Clinical trial NCT05590143: proMoting Effective Renoprotection in Cardiac sURgery Patients by Inhibition of SGLT-2
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Acute Kidney Injury
Cardiac Surgery
Sodium-Glucose Transporter 2 Inhibitor
Keywords: Cardiac Surgery
Acute Kidney Injury
SGLT2i
Dapagliflozin
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2022-10-21
Enrollment: 784
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Multi-centre, triple-blinded (patients, physicians, investigators), parallel-group, balanced (1:1), stratified (sex, type 2 diabetes mellitus), 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 (sex, type 2 diabetes mellitus), 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:

1. Incidence of Stage 3 AKI.
2. Postoperative change of eGFR.
3. Postoperative Atrial Fibrillation for which treatment is initiated.
4. Length of Stay in the Intensive Care Unit.
5. Length of Stay in hospital.
6. MAKE: Major Adverse Kidney Events
7. MACE: Major Adverse Cardiovascular Events
8. Patient-reported quality of recovery 1: DAH30: Days at Home in first 30 days
9. Patient-reported quality of recovery 2: WHO-DAS 2.0: World Health Organisation Disability Assessment Schedule 2.0
10. Patient-reported quality of recovery 3: EQ5D5L: 5 level EuroQol 5D questionnaire.
11. Safety outcomes: incidence of genital mycotic infections, diabetic keto-acidosis, hypoglycaemia, postoperative complications and Serious Adverse Events (SAEs).
12. Productivity costs
13. Healthcare costs
14. Hyperglycaemia (\> 10 mmol/l)
15. Hypoglycaemia (\< 4 mmol/l)
16. Heart Rate
17. Mean Arterial Pressure
18. Cardiac Output
19. Peak postoperative Troponin
20. Peak postoperative CK-MB
21. Postoperative Left Ventricular Function
22. Urinary oxygenation (patients included at Amsterdam UMC only)

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:

1. 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.
2. 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.
3. 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

Eligibility criteria: Inclusion Criteria:

1. \> 18 years-old
2. Undergoing elective cardiac surgery.
3. Providing informed consent

Exclusion Criteria:

1. Current treatment with SGLT2 inhibitors
2. Reduced kidney function at baseline with eGFR \< 20 ml/min at time of inclusion
3. Diabetes Mellitus Type 1
4. History of diabetic keto acidosis
5. 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)
6. Systolic blood pressure \< 100 mmHg at time of inclusion
7. Emergency surgery, defined as in need of surgery for medical reasons \< 7 days, i.e. "S1-4" according to the Amsterdam UMC classification
8. Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods
9. Known or suspected allergy to trial products or other drugs in the same class

Primary outcomes:
measure: AKI
timeFrame: Recorded daily until day 7 postoperatively or until discharge from hospital (earlier).
Secondary outcomes:
measure: AKI-3
timeFrame: Recorded daily until day 7 postoperatively or until discharge from hospital (earlier).
measure: eGFR
timeFrame: Recorded daily until day 7 postoperatively or until discharge from hospital (earlier).
measure: AF
timeFrame: Recorded daily until day 7 postoperatively or until discharge from hospital (earlier).
measure: LoS-ICU
timeFrame: Recorded on day of discharge from ICU, assessed up to 30 days.
measure: LoS-Hos
timeFrame: Recorded on day of discharge from the hospital, assessed up to 30 days.
measure: MAKE
timeFrame: Within 30 days postoperatively.
measure: MACE
timeFrame: Within 30 days postoperatively.
measure: QoR 1: DAH30
timeFrame: Recorded at 30 days postoperatively.
measure: QoR 2: WHODAS2
timeFrame: Recorded at 30 days postoperatively.
measure: QoR 3: EQ5D5L
timeFrame: Recorded at 30 days postoperatively.
measure: Safety outcomes
timeFrame: Within 30 days postoperatively.
measure: Health care costs
timeFrame: Recorded at 30 days postoperatively.
measure: Productivity costs
timeFrame: Recorded at 30 days postoperatively.
measure: Hypoglyceamia
timeFrame: From admission to hospital until day 3 postoperatively.
measure: Hyperglyceamia
timeFrame: From admission to hospital until day 3 postoperatively.
measure: Haemodynamics 1: HR
timeFrame: From start of anaesthesia until discharge from the Intensive Care Unit, assessed up to 72 hours.
measure: Haemodynamics 2: MAP
timeFrame: From start of anaesthesia until discharge from the Intensive Care Unit, assessed up to 72 hours.
measure: Haemodynamics 3: CO
timeFrame: From start of anaesthesia until discharge from the Intensive Care Unit, assessed up to 72 hours.
measure: Cardiac biomarker 1: Troponin
timeFrame: From transfer to ICU until 48 hours postoperatively.
measure: Cardiac biomarker 2: CK-MB
timeFrame: From transfer to ICU until 48 hours postoperatively.
measure: Postoperative LVF
timeFrame: Within 30 days postoperatively.
measure: Urinary Oxygenation (Amsterdam UMC only)
timeFrame: From end to start of surgery and from transfer to ICU until discharge or 48 hours postoperatively.
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: OLVG
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Nieuwegein
country: Netherlands
facility: St Antonius Hospital
Study officials:
affiliation: Internal Medicine Specialist
name: Daniël H. van Raalte, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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citation: Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: A systematic review and meta-analysis. PLoS Med. 2019 Dec 9;16(12):e1002983. doi: 10.1371/journal.pmed.1002983. eCollection 2019 Dec.
citation: Gilbert RE, Thorpe KE. Acute kidney injury with sodium-glucose co-transporter-2 inhibitors: A meta-analysis of cardiovascular outcome trials. Diabetes Obes Metab. 2019 Aug;21(8):1996-2000. doi: 10.1111/dom.13754. Epub 2019 May 24.