Cardiogenic Shock
Conditions
Keywords
heart failure, levosimendan
Brief summary
Cardiogenic shock (CS) mortality remains high (40%). Despite their frequent use, few clinical outcome data are available to guide the initial selection of vasoactive drug therapies in patients with CS. Based on experts' opinions, the combination of norepinephrine-dobutamine is generally recommended as a first line strategy. Inotropic agents increase myocardial contractility, thereby increasing cardiac output. Dobutamine is commonly recommended to be the inotropic agent of choice and levosimendan is generally used following dobutamine failure. It may represent an ideal agent in cardiogenic shock, since it improves myocardial contractility without increasing cAMP or calcium concentration. At present, there are no convincing data to support a specific inotropic agent in patients with cardiogenic shock. Our hypothesis is that the early use of levosimendan, by enabling the discontinuation of dobutamine, would accelerate the resolution of signs of low cardiac output and facilitate myocardial recovery.
Interventions
Levosimendan will be diluted with Glucose G5%. The reconstitution of levosimendan will be performed, as close as possible to the start of the infusion. A continuous infusion of levosimendan will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.
DRUGPlacebo
Placebo will be diluted with Glucose G5%. The reconstitution of Placebo will be performed, as close as possible to the start of the infusion. A continuous infusion of Placebo will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.
Sponsors
Pr Bruno LEVY
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The study will be double-blinded. Investigator masking to group assignment after randomization will be guaranteed by use of a placebo.
Intervention model description
The LevoHeartShock trial is a prospective, double-blind, multicenter, randomized controlled trial comparing the early initiation of levosimendan versus placebo in patients with cardiogenic shock treated with vasopressor therapy according to a conventional strategy of inotrope use (dobutamine as first line agent).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Adult patient ≥ 18 years with cardiogenic shock defined by: * Adequate intravascular volume * Norepinephrine to maintain MAP at least at 65 mmHg for at least 3 hours and less than 24h. At inclusion the dose must be \<1 microgram/kg/min under norepinephrine base or \<2 microgram/kg/min under norepinephrine tartrate, OR/AND Dobutamine since at least 3h and less than 24h at inclusion. * Tissue hypoperfusion: at least 1 sign within 24h prior to inclusion (lactate ≥ 2 mmol/l; mottling, capillary refeel time \> 3 seconds, oliguria \<500ml/24h or ≤ 20 ml/h during the last 2 hours, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg);
Exclusion criteria
* Myocardial sideration after cardiac arrest of non-cardiac etiology * Immediate or anticipated (within 6 hours) indication of Extra Corporel Life Support * Use of VA-ECMO or IMPELLA or LVAD; * Chronic renal failure requiring hemodialysis * Cardiotoxic poisoning * Septic cardiomyopathy * Previous levosimendan administration within 15 days * Cardiac arrest with non-shockable rhythm; * No flow time higher \> 3 minutes; * Cardiac arrest with unknown no flow duration; * Total duration of cardiac arrest (no flow plus low flow) \> 45 minutes; * Cerebral deficit with fixed dilated pupils * Patient moribund on the day of enrollment * Irreversible neurological pathology * Known hypersensitivity to levosimendan or placebo, or one of its excipients * Pregnant woman, birthing or breastfeeding mother * Minor (not emancipated) * Person deprived of liberty for judicial or administrative decision; * Adult subject to a legal protection measure (such as guardianship, conservatorship)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of All-cause mortality | Day 30 following randomization | Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis) |
| Proportion of Extra Corporel Life Support implantation | Day 30 following randomization | Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis) |
| Proportion of Dialysis | Day 30 following randomization | Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to ECLS requirement | Day 90 | Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure). |
| number of cardiovascular events | Day 90 | Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure). |
| Proportion of death. | Day 90 | — |
| Proportion of Extra Corporel Life Support implantation | Day 90 | — |
| Proportion of dialysis | Day 90 | — |
| Proportion of cardiac transplantation | Day 90 | — |
| Proportion of escalation to permanent Left Ventricular Assist Device | Day 90 | — |
| Proportion of stroke | Day 90 | — |
| Proportion of recurrent myocardial infarction | Day 90 | — |
| Proportion of urgent coronary revascularization | Day 90 | — |
| Proportion of re-hospitalization for heart failure | Day 90 | — |
| Proportion of All-cause mortality | Day 90 | Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90. |
| Proportion of Dialysis | Day 90 | Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90. |
| Number of dobutamine free days | From randomization to day 30 | — |
| Time to death | Day 90 | Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure). |
| Number of ventilatory free days | From randomization to day 30 | — |
| Number of renal replacement free days | From randomization to day 90 | — |
| Lactate clearance | from randomization to day 7 | — |
| Duration of intensive care unit stay | Up to Intensive Care Unit discharge (assessed up to 1 month) | — |
| Duration of hospitalization | Up to hospitalization discharge (assessed up to 1 month) | — |
| Proportion of death | days 180 and at 12 months | — |
| proportion of cardiac transplantation | days 180 and at 12 months | — |
| proportion of escalation to permanent left ventricular assist device | days 180 and at 12 months | — |
| Proportion urgent coronary revascularization | days 180 and at 12 months | — |
| proportion of re-hospitalization for heart failure | days 180 and at 12 months | — |
| Occurrence of arrhythmias requiring therapy | from randomization to intensive care unit discharge. | Occurrence of arrhythmias requiring therapy with anti-arrhythmic drugs or electric cardioversion (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe) |
| the changes in biomarkers | from randomization to intensive care unit discharge. | From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the effect of Levosimendan on the changes in biomarkers between randomization and ICU/CCU discharge |
| All-cause mortality and/or ECLS and/or dialysis | Day 30 | From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the ability of clinical and biological measure to predict levosimendan effect for the primary endpoint. |
| Number of vasopressors free days | From randomization to day 30 | — |
| Time to escalation to permanent left ventricular assist device or cardiac transplantation | Day 90 | Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure). |
| Time to dialysis | Day 90 | Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure). |
Countries
France
Contacts
Primary ContactBruno LEVY, Pr
Outcome results
None listed