Heart Failure
Conditions
Keywords
Cardiac Failure, Severe Heart Failure
Brief summary
The present study was conceived to evaluate the effects of levosimendan on cardiopulmonary exercise test (CPET) and DLCO ( Diffusion capacity of Lung for carbon monoxide) in patients with severe heart failure in stable clinical conditions (NYHA - New York Heart Association - class III, with a peak VO2 (Oxygen consumption ) \< 12 ml/min/kg) on top of optimized standard therapy.
Detailed description
Eligible patients should have chronic HF (Heart Failure -class NYHA III or IV) in stable clinical conditions. Inclusion criteria were: left ejection fraction (EF) at echocardiography ≤35%, age ≥18 years old, peak VO2 \<12 ml/min/kg measured by a CPET, a standard optimized therapy for HF that include ACE-inhibitors, ARBs (angiotensin II Receptor Blocker), aldosterone blocking agents (spironolactone), diuretics, and beta-blockers. The exclusion criteria are: ongoing mechanical ventilation; recent or acute coronary syndromes; sustained ventricular tachycardia or ventricular fibrillation; severe aortic or mitral regurgitation, or known malfunctioning artificial heart valve; uncorrected obstructive valvular disease; hypertrophic obstructive cardiomyopathy; uncorrected thyroid disease. Patients will be randomly assigned by means of prepared letters to the levosimendan or placebo group stratified by clinical centre in a 1:1 allocation using block randomization. The placebo infusion will be coloured identically to its respective active counterpart. Patients and investigators will be kept blinded to the treatment allocation for the entire duration of the trial. Study drug will be infused with an injection speed between 6 and 20 ml/min based on blood pressure, without a bolus, for 24 hours. Medical history, physical examination and a blood sample examination will be recorded: NYHA class, BNP (Brain Natriuretic Peptide), haemoglobin, creatinine, blood urea nitrogen (BUN) will be recorded before and 24 hours after the drug infusion. A two-dimensional standard echocardiography evaluation will be performed at the admission in the hospital. A maximal CPET performed on a cycle ergometer (Sensor Medics Ergo 800S and V-max, Yorba-Linda, CA) with a personalized ramp aimed at achieving peak exercise in 10 minutes will be performed before and 24 hours after the drug infusion. Expiratory O2, CO2 (Carbon dioxide) and ventilation (VE) will be measured breath by breath. Peak VO2 (Carbon dioxide production) was considered to be the highest VO2 achieved during the exercise. A 12-lead electrocardiogram will be also recorded. Spirometry and DLCO measurements will be performed before ad 24-hours after the drug infusion. . DLCO will be measured by the single breath-constant expiratory flow technique
Interventions
DRUGLevosimendan
Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.
DRUGPlacebo
Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min.
Sponsors
Orion Corporation, Orion Pharma
Centro Cardiologico Monzino
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* informed consent of the study signed * severe heart failure in stable clinical condition (NYHA class III, peak VO2 \<12 ml / kg / min) in optimized medical therapy. The clinical stability is defined by the stability of the therapy, the weight and urine output for 3 days
Exclusion criteria
* unstable patients from a clinical point of view, not in optimized therapy * patients unable to perform a CPET (Cardiopulmonary Exercise Test) . * are excluded from the protocol also patients with absolute contraindications to CPET (acute myocardial infarction, severe aortic stenosis, myocarditis or pericarditis, active, acute thromboembolism, sepsis,unstable angina, uncontrolled arrhythmia. * age \< 18 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak VO2 (Oxygen Consumption ) | 48 hours | Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption ) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in VE/VCO2 | 48 hours | Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship |
| Change in DLCO (Diffusion Lung CO) | 48 hours | Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume. |
Countries
Italy
Participant flow
Recruitment details
From September 2012 to December 2014 we enrolled forty-two patients who fulfilled the study inclusion/ exclusion criteria:19 patients received placebo and 23 received levosimendan. All patients was enrolled at Centro Cardiologico Monzino.
Pre-assignment details
Eligible patients had advanced chronic heart failure and were admitted because of worsening HF (Heart Failure),although the patients included in the study had been returned to a stable clinical condition and were free from both inotrope support and other i.v. therapies for at least 48h prior to study inclusion, except for diuretics where needed.
Participants by arm
| Arm | Count |
|---|---|
| Levosimendan Levosimendan must be diluted before the administration (500 ml of glucose). The intravenous infusion may be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.
Levosimendan: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. | 23 |
| Placebo Placebo must be diluted before the administration (500 ml of glucose). The intravenous infusion may' be administered either by the peripheral or central. The dose and duration of therapy should be decided according to the patient's clinical condition and response to the drug. Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. A low infusion bolus (6 mcg / kg) is recommended for patients who have a concomitant intravenous treatment with vasodilators or inotropic. The patient's response should be evaluated during the infusion bolus or within 30 to 60 minutes and a dose adjustment based on clinical response.
Placebo: Treatment should be initiated with a loading dose of 6-12 mcg / kg infused over 10 minutes followed by a continuous infusion of 0.1 mcg / kg / min. | 19 |
| Total | 42 |
Baseline characteristics
| Characteristic | Levosimendan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 15 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 4 Participants | 10 Participants |
| Age, Continuous | 70.39 years STANDARD_DEVIATION 9.4 | 68.2 years STANDARD_DEVIATION 8.3 | 69 years STANDARD_DEVIATION 8.7 |
| NYHA class | 3.3 units on a scale STANDARD_DEVIATION 0.4 | 3.2 units on a scale STANDARD_DEVIATION 0.4 | 3.3 units on a scale STANDARD_DEVIATION 0.47 |
| Region of Enrollment Italy | 23 participants | 19 participants | 42 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 19 Participants | 16 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 19 |
| serious Total, serious adverse events | 0 / 23 | 0 / 19 |
Outcome results
Primary
Change in Peak VO2 (Oxygen Consumption )
Primary endpoints: Levosimendan induced changes in peak VO2 (Oxygen consumption )
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan | Change in Peak VO2 (Oxygen Consumption ) | 1.21 ml/kg/min | Standard Deviation 1.9 |
| Placebo | Change in Peak VO2 (Oxygen Consumption ) | 0.48 ml/kg/min | Standard Deviation 1.2 |
Secondary
Change in DLCO (Diffusion Lung CO)
Levosimendan induced changes on DLCO ( Diffusion Lung CO). DLCO is measured by the single breath-constant expiratory flow technique (Sensor Medics 2200, Yorba Linda, CA) and we calculate also the DLCO adjusted for hemoglobin. Dilution of CH4 is used to measure alveolar volume.
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan | Change in DLCO (Diffusion Lung CO) | -0.96 ml/mmHg/min | Standard Deviation 2 |
| Placebo | Change in DLCO (Diffusion Lung CO) | 0.88 ml/mmHg/min | Standard Deviation 3.14 |
Secondary
Changes in VE/VCO2
Levosimendan induced changes on VE/VCO2 (VE: Expired Volume - VCO2: carbon dioxide production) relationship
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Levosimendan | Changes in VE/VCO2 | -5.34 VE/VCO2 Slope | Standard Deviation 7 |
| Placebo | Changes in VE/VCO2 | -0.91 VE/VCO2 Slope | Standard Deviation 4.7 |