Prospective randomized double-blind study evaluating the superiority of VAsopressin versus NOradrenaline in the management of the renal risk patient undergoing cardiac surgery with extracorporeal circulation

The primary objective of this study is to compare two **blood pressure** optimization strategies, specifically vasopressin versus norepinephrine, in terms of their impact on the occurrence of a composite endpoint that includes renal complications and death at day 7 following the onset of **vasoplegic syndrome** in patients undergoing cardiac surgery with extracorporeal circulation. This is clinically relevant as optimizing blood pressure management in such patients could potentially reduce the incidence of severe complications and improve survival outcomes.

Secondary objectives include:

• Comparing the occurrence of a composite endpoint combining acute renal failure and death at days 30 and 90.
• Comparing mortality within 90 days of the onset of vasoplegic syndrome.
• Comparing cardiac complications, including cardiac arrest and atrial fibrillation, at days 7, 30, and 90.
• Comparing digestive complications at days 7, 30, and 90.
• Comparing cerebral complications, such as stroke and confusion/disorientation, at day 7.
• Comparing the use of rescue norepinephrine after the onset of vasoplegic syndrome.
• Comparing the use of inotropic and vasopressor agents from day 0 to day 7.
• Comparing the length of stay in the ICU and hospital, and associated costs within 90 days.
• Comparing the cost-effectiveness ratio at day 90, expressed in terms of costs per complication (acute renal failure or death) avoided, from a societal perspective.
• Comparing the cost-effectiveness ratio at day 90, expressed in terms of costs per life-year gained, from a societal perspective.
• Comparing the cost-utility ratio at day 90, expressed in terms of costs per healthy life-year gained, from a societal perspective.
• Comparing complications related to the use of vasopressors at day 7, including hyponatremia, hypoperfusion of the extremities, and mesenteric ischemia.

The clinical trial involves participants diagnosed with **vasoplegic syndrome** undergoing cardiac surgery with extracorporeal circulation. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating adults and older adults. Participants are required to be of legal age and must have provided informed consent. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Key lifestyle considerations such as diet and physical activity are not specified. Participants must have at least three risk factors for acute kidney failure, such as age over 70 years, diabetes, or chronic respiratory failure. Women of childbearing age must have a negative pregnancy test. The selection criteria ensure that the study population is representative of patients who are at risk of renal complications and death following cardiac surgery.

The clinical trial is a **prospective randomized double-blind** study designed to evaluate the superiority of **vasopressin** versus **norepinephrine** in managing patients with **vasoplegic syndrome** undergoing cardiac surgery with extracorporeal circulation. The primary objective is to compare two blood pressure optimization strategies on the occurrence of a composite endpoint combining renal complications and death within seven days of the onset of vasoplegic syndrome. The trial is expected to run from October 31, 2022, to January 31, 2026, with participant involvement lasting up to 90 days post-onset of vasoplegic syndrome.

Participants will be randomly assigned to receive either vasopressin or norepinephrine, with both treatments administered as a **solution for infusion** via intravenous routes. The study will include an initial screening visit to confirm eligibility based on criteria such as age, surgical requirements, and risk factors for acute kidney failure. Following the screening, participants will undergo the intervention during their cardiac surgery, with subsequent follow-up visits scheduled at 7, 30, and 90 days post-onset of vasoplegic syndrome to monitor for primary and secondary endpoints, including renal, cardiac, digestive, and cerebral complications, as well as mortality and cost-effectiveness measures.

The trial will conclude with an end-of-study visit to assess the final outcomes and gather data on the length of ICU and hospital stays. Participants may be withdrawn from the study if they experience adverse events that necessitate discontinuation of the investigational product or if they withdraw consent. The study is conducted under conditions that align with the marketing authorization of the medicinal products, ensuring adherence to regulatory standards and participant safety throughout the trial duration.

The clinical trial involves the administration of **REVERPLEG**, a pharmaceutical product containing the active substance **argipressin**. This medication is provided in the form of a **solution for infusion** and is intended for **intravenous perfusion use**. The product is supplied as a 40 IU/2 mL solution, which must be diluted prior to administration. The maximum daily dose is 86.4 IU, with a total treatment period not exceeding one day. The administration of REVERPLEG is monitored to ensure compliance with the dosing schedule, and the product is manufactured by ORPHA-DEVEL HANDELS UND VERTRIEBS GMBH. The active substance, argipressin, is a protein of non-human origin, classified under the ATC code H01BA01, which corresponds to vasopressin analogs.

The comparator treatment in this study is **NORADRENALINE RENAUDIN**, which contains the active substance **noradrenaline tartrate**. This medication is also provided as a **solution for infusion** and is administered via **intravenous use**. The solution is formulated at a concentration of 2 mg/mL and is preservative-free. The maximum daily dose for noradrenaline tartrate is 36 mg, with a treatment period limited to one day. Compliance with the dosing regimen is closely monitored throughout the trial. NORADRENALINE RENAUDIN is produced by LABORATOIRE RENAUDIN and is classified under the ATC code C01CA03, indicating its role as a cardiac stimulant. The active substance is of chemical origin and is known by several synonyms, including norepinephrine bitartrate and levaterenol acid tartrate.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints related to the management of vasoplegic syndrome in patients undergoing cardiac surgery with extracorporeal circulation. The primary endpoint is the occurrence of a renal complication or death from the onset of vasoplegic syndrome until 7 days after. Renal complications are defined according to the KDIGO criteria for acute kidney failure (stage 1 or higher) and/or the initiation of renal replacement therapy.

Secondary endpoints include the occurrence of renal complications or death within 90 days, mortality within 90 days, and the occurrence of cardiac, digestive, and cerebral complications at specified timepoints (7, 30, and 90 days). Cardiac complications include arrhythmia requiring treatment, postoperative myocardial damage, myocardial infarction, and cardiorespiratory arrest. Digestive complications include mesenteric ischemia and ischemic colitis, while cerebral complications include stroke and delirium identified by the CAM-ICU test.

Additional secondary endpoints involve the number of patients requiring rescue norepinephrine, the total dose of norepinephrine used, and the Vasoactive Inotropic Score (VIS) at days 0, 1, 2, and 7. The length of stay in the ICU and hospital, the mean costs of these stays, and the incremental cost-effectiveness ratios at 90 days are also evaluated. These ratios are expressed as the cost per additional complication avoided, cost per additional year of life gained, and cost per additional healthy life-year gained with the vasopressin strategy compared to the norepinephrine strategy. The occurrence of hyponatremia and hypoperfusion of the extremities at day 7 is also monitored.