ELEVATE Early LEvosimendan Vs Usual Care in Advanced Chronic hearT failurE

Sponsor

Niguarda Hospital (Other)

Overall Status

Terminated

CT.gov ID

NCT01290146

Collaborator

Orion Corporation, Orion Pharma (Industry)

Enrollment

Locations

Arms

72.9

Actual Duration (Months)

0.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Chronic Heart Failure	Drug: Diuretics Drug: Levosimendan	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Participant)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 1, 2011

Actual Primary Completion Date :

Jun 1, 2015

Actual Study Completion Date :

Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Diuretics Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h	Drug: Diuretics Patients randomized to diuretics receive a 24-hour diuretic infusion with a maximum cumulative dose up to 200 mg furosemide/24 h
Experimental: 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	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

Arm

Intervention/Treatment

Active Comparator: Diuretics

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

Drug: Diuretics

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

Experimental: 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

Drug: Levosimendan

Outcome Measures

Primary Outcome Measures

Number of days alive free of Transplant and out-of-hospital (DAOH) [Measured at 12 months]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fondazione S. Maugeri. IRCCS Istituto di Cassano Murge	Cassano Murge	Bari	Italy	70020
2	Ospedali Riuniti di Ancona Cardiology Presidio Lancisi	Ancona		Italy	60020
3	Azienda Ospedaliero-Universitaria, Consorziale Policlinico di Bari, U.O. Cardiologia Universitaria, Dipartimento Emergenza e Trapianti di Organi	Bari		Italy
4	Ospedali Riuniti di Bergamo Cardiovascular Medicine	Bergamo		Italy	24128
5	Ospedale Brotzu Cardiology	Cagliari		Italy	09134
6	Ospedale Sant'Anna Cardiology	Como		Italy	22100
7	Ospedale SS Annunziata Cardiology	Cosenza		Italy	87100
8	Istituti Ospitalieri di Cremona Cardiology	Cremona		Italy	26100
9	Ospedale Santa Maria Nuova Cardiology	Firenze		Italy	50100
10	Ospedale Vito Fazzi	Lecce		Italy	73199
11	Istituto Auxologico Italiano - IRCCS Clinical Cardiology Cardiovascular Department	Milan		Italy	20148
12	Azienda Ospedaliera Niguarda Heart Failure and Heart Transplant Program	Milan		Italy	20162
13	Azienda Ospedaliera S. Gerardo Hear Failure and Cardiomyopathy Clinic	Monza		Italy	20052
14	Gruppo Policlinico di Monza Clinical Cardiology and Heart Failure Unit Cardiology Department	Monza		Italy	20052
15	Ospedale Santa Maria della Misericordia Cardiology	Perugia		Italy	06156
16	Ospedale Guglielmo da Saliceto Cardiology Department	Piacenza		Italy	29100
17	Azienda Ospedaliera San Camillo-Forlanini, Cardiology, Heart Failure Clinic	Roma		Italy	00151
18	Università di Roma Sapienza Dipartimento di Scienze Cardiovascolari e Respiratorie	Roma		Italy	00161
19	Azienda Ospedaliera San Giovanni- Addolorata 1st Cardiology Unit	Roma		Italy	00184
20	Ospedale Santo Spirito, Cardiology	Roma		Italy	00193
21	Azienda Ospedaliero-Universitaria, Ospedale di Cattinara Cardiology	Trieste		Italy	34149
22	Ospedale di Circolo e Fondazione Macchi Cardiology	Varese		Italy	21100

Sponsors and Collaborators

Niguarda Hospital
Orion Corporation, Orion Pharma

Investigators

Study Chair: Fabrizio Oliva, MD, Heart Failure Heart Transplant Program, Cardiovascular Department, Niguarda Hospital, Milan, Italy
Study Chair: Michele Senni, MD, Cardiovascular Medicine Ospedali Riuniti, Bergamo, Italy