12 months
measure: BNP changes
timeFrame: Measured at at end-of- study and at each eventual destabilization
measure: Number of hospital admissions for acute worsening HF
timeFrame: Measured at 12 months
measure: Costs
timeFrame: Measured at 12 months
measure: Treatment-related adverse events
timeFrame: Measured at 12 months
measure: Adverse changes in blood pressure or heart rate
timeFrame: Measured at 24 hours after iv treatment
measure: ECG changes
timeFrame: Measured at 24 hours after iv treatment
Other outcomes:
Locations:
city: Cassano Murge
country: Italy
facility: Fondazione S. Maugeri. IRCCS Istituto di Cassano Murge
state: Bari
city: Ancona
country: Italy
facility: Ospedali Riuniti di Ancona Cardiology Presidio Lancisi
city: Bari
country: Italy
facility: Azienda Ospedaliero-Universitaria, Consorziale Policlinico di Bari, U.O. Cardiologia Universitaria, Dipartimento Emergenza e Trapianti di Organi
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo Cardiovascular Medicine
city: Cagliari
country: Italy
facility: Ospedale Brotzu Cardiology
city: Como
country: Italy
facility: Ospedale Sant'Anna Cardiology
city: Cosenza
country: Italy
facility: Ospedale SS Annunziata Cardiology
city: Cremona
country: Italy
facility: Istituti Ospitalieri di Cremona Cardiology
city: Firenze
country: Italy
facility: Ospedale Santa Maria Nuova Cardiology
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi
city: Milan
country: Italy
facility: Istituto Auxologico Italiano - IRCCS Clinical Cardiology Cardiovascular Department
city: Milan
country: Italy
facility: Azienda Ospedaliera Niguarda Heart Failure and Heart Transplant Program
city: Monza
country: Italy
facility: Azienda Ospedaliera S. Gerardo Hear Failure and Cardiomyopathy Clinic
city: Monza
country: Italy
facility: Gruppo Policlinico di Monza Clinical Cardiology and Heart Failure Unit Cardiology Department
city: Perugia
country: Italy
facility: Ospedale Santa Maria della Misericordia Cardiology
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto Cardiology Department
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo-Forlanini, Cardiology, Heart Failure Clinic
city: Roma
country: Italy
facility: Università di Roma Sapienza Dipartimento di Scienze Cardiovascolari e Respiratorie
city: Roma
country: Italy
facility: Azienda Ospedaliera San Giovanni- Addolorata 1st Cardiology Unit
city: Roma
country: Italy
facility: Ospedale Santo Spirito, Cardiology
city: Trieste
country: Italy
facility: Azienda Ospedaliero-Universitaria, Ospedale di Cattinara Cardiology
city: Varese
country: Italy
facility: Ospedale di Circolo e Fondazione Macchi Cardiology
Study officials:
affiliation: Heart Failure Heart Transplant Program, Cardiovascular Department, Niguarda Hospital, Milan, Italy
name: Fabrizio Oliva, MD
role: STUDY_CHAIR
affiliation: Cardiovascular Medicine Ospedali Riuniti, Bergamo, Italy
name: Michele Senni, MD
role: STUDY_CHAIR
References: