proMoting Effective Renoprotection in Cardiac sURgery Patients by Inhibition of SGLT-2

Study Overview
=================
Brief Summary
-----------------
Multi-centre, triple-blinded (patients, physicians, investigators), parallel-group, balanced (1:1), stratified (male-female 50-50), randomized, controlled (placebo), phase IV clinical trial to investigate the potential of preoperative initiation (from day 1 before surgery) and perioperative continuation (until day 2 after surgery) of the SGLT2 inhibitor dapagliflozin 10 mg once daily to prevent AKI according to the KDIGO criteria (an increase in serum creatinine by 0.3 mg/dl (26.5 mmol/l) within 48 hours; or an increase in serum creatinine to 1.5 times baseline, within 7 days; or a urine output <0.5 ml/kg/h for >6 hours) in adult (>18 years old) patients undergoing cardiopulmonary bypass surgery.

Detailed Description
-----------------
Background of the study: Acute kidney injury is one of the most common complications after cardiac surgery. The new glucose-lowering therapy, sodium glucose transport protein 2 inhibitors (SGLT2i) possess renoprotective properties in people with chronic kidney disease in the presence or absence of type 2 diabetes. Large cardiovascular outcome trials in patients with diabetes observed a lower incidence of acute kidney injury. However, these studies were not powered to investigate this nor did acute kidney injury concern an adjudicated endpoint. Objective of the study: To investigate the potential of preoperative initiation (from day 1 before surgery) and perioperative continuation (until day 2 after surgery) of the SGLT2 inhibitor dapagliflozin 10 mg once daily to prevent AKI according to the KDIGO criteria in patients undergoing cardiopulmonary bypass surgery. Study design: Multi-centre, triple-blinded (patients, physicians, investigators), parallel-group, balanced (1:1), stratified (male-female 50-50), randomized, controlled (placebo), phase IV clinical trial. Study population: Patients undergoing cardiac surgery, aged >18 years-old. Intervention: Participants receive 10 mg dapagliflozin once daily or matching placebo starting 1 day prior to surgery and continued until two days postoperatively (four doses). Primary outcome of the study: Incidence of AKI occurring in 7 days after surgery, according to KDIGO criteria, defined as an increase in serum creatinine by 0.3 mg/dl (26.5 mmol/l) within 48 hours; or an increase in serum creatinine to 1.5 times baseline, within 7 days; or a urine output <0.5 ml/kg/h for >6 hours. Secondary outcomes of the study: Incidence of Stage 3 AKI. Postoperative change of eGFR. Postoperative Atrial Fibrillation for which treatment is initiated. Length of Stay in the Intensive Care Unit. Length of Stay in hospital. MAKE: Major Adverse Kidney Events MACE: Major Adverse Cardiovascular Events Patient-reported quality of recovery 1: DAH30: Days at Home in first 30 days Patient-reported quality of recovery 2: WHO-DAS 2.0: World Health Organisation Disability Assessment Schedule 2.0 Patient-reported quality of recovery 3: EQ5D5L: 5 level EuroQol 5D questionnaire. Safety outcomes: incidence of genital mycotic infections, diabetic keto-acidosis, hypoglycaemia, postoperative complications and Serious Adverse Events (SAEs). Productivity costs Healthcare costs Hyperglycaemia (> 10 mmol/l) Hypoglycaemia (< 4 mmol/l) Heart Rate Mean Arterial Pressure Cardiac Output Peak postoperative Troponin Peak postoperative CK-MB Postoperative Left Ventricular Function Nature and extent of the burden and risks associated with participation, benefit and group relatedness: General trial-related burden: The investigators will withdraw 4.5 mL of blood at one day before surgery and one day postoperatively for biomarker analysis. No extra venepunctures are required, as these measurements coincide with routine clinical care. Intervention group-related burden: Participants will be asked to take either 1 tablet of 10 mg dapagliflozin once daily from 1 days before surgery until 2 days postoperative (including the day of surgery, four doses total) or a matching placebo regimen. Patients randomized to dapagliflozin will run a small risk of treatable side effects related to the study drug. These are rare for short-term treatments. Participants will be informed about the following side effects: Genital mycotic infections: these usually only occur after longer-term use of SGLT2 inhibitors. In this study, patients will only receive this medication for up to 10 doses. Treatment of this side effect is straightforward with antifungal treatment. Euglycemic ketoacidosis: a lowering of the pH in the blood through the build-up of ketones. This has been described in patients on long-term treatment and is ascribed to altered insulin sensitivity through increased glucose loss by SGLT2 inhibition. For this and other reasons, patients with type 1 diabetes mellitus and patients with type 2 diabetes mellitus and a body mass index <25 kg/m2 are excluded from this trial. We will monitor perioperative glucose and pH levels in all participants according to routine perioperative care. In addition, patients using insulin therapy will receive a perioperative glucose/insulin infusion, which suppresses ketone production. Should keto acidosis occur in any other patient, treatment is straightforward with a glucose-insulin infusion. Hypoglycemia: only patients with diabetes mellitus using sulfonylurea or insulin are at risk, according to previous research. To prevent this side effect: patients will receive an individualized adaptation of their glucose-lowering medication by the investigator team. To treat this side effect, blood glucose will be monitored in all patients according to standard perioperative cardiac surgery care and hypoglycaemia treatment protocols with urgent administration of intravenous glucose are in place. Risk-benefit: There is solid evidence to support that SGLT2 inhibitors offer kidney protection. Acute kidney injury is a common complication after cardiac surgery. The investigator's hypothesis is, therefore, that patients in the intervention group will receive protection against acute kidney injury. In addition, the results from this trial could lead to the improvement of care and protection of future patients undergoing cardiac surgery. The side-effect profile of dapagliflozin is mild, and participants will be intensively monitored in this study. Therefore, the investigators estimate that the benefits outweigh the risks of participation in this trial. Relevance and intended applications: The aim of this study is to determine whether SGLT2i can reduce the incidence of AKI following cardiac surgery. Based on the results of this trial, SGLT2 inhibitors can be applied as a standard prophylactic treatment in cardiac surgery patients to prevent AKI. Sample size: The investigators expect an incidence of AKI in the placebo group of 22%, as a conservative estimation, based on previous cohorts. Large outcome trails found a relative risk reduction for AKI of 0.64 with SGLT2 inhibition. This translates into an absolute risk reduction of 7.9% and an expected incidence in the intervention group of 14.1%. The required total sample size to find such a difference based on Fisher Exact test, with two-sided alpha at 0.05 and 80% power is 784. Therefore, the aim is to include 392 patients per arm. Keywords: SGLT2i; Acute Kidney Injury (AKI); Cardiac Surgery

Official Title
-----------------
Preoperative Sodium Glucose Cotransporter 2 Inhibitors for Prevention of Postoperative Acute Kidney Injury in Cardiac Surgery Patients - a Randomized, Placebo-controlled, Multi-centre, Phase IV Clinical Trial

Conditions
-----------------
Acute Kidney Injury, Cardiac Surgery, Sodium-Glucose Transporter 2 Inhibitor

Intervention / Treatment
-----------------
* Drug: Dapagliflozin 10 MG Oral Tablet [Farxiga]
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: > 18 years-old Undergoing elective cardiac surgery. Providing informed consent Exclusion Criteria: Current treatment with SGLT2 inhibitors Reduced kidney function at baseline with eGFR < 20 ml/min at time of inclusion Diabetes Mellitus Type 1 History of diabetic keto acidosis Diabetes Mellitus Type 2 with BMI<25 for people with type 2 diabetes who are using multiple daily insulin injections (both short and long-acting insulin) Systolic blood pressure < 100 mmHg at time of inclusion Emergency surgery, defined as in need of surgery for medical reasons < 7 days, i.e. S1-4 according to the Amsterdam UMC classification Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods Known or suspected allergy to trial products or other drugs in the same class

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Dapagliflozin 10 mg | Drug: Dapagliflozin 10 MG Oral Tablet [Farxiga]<br>* One oral tablet, once daily starting one day prior to surgery and continued until two days postoperatively (four doses).<br>* Other names: Sodium glucose co-transporter-2 inhibitor;|
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Placebo<br>* One oral tablet, once daily starting one day prior to surgery and continued until two days postoperatively (four doses).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AKI | Incidence of Acute Kidney Injury (AKI) occurring in 7 days after surgery, according to KDIGO criteria, defined as an increase in serum creatinine by 0.3 mg/dl (26.5 mmol/l) within 48 hours; or an increase in serum creatinine to 1.5 times baseline, within 7 days; or a urine output <0.5 ml/kg/h for >6 hours. | Recorded daily until day 7 postoperatively or until discharge from hospital (earlier). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AKI-3 | Incidence of Stage 3 AKI according to KDIGO (Kidney Disease Improving Globel Outcomes) criteria. | Recorded daily until day 7 postoperatively or until discharge from hospital (earlier). | 
| eGFR | Postoperative maximum change of estimated Glomerular Filtration Rate (eGFR) compared to the baseline eGFR. | Recorded daily until day 7 postoperatively or until discharge from hospital (earlier). | 
| AF | Postoperative Atrial Fibrillation (AF) defined as any episode for which treatment is initiated. | Recorded daily until day 7 postoperatively or until discharge from hospital (earlier). | 
| LoS-ICU | Length of Stay in the Intensive Care Unit (LoS-ICU), measured in days from transfer to ICU. | Recorded on day of discharge from ICU, assessed up to 30 days. | 
| LoS-Hos | Length of Stay in the Hospital, measured in days from admission to hospital. | Recorded on day of discharge from the hospital, assessed up to 30 days. | 
| MAKE | Major Adverse Kidney Events (MAKE). Composite endpoint of death, new dialysis, and worsened renal function. | Within 30 days postoperatively. | 
| MACE | Major Adverse Cardiovascular Events (MACE). Composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal ischaemic cerebral vascular accident (iCVA) and hospitalization for heart failure. | Within 30 days postoperatively. | 
| QoR 1: DAH30 | Patient-reported quality of recovery, according DAH30: Days at Home in first 30 days. | Recorded at 30 days postoperatively. | 
| QoR 2: WHODAS2 | Patient-reported Quality of Recovery (QoR), according to World Health Organisation Disability Assessment Schedule 2.0 (WHO-DAS2.0). Summarized in a score between 0 - 100 with 0 being the best score (no disability) and 100 the worst (maximal disability). | Recorded at 30 days postoperatively. | 
| QoR 3: EQ5D5L | Patient-reported Quality of Recovery (QoR), according to 5 level EuroQol 5D questionnaire (EQ5D5L): a standardised measure of health status developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal. Summarized in a score between 0 - 1 with 0 being the best score (no disability) and 1 the worst (maximal disability). | Recorded at 30 days postoperatively. | 
| Safety outcomes | Genital mycotic infections, diabetic keto-acidosis, and hypoglycaemia, in addition to incidence of postoperative complications and Serious Adverse Events (SAEs) | Within 30 days postoperatively. | 
| Health care costs | Healthcare costs will be objectified to weigh cost-effectiveness, using the iMCQ: IMCQ: IMTA (Institute for Medical Technology Assessment) Medical Consumption Questionnaire | Recorded at 30 days postoperatively. | 
| Productivity costs | Productivity costs will be objectified to weigh cost-effectiveness, using the iPCQ: IMTA (Institute for Medical Technology Assessment) Productivity Cost Questionnaire | Recorded at 30 days postoperatively. | 
| Hypoglyceamia | Incidence of hypoglycaemia (blood glucose < 4 mmol/l) detected during routine peri-operative glucose measurements. | From admission to hospital until day 3 postoperatively. | 
| Hyperglyceamia | Incidence of hyperglycaemia (blood glucose > 10 mmol/l) detected during routine peri-operative glucose measurements. | From admission to hospital until day 3 postoperatively. | 
| Haemodynamics 1: HR | Peri-operative hourly average heart rate (HR, beats per minute) from the start of anaesthesia until discharge from the Intensive Care Unit. | From start of anaesthesia until discharge from the Intensive Care Unit, assessed up to 72 hours. | 
| Haemodynamics 2: MAP | Peri-operative hourly average mean arterial blood pressure (MAP, mmHg) from start of anaesthesia until discharge from the Intensive Care Unit. | From start of anaesthesia until discharge from the Intensive Care Unit, assessed up to 72 hours. | 
| Haemodynamics 3: CO | Peri-operative average hourly cardiac output (CO, l/min) from start of anaesthesia until discharge from the Intensive Care Unit. | From start of anaesthesia until discharge from the Intensive Care Unit, assessed up to 72 hours. | 
| Cardiac biomarker 1: Troponin | Peak troponin concentration, routinely measured during clinical practice. | From transfer to ICU until 48 hours postoperatively. | 
| Cardiac biomarker 2: CK-MB | Peak CK-MB concentration, as routinely measured during clinical practice. | From transfer to ICU until 48 hours postoperatively. | 
| Postoperative LVF | Qualitative assessment (categorised as normal, or mildly, moderately or severely reduced function) of left ventricular function (LVF) as noted by the echocardiographer for routinely performed postoperative echocardiography performed during routine follow-up. | Within 30 days postoperatively. |