ELEVATE Early LEvosimendan Vs Usual Care in Advanced Chronic hearT failurE

Advanced Chronic Heart Failure Clinical Trial

— ELEVATE  

Official title:

Early Use of Levosimendan Compared to Usual Care in Advanced Chronic Heart Failure (ACHF)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01290146
• Other study ID #: EudraCT code 2009-016958-41
• Secondary ID: FO002
• Status: Terminated
• Phase: Phase 3
• First received: February 3, 2011
• Last updated: April 7, 2017
• Start date: February 2011
• Est. completion date: March 2017

Study information

• Verified date: April 2017
• Source: Niguarda Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: March 2017
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Advanced Chronic Heart Failure
• Heart Failure

Intervention

Drug:
• Diuretics
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

Locations

Country	Name	City	State
Italy	Ospedali Riuniti di Ancona Cardiology Presidio Lancisi	Ancona
Italy	Azienda Ospedaliero-Universitaria, Consorziale Policlinico di Bari, U.O. Cardiologia Universitaria, Dipartimento Emergenza e Trapianti di Organi	Bari
Italy	Ospedali Riuniti di Bergamo Cardiovascular Medicine	Bergamo
Italy	Ospedale Brotzu Cardiology	Cagliari
Italy	Fondazione S. Maugeri. IRCCS Istituto di Cassano Murge	Cassano Murge	Bari
Italy	Ospedale Sant'Anna Cardiology	Como
Italy	Ospedale SS Annunziata Cardiology	Cosenza
Italy	Istituti Ospitalieri di Cremona Cardiology	Cremona
Italy	Ospedale Santa Maria Nuova Cardiology	Firenze
Italy	Ospedale Vito Fazzi	Lecce
Italy	Azienda Ospedaliera Niguarda Heart Failure and Heart Transplant Program	Milan
Italy	Istituto Auxologico Italiano - IRCCS Clinical Cardiology Cardiovascular Department	Milan
Italy	Azienda Ospedaliera S. Gerardo Hear Failure and Cardiomyopathy Clinic	Monza
Italy	Gruppo Policlinico di Monza Clinical Cardiology and Heart Failure Unit Cardiology Department	Monza
Italy	Ospedale Santa Maria della Misericordia Cardiology	Perugia
Italy	Ospedale Guglielmo da Saliceto Cardiology Department	Piacenza
Italy	Azienda Ospedaliera San Camillo-Forlanini, Cardiology, Heart Failure Clinic	Roma
Italy	Azienda Ospedaliera San Giovanni- Addolorata 1st Cardiology Unit	Roma
Italy	Ospedale Santo Spirito, Cardiology	Roma
Italy	Università di Roma Sapienza Dipartimento di Scienze Cardiovascolari e Respiratorie	Roma
Italy	Azienda Ospedaliero-Universitaria, Ospedale di Cattinara Cardiology	Trieste
Italy	Ospedale di Circolo e Fondazione Macchi Cardiology	Varese

Sponsors (2)

Lead Sponsor	Collaborator
Niguarda Hospital	Orion Corporation, Orion Pharma

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of days alive free of Transplant and out-of-hospital (DAOH)		Measured at 12 months
Secondary	Incidence of acute renal dysfunction	proportion of subjects who develop AKIN stage 1 (increase > 0.3 mg/dl or > 25% in serum creatinine from previous visit)	Measured at at 24 hours since inception of randomized treatment for acute worsening HF
Secondary	All cause mortality, hospital readmission and unscheduled office and emergency department visits for ADCHF	A combination of all cause hospital admissions/death/urgent heart transplantation/LV assist device implantation	Measured at 12 months
Secondary	BNP changes	Percent changes in BNP vs baseline	Measured at at end-of- study and at each eventual destabilization
Secondary	Number of hospital admissions for acute worsening HF	Number of hospital admissions for acute worsening HF	Measured at 12 months
Secondary	Costs	Direct health care costs for days in hospital, supplementary visits, drug treatment	Measured at 12 months
Secondary	Treatment-related adverse events	death, hospital a dimission, emergency room or clinic unscheduled visits	Measured at 12 months
Secondary	Adverse changes in blood pressure or heart rate	Hypotension (< 90 mmHg), tachycardia (> 110 bpm)	Measured at 24 hours after iv treatment
Secondary	ECG changes	Rhythm, rate, conduction disturbances, ventricular arrhythmias, repolarization changes	Measured at 24 hours after iv treatment