Clinical trial NCT04179604: Spanish Randomized Clinical Trial to Compare Levosimendan Versus Placebo in Postoperative Cardiac Surgery (SPARTANS)
Official title: Rationale and Design of a Multicenter Randomized Trial of Levosimendan to Reduce Low Cardiac Output Syndrome in Low Ejection Fraction (≤ 35%) Cardiac Surgery Patients. Spanish Randomized Clinical Trial on Levosimendan (SPARTANS Study)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Cardiac Output, Low
Keywords: Poor left ventricule eyection fraction
Levosimendan
Cardiac surgery
Preoperative Treatment
Low cardiac output syndrome
Clinical Trial
Lead sponsor: Dr. Negrin University Hospital
Sponsor class: OTHER
Collaborators: name: Orion Corporation, Orion Pharma
name: Canary Foundation
name: Dr Negrin Hospital Statistician
name: Dr Negrin Hospital Farmacy
name: CRO TRIDE Asesores SL
name: QBE Europe SA/NV
First posted: 2019-11-27
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: SPARTANS is a phase II-III, prospective, randomized, triple-blind, placebo-controlled, multicenter clinical trial to evaluate the efficacy of levosimendan in decrease perioperative low cardiac output Syndrome in patients with preoperatively severe left ventricular dysfunction (LVEF ≤ 35%) who will be scheduled for cardiac surgery on cardipulmonary bypass. Follow-up duration will be one year.
Primary purpose: TREATMENT

Brief summary: Low cardiac output Syndrome (LCOS) is a complication that appears in approximately 20% of cardiac surgeries with extracorporeal circulation. LCOS is associated with increased mortality, delayed recovery and prolonged hospital stay. The Spanish Randomized Clinical Trial on Levosimendan (brand name: Sindax) (SPARTANS) aims to demonstrate the effectiveness of the preoperative use of Levosimendan in reducing LCOS in patients with poor left ventricle ejection fraction (LVEF) undergoing elective cardiac surgery.

SPARTANS study is a multicenter, randomized triple-blind, placebo-controlled trial. 300 patients with LVEF ≤ 35%, undergoing elective cardiac surgery will be recruited from 9 Spanish hospitals and randomized into two groups: Preoperative administration of levosimendan or placebo for 24 hours. The study drug will be started as a continuous infusion (0.1 µg/kg/min) at least 8 hours before surgery to complete 24h duration.

The primary endpoint will be 30-day LCOS. It will be evaluated using any of the following criteria:

1) postoperated cardiac index ≤2.0 L / min / m2, 2) a need to implant a intra-aortic balloon pump/ left ventricular assist device, 3) a vasoactive inotropic scale (VIS) \> 5.5.

The secondary end-point will be composite event rate at one year including any of the following events: death from any cause, need for renal replacement therapy or dialysis and LCOS.

The sample size is based on the assumption that levosimendan reduces LCOS by 50% being necessary a sample size of 300 patients to carry out the study.

The Research Team of each hospital, will carry out the clinical follow-up by telephone or clinical interview of the patient according to the time intervals: 30 days and 1 year. We estimate that the total sample size of 300 patients will be reached in 2-2.5 years.

In conclusion, the effectiveness of levosimendan has not yet been reported with a good evidence in cardiac surgery. The purpose of the "Spanish Randomized Clinical Trial on Sindax" (SPARTANS) trial is to evaluate the beneficial effect of preoperative use of levosimendan compared with placebo to reduce perioperative LCOS in patients undergoing cardiac surgery with poor LVEF ≤ 35%.

Detailed description: Low cardiac output syndrome (LCOS) is defined, by the Working Group of Cardiac Intensive Care of the Spanish Society of Intensive, Critical Medicine and Coronary Units, as a cardiac index (CI) \<2.2 l / min / m2. LCOS is due to left and/or right ventricular failure and may be associated with pulmonary congestion and may occur with normal or low blood pressure. LCO after cardiac surgery is associated with increased mortality, delayed functional and organic recovery and prolonged stay in the Intensive Care Unit. It is characterized by a decrease in cardiac function, a reduction in oxygen supply and subsequent tissue hypoxia, together with signs of tissue hypoperfusion (peripheral coldness, confusion, oliguria and elevated lactate level) and in absence of hypovolemia.

LCOS appears in approximately 20% of cardiopulmonary bypass (CPB) surgeries. Levosimendan, a calcium-sensitizing inotrope and an ATP-sensitive potassium channel opener, has been reported to be effective in decreasing LCOS and mortality after cardiac surgery. Simdax, which is its trade name, is indicated for the short-term treatment of severe acute decompensation of chronic heart failure in situations where conventional treatment is not sufficient or in cases where an inotropic support is considered appropriate.

The recent publication of 2 large randomized clinical trials LEVO-CTS and LICORN failed to meet any benefit of levosimendan in terms of survival in cardiac surgery. Still, in a recently published meta-analysis, researchers showed that Levosimendan is effective in reducing low-cardiac output Syndrome compared to placebo (14.8% in the Levosimendan group versus 29.0% in the placebo group; RR = 0.40 , 95% CI = 0.22-0.73; P = 0.003).

The purpose of the "Spanish Randomized Clinical Trial on Sindax" (SPARTANS) trial is to evaluate the beneficial effect of preoperative use of Levosimendan compared with placebo to reduce perioperative LCOS in patients undergoing cardiac surgery with poor LVF.

The study was approved by the Ethical Committee of all participating centers. SPARTANS is a phase III, randomized, triple-blind, placebo-controlled, multicenter clinical trial to evaluate the efficacy of levosimendan in decrease perioperative LCOS in patients with preoperatively severe left ventricular dysfunction (LVEF ≤ 35%) who will be scheduled for cardiac surgery on CBP.

The sample size was calculated based on an earlier meta-analysis (Tena MA, Urso S et al. Levosimendan versus placebo in cardiac surgery: a systematic review and a meta-analysis. Interact Cardiovasc Thorac Surg. 2018 27: 677-685) where researches document that Levosimendan is effective in reducing the rate of low postoperative cardiac output Syndrome compared to placebo (14.8% in the Levosimendan group versus 29.0% in the placebo group; RR = 0.40, 95% CI = 0.22-0.73; P = 0.003 ). Thus, considering a type I error of 0.05, a type II error of 0.20, a ratio of 1/1, an event rate of 29% in the Placebo group and an event rate of 15% in the Levosimendan group, a sample population of at least 137 patients for each group is required. Assuming a 9,5% patient drop rate, researches obtain a total sample of 300 patients (MedCalc Software bvba, Ostende, Belgium, http://www.medcalc.org, 2017).

Thus, 300 patients will be enroll at 9 Spanish University hospitals scheduled for isolated aortic valve replacement (AVR) and/or coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). All enrolled patients will have a preoperative LVEF equal to, or less than 35 % detected by echocardiography measurement one week before surgery and will be required to give written informed consent, prior to being properly informed about participation in the trial, before enrollment. Researches hope to recruit 300 patients in 2 years.

150 patients will receive randomly levosimendan and another 150 patients placebo with identical appearance and doses to the medication under study. The study drug or placebo infusion will start one day before surgery in an Intensive Care Unit with at least 8 hours of administration before surgery. A continuous infusion at 0.1 µg/kg/min will be administered to complete 24h duration. If patients once randomized, suffering from one adverse event during the infusion, they will be registered stopping the infusion. In the case that the adverse event occurred in the postoperative period and if it was demonstrated due to the cause of the medication under study, it will be registered too.

Researches will use a computer-generated permuted block randomization established by an independent statistician. Pharmacy of each hospital will prepare randomized treatment, without being involved in the trial. Patients and physicians will be blind to the randomized therapeutic strategy that each patient will receive. The data will be entered into a specific electronic database in an anonymized and dissociated manner.

Patients Data will be collected by a Research Team for each participating hospital that will consist of at least one Cardiac Surgeon, an Anesthesiologist and a specialist in postoperative Critical Care. These investigators will receive training about patient selection and clinical events registration with the help of Contract Research Organization (CRO TRIDE ASESORES SL). This CRO will carry out regulatory execution of the trial, oversight and collection of electronic data, follow up and scientific regulation of procedures between different ethical Committees and hospitals involved. All data will be evaluated by trial main researcher and CRO identifying possible data collection errors and acting according to good clinical practice. The identification of a clinical event will be done by absolute majority by the members of the Research Team.

Anesthesia, surgery and CBP will be performed according to standard operating procedures and following the usual clinical practice of each hospital.

The primary endpoint is to demonstrate that preoperative levosimendan administration in patients undergoing AVR and/or CABG with poor LVEF ≤ 35% halve perioperative LCOS during the first 30 days of surgery. The secondary endopoint is to analyze composite event rate up to one year after surgery. The results will be expressed as means (±SD) or as medians and interquartile range to express quantitative variables. Qualitative variables will be expressed by frequency and percentage. Categorical variables will be compared by Fisher's exact test and continuous variables will be compared by Student's test or Mann-Whitney U. Incidence of composite endpoint will be compared between the two groups using a Chi-square test o Fisher's exact test. The Friedman or Anova test of repeated measures will be used to compare measures repeated through the study time. The risk factors will be expressed through relative risks (ratio of cumulative incidents), Odds Ratio or Hazard Ratio and their respective confidence intervals. Survival curves will be compared using the Log-rank test. All analyzes will be performed 2-sided and with an alpha level of 5%. All analyzes will be performed using the R program, version 3.5.2 or higher (R Foundation). The statistical calculation procedure will be carried out by an independent statistician and during the third year.

Researches will follow the recommendations of Helsinki and Consort to carry out the trial and give greater validity to study results.The patients, sponsor or researchers included in trial will not receive financial compensation and declare that there has been no conflict of interest.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Written informed consent
* LVEF ≤35% detected by echocardiography carried out at least one week before surgery.
* Scheduled AVR or/and Scheduled CABG with CBP.

Exclusion Criteria:

* Previous levosimendan administration.
* Emergency operation.
* Kidney or liver trasplant or awaiting it.
* Hepatic cirrhosis Child C. In case Child B, contact coordinating center.
* Any degree of preoperative right ventricular failure.
* Preoperative creatinine \> 2 mg / dl.
* Valve desease other than aortic.
* Renal failure requering dialysis (or creatinine clearance \< 30ml / min).
* Hemodynamic instability (need for inotropics, unstable angina, acute myocardial infarction, intra-aortic balloon pump).
* Patients underwent previous cardiac surgery.
* Allergy or hypersensitivity to levosimendan or any of its excipients
* Severe hypotension (sistolic arterial tension \< 80 mmHg or mean arterial pressure \<50 mmHg ) and tachycardia ( heart rate \>130 bpm).
* History of Torsades de Pointes.
* Pregnancy or breast-feeding

Primary outcomes:
measure: Number of Participants with LCOS
timeFrame: up to 30 days of cardiac surgery
measure: Number of Participants with LCOS
timeFrame: up to 30 days of cardiac surgery
measure: Number of Participants with LCOS
timeFrame: up to 30 days of cardiac surgery
measure: Number of Participants with LCOS
timeFrame: up to 30 days of cardiac surgery
Secondary outcomes:
measure: Composite event rate
timeFrame: up to one year after surgery
measure: Composite event rate
timeFrame: up to one year after surgery
measure: Composite event rate
timeFrame: up to one year after surgery
Other outcomes:
measure: Number of Patients with need for renal replacement therapy or dialysis
timeFrame: up to 30 days
measure: Intensive Care Unit stay
timeFrame: until discharge from Intensive Care Unit
measure: Total post-surgical stay
timeFrame: until discharge from hospital
measure: Number of Patients with hospital cardiac mortality
timeFrame: until discharge from hospital
measure: Number of Patients with need for ventricular assistance or intra-aortic balloon pump
timeFrame: up to 1 year after surgery
Locations:
city: Badalona
country: Spain
facility: GERMANS TRIAS I PUJOL DE BADALONA university Hospital
state: Barcelona
city: Girona
country: Spain
facility: Doctor Josep Trueta university Hospital
state: Gerona
city: Las Palmas De Gran Canaria
country: Spain
facility: Doctor Negrin University Hospital
state: Gran Canarias
city: Majadahonda
country: Spain
facility: Puerta del Hierro University Hospital
state: Madrid
city: Málaga
country: Spain
facility: Virgen de la Victoria University Hospital
state: Malaga
city: La Coruña
country: Spain
facility: A coruña UNIVERSITY HOSPITAL COMPLEX A CORUÑA
city: Madrid
country: Spain
facility: 12 de Octubre University Hospital
city: Sevilla
country: Spain
facility: Virgen Macarena University Hospital
city: Valladolid
country: Spain
facility: Valladolid universitary Hospital
Study officials:
affiliation: Doctor Negrin University Hospital
name: Maria Ángeles T Tena Pajuelo, Cardiac surgery
role: PRINCIPAL_INVESTIGATOR
affiliation: A Coruña University Complex
name: Marta P Perez de Lis Novo, anesthesiology
role: PRINCIPAL_INVESTIGATOR
affiliation: Valladolid UNIVERSITY CLINICAL HOSPITAL
name: Juan B Bustamante Munguira, Cardiac surgery
role: PRINCIPAL_INVESTIGATOR
affiliation: Doctor Joseh Trueta, Girona university clinical Hospital
name: Marc V Vives Santacana, anesthesiology
role: PRINCIPAL_INVESTIGATOR
affiliation: GERMANS TRIAS I PUJOL DE BADALONA University Hospital
name: Elisabet B Berastegui Garcia, Cardiac surgery
role: PRINCIPAL_INVESTIGATOR
affiliation: 12 de Octubre University Hospital
name: Pedro M Muñoz Ramirez, anesthesiology
role: PRINCIPAL_INVESTIGATOR
affiliation: Puerta del Hierro University Hospital
name: Ana Isabel G Gonzalez Roman, anesthesiology
role: PRINCIPAL_INVESTIGATOR
affiliation: Virgen de la Victoria University Hospital
name: Gemma S Sanchez Espin, Cardiac Surgery
role: PRINCIPAL_INVESTIGATOR
affiliation: Virgen Macarena University Hospital
name: Emiliano Andres R Rodriguez Caulo, Cardiac Surgery
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tena MA, Urso S, Gonzalez JM, Santana L, Sadaba R, Juarez P, Gonzalez L, Portela F. Levosimendan versus placebo in cardiac surgery: a systematic review and meta-analysis. Interact Cardiovasc Thorac Surg. 2018 Nov 1;27(5):677-685. doi: 10.1093/icvts/ivy133.
citation: Landoni G, Mizzi A, Biondi-Zoccai G, Bruno G, Bignami E, Corno L, Zambon M, Gerli C, Zangrillo A. Reducing mortality in cardiac surgery with levosimendan: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth. 2010 Feb;24(1):51-7. doi: 10.1053/j.jvca.2009.05.031. Epub 2009 Aug 22.
citation: Niu ZZ, Wu SM, Sun WY, Hou WM, Chi YF. Perioperative levosimendan therapy is associated with a lower incidence of acute kidney injury after cardiac surgery: a meta-analysis. J Cardiovasc Pharmacol. 2014 Feb;63(2):107-12. doi: 10.1097/FJC.0000000000000028.
citation: Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012 Sep;17(3):125-30.