Clinical trial NCT06615102: Reducing Cardiac-surgery Associated Acute Kidney Injury Occurence by Administering Angiotensin II
Official title: A Prospective Angiotensin II Versus Noradrenaline Trial for Hypotension Management to Reduce Cardiac-surgery Associated Acute Kidney Injury (PAN-AKI)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Cardiac Surgery
Vasoplegia
Keywords: cardiac surgery
acute kidney injury
Angiotensin II
Lead sponsor: Universität Münster
Sponsor class: OTHER
Collaborators: name: German Research Foundation
First posted: 2024-09-26
Enrollment: 1022
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study intervention focuses on exploring the use of angiotensin II as a primary vasopressor compared to norepinephrine in cardiac surgery patients to investigate whether angiotensin II can reduce the occurrence of moderate/severe acute kidney injury (AKI). Despite its potential, as suggested by trials involving surgical patients, there is currently no human data confirming its effectiveness in preventing moderate/severe AKI in this context. The intervention aims to address this gap by evaluating angiotensin II's impact compared to norepinephrine.

Detailed description: Acute kidney injury (AKI) is defined by changes in serum creatinine and/or urine output, according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In cardiac surgical patients, the AKI rate is up to 30%, with 1-2% of the patients requiring renal replacement therapy (RRT). Cardiac-surgery associated AKI (CSA-AKI) is associated with increased short- and long-term morbidity and mortality as well as increased hospital costs.

Shock after cardiac surgery is also associated with increased mortality. In the context of cardiac surgery with the use of the cardiopulmonary bypass (CPB), sympathetic nervous system activation and cardiovascular instability are common sequelae. Vasoplegic syndrome is a form of distributive shock that is characterized by low arterial pressure, reduced systemic vascular resistance, and normal or elevated cardiac output. It occurs in 5 to 25% of the patients undergoing cardiac surgery. Patients with vasoplegic shock are at higher risk of organ failure, including AKI, and show increased mortality rates and longer hospital length of stays. Currently, norepinephrine is the established first-line vasopressor for the treatment of vasoplegic shock, but all vasopressors have adverse effects, including myocardial ischemia and arrhythmias. Moreover, in vasoplegic situations, vascular smooth muscle cells may become unresponsive to vasopressors. The underlying mechanisms are complex and include adrenoceptor desensitization, increased nitric oxide (NO) synthesis, activation of adenosine triphosphate-sensitive K+ channels, and vasopressin and corticosteroid deficiency.

Physiologically, the renin-angiotensin-aldosterone system (RAAS) is a hormone system that plays a central role in regulating blood pressure and fluid balance, glomerular filtration rate, and electrolyte levels. Renin, a proteolytic enzyme released by juxtaglomerular cells in response to hypotension, decreases sodium delivery to the distal tubule, activates the sympathetic nervous system, and cleaves angiotensinogen to angiotensin I which is a precursor of the vasoactive angiotensin II. RAAS is regulated by a biofeedback loop. Angiotensin II generation inhibits renin release, whereas renin levels increase when there is insufficient activation of the angiotensin II type 1 receptor. Administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) and reduced angiotensin II generation cause a corresponding increase in renin levels.

Despite numerous clinical trials using several interventions, a reliable means to prevent AKI remains elusive. Clinical trials focusing on surgical patients suggest that angiotensin II is a potent vasopressor. However, no human data exist whether the application of angiotensin II as a primary vasopressor reduces the occurrence of AKI in patients undergoing cardiac surgery.

Eligibility criteria: Inclusion Criteria:

1. Cardiac surgery using cardiopulmonary bypass including coronary artery bypass grafting (CABG) surgery, valve surgery, or combined CABG/valve surgery
2. Elevated risk of AKI as predicted by a score ≥ 1.5 on the following scale:

   1. hemoglobin \< 130g/l = 2
   2. creatinine \> 1.1 mg/dl = 2
   3. age \> 70 years =1.5
   4. New York Heart Association Classification (NYHA) 4 =1.5
   5. Body Mass Index (BMI) \> 30 =1.5
3. Adult ≥ 18 years
4. Written informed consent

Exclusion Criteria:

1. Major aortic surgery (aortic arch replacement), transplant surgery, pulmonary thrombendarterectomy, ventricular assist device placement
2. Already receiving inotropic/vasopressor support before surgery
3. Dialysis dependent
4. Pre-existing AKI within the last 30 days
5. Pre-existing chronic kidney injury with an eGFR\<20 ml/min/1.73m2
6. Pre-existing significant hypertension (persistent SBP \> 180mmHg)
7. Significant pulmonary hypertension (ePSAP \> 70mmHg, mPAP \> 40mmHg) with right ventricular systolic dysfunction (graded more severe than mild)
8. Hypersensitivity to the active substance or to any of the excipients
9. Pregnancy (a negative pregnancy test for women of childbearing age) or breastfeeding women
10. Persons with any kind of dependency on the investigator or employed by the sponsor/investigator
11. Participation in another interventional trial within the last three months that investigates kidney function

Primary outcomes:
measure: Rate of AKI KDIGO stage 2 or 3 or death within 72 hours after end of cardiac surgery.
timeFrame: 72 hours after end of surgery
Secondary outcomes:
measure: Major Adverse Kidney Events (MAKE90)
timeFrame: 90 after cardiac surgery
measure: Severity of Acute Kidney Injury
timeFrame: 72 hours after cardiac surgery
measure: Development or progression of chronic kidney injury
timeFrame: 90 to 120 days after cardiac surgery
Other outcomes:
measure: Use of additional open-label vasopressors or inotropes
timeFrame: within 72 h after cardiac surgery
measure: Volume of fluid application within the first 72 hours
timeFrame: within 72 h after cardiac surgery
measure: Volume status
timeFrame: within 72 h after cardiac surgery
measure: Time to death
timeFrame: 30 days after cardiac surgery
measure: Time to death
timeFrame: 60 days after cardiac surgery
measure: Time to death
timeFrame: 90 days after cardiac surgery
measure: Days alive and in (index) ICU
timeFrame: From start of intervention until 60 days after cardiac surgery
measure: Days alive and in (index) Hospital
timeFrame: From start of intervention until 60 days after cardiac surgery
measure: Incidence of adverse events (AEs) and serious AEs (SAEs)
timeFrame: From start of intervention until discharge / day 7
measure: Occurence of AKI according to the KDIGO criteria
timeFrame: From start of intervention unto 72 hours after cardiac surgery
measure: Number of patients with persistent renal dysfunction
timeFrame: On day 90 after cardiac surgery
measure: Number of patients with dialysis renal/replacement therapy
timeFrame: On day 90 after cardiac surgery
measure: Mortality
timeFrame: On day after cardiac surgery
measure: Dose of vasopressors
timeFrame: from start of surgery unto 72 hours after cardiac surgery
measure: Days alive and free of mechanical ventilation until day 60
timeFrame: From start of intervention unto 60 days after cardiac surgery
measure: Duration of mechanical ventilation
timeFrame: From start of intervention unto discharge from hospital or day seven after cardiac surgery (whatever comes first)
measure: Days alive and free of vasopressors and mechanical ventilation
timeFrame: From start of intervention unto 60 days after cardiac surgery
measure: Number of days alive and free of vasopressors and mechanical ventilation
timeFrame: From start of intervention until 28 days after cardiac surgery
measure: Change in total and individual organ failure scores through 72 hours
timeFrame: Start of intervention and 72 hours after cardiac surgery
measure: Duration of renal replacement therapy
timeFrame: From start of intervention unto 90 days after cardiac surgery
measure: Number of patients with renal replacement therapy
timeFrame: Day 90 after cardiac surgery
measure: Creatinine clearance on day one after cardiac surgery
timeFrame: 24 hours after cardiac surgery
measure: Incidence of documented new onset atrial fibrillation
timeFrame: From end of surgery to hospital discharge
measure: Occurrence of transient (&lt; 48 hours) and persistent (≥ 48 hours) AKI
timeFrame: From start of intervention to hospital discharge
measure: Identification and evaluation of biomarkers
timeFrame: From start of intervention to 48 hours after cardiac surgery
Locations:
Study officials:
affiliation: University Hospital Muenster, Dept. of Anesthesiology, Intensive Care Medicine and Pain Therapy
name: Alexander Zarbock, MD
role: PRINCIPAL_INVESTIGATOR
References: