SGLT2 Inhibitor TrEatment iN Patients Awaiting cOronary arTery bYpass Surgery to Reduce Post-opErative AF (STENOTYPE)

SGLT2 Inhibitor TrEatment iN Patients Awaiting cOronary arTery bYpass Surgery to Reduce Post-opErative Atrial Fibrillation and Kidney Injury (STENOTYPE Trial)

The goal of this randomized, double-blinded, controlled clinical trial is to investigate if treatment with an sodium-glucose cotransporter-2 inhibitor (SGLT2) during the unique time window before coronary artery bypass surgery (CABG), can reduce the incidence of post-operative atrial fibrillation and/or acute kidney injury in patients with chronic coronary syndrome. The main questions it aims to answer are:

• Does treatment with an SGLT2 inhibitor during the waiting time and stable post-operative period, in patients with chronic coronary syndrome scheduled for CABG, reduce the risk of new onset atrial fibrillation compared to placebo?
• Does treatment with an SGLT2 inhibitor during the waiting time and stable post-operative period, in patients with chronic coronary syndrome scheduled for CABG, reduce the risk of acute kidney injury before hospital discharge compared to placebo?

Participants will be administered dapagliflozin 10 mg once daily or placebo for a minimum of seven days while awaiting scheduled CABG and up until discharge, with a short interruption for surgery. The active arm will be compared to the placebo arm to see if dapagliflozin can reduce the incidence of post-operative atrial fibrillation and/or acute kidney injury.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation; Chronic Coronary Syndrome
• Intervention / Treatment: Drug: Dapagliflozin 10mg Tab; Drug: Placebo Tab

Detailed Description

Study centers: Up to 7 centers in Sweden, Denmark, and the Czech Republic.

Phase of development: III.

Objectives: In a multicenter, prospective, randomized, controlled clinical trial to compare dapagliflozin 10 mg once daily and placebo in preventing post-operative atrial fibrillation (AF) and acute kidney injury (AKI) in patients with chronic coronary syndrome undergoing coronary artery bypass surgery (CABG).

Methodology: Following informed consent, 800 participants are randomized in a 1:1 fashion to the intervention arm receiving a 10 mg tablet of dapagliflozin once daily and the comparator arm receiving a placebo tablet once daily for a minimum of 1 week while awaiting scheduled CABG surgery. Treatment will be terminated at the time of discharge from hospital after CABG surgery. Aside from a follow-up telephone call one week after discharge to collect safety data-and an on-site visit for type 2 diabetes patients-no extra monitoring or visits are included in the trial. Patients will be followed up 30 days and 12 months through national registries.

Primary endpoint: Incidence of new onset post-operative AF during hospitalization following CABG surgery.

Secondary endpoints:

Key secondary endpoint: AKI (as defined by at least a 1.5-fold increase from baseline in serum creatinine within the prior seven days, an absolute increase in serum creatinine of 26.5 µmol/L or more within 48 hours, or a urine volume of less than 0.5 mL/kg/h for at least six hours, following Kidney Disease Improving Global Outcomes grade 1 or above) in-hospital after CABG surgery.

Safety endpoint: The safety and tolerability of dapagliflozin will be evaluated by reporting adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse events (SUSARs) from the start of treatment until one week post-discharge.

Other secondary variables during hospitalization after CABG surgery include:

1. All-cause mortality; 2. Stroke; 3. New onset heart failure; 4. Ventricular arrhythmia; 5. Electrical cardioversion for AF; 6. Use of amiodarone for AF; 7. Change in inflammatory and cardiac biomarkers from baseline to three days after CABG surgery; 8. Change in HbA1c from baseline to three days after CABG surgery; 9. Length of intensive care unit and hospital stay.

Secondary variables after hospital discharge include:

1. 30-day all-cause mortality; 2. 12-month all-cause mortality; 3. 12-month myocardial infarction; 4. 12-month stroke; 5. 12-month hospital admission for AF or heart failure; 6.

12-month dialysis treatment.

All events will be adjudicated by an independent clinical endpoint committee.

Quality assurance: Sites will be monitored according to a specific study monitoring plan.

Before starting the clinical trial all centers will have a telephone/web-based start meeting with presentation of the study, study procedures and documentation. The first visit at site will be when the center has included some patients into the study. During the study period, monitors will have regular contact with the participating departments to ensure that the trial is conducted in compliance with the protocol and applicable regulatory requirements. The monitors will also provide information and support to the investigator(s). The monitors will review source documents for verification of consistency with the study data recorded in case report forms according to risk based monitoring. Investigators and other responsible personnel must be available during the monitoring visits, possible audits and inspections and should devote sufficient time to these processes. Patient recruitment status is continuous (updated every 24 hours on weekdays).

Reporting for adverse events: Registration of adverse events will start after informed consent and when treatment with study medication has been given and continue until the patient leaves the hospital after the CABG. The patients will be informed to contact the investigator or study nurse if any adverse event should occur during this timeframe.

Reporting procedures for Adverse Events and Serious Adverse Events: Only adverse events and serious adverse events that are not considered as signs and symptoms expected and related to CABG or known side effects from the study drug will be reported in this study. Events defined as endpoints in the study (e.g. all-cause death, stroke, new onset heart failure) will not be reported as adverse events. This means that other clinical signs and symptoms, which are reported by the patient and observed by the investigator, and in the opinion of the investigator are unexpected in relation to actual diagnosis, will be reported.

SUSAR reporting procedure: If the responsible investigator judges the SAE as being drug-related and unexpected the event must be reported to the sponsor within one working day. The documentation will be on a CIOMS form (http://www.cioms.ch/index.php/cioms-form-i). The sponsor is then responsible for reporting SUSAR to the regulatory authorities and ethics committee. The sponsor is also responsible for information to all involved investigators in the study.

A SUSAR resulting in death or judged as life threatening must be reported to regulatory authorities and ethics committee within 7 days after the sponsor has been notified about the event. A full report must be sent to the authorities within 15 days.

A SUSAR which is not resulting in death or is life threatening has to be reported to regulatory authorities and ethics committee within 15 days after the sponsor has been notified about the event. A full report has to be sent to the authorities as soon as possible.

Annual report: A safety report, including assessment of overall safety and all reported SUSARs will be submitted yearly to the Regulatory Authorities and if requested to the Ethics Committee.

Sample size: We assumed an incidence of post-operative AF of 22% in the control group and of 14% in the SGLT2 inhibitor group (a 36% relative decrease). With a power of 80% and alpha of 5%, a total of 361 subjects completing the trial in each of the two groups are required. To account for drop-outs, 400 subjects will be randomly assigned to each of the two groups.

Statistical analyses: All results will be reported and analyzed according to the intention-to-treat principle. Baseline characteristics will be reported by randomized treatment and overall. For continuous variables, we will report the frequency, mean and standard deviation, or median and interquartile range, as appropriate. For binary or categorical variables, the frequency and percentage will be reported. The number of missing values, if any, will be reported. The disposition of subjects in the trial, including the number randomized, the number lost to follow-up/withdrawn, and the number of subjects at each follow-up visit will be summarized in a CONSORT figure. For binary outcomes, we will report the number and percentage of subjects with the outcome by randomized group. A risk ratio and 95% confidence interval (CI) will be calculated and reported along with the corresponding p value from a chi-squared test or Fisher´s exact test, as appropriate. These include: incidence of AF before hospital discharge (primary endpoint); AKI before hospital discharge (key secondary endpoint); in-hospital all-cause mortality, and stroke, new onset heart failure, ventricular arrhythmia, electrical cardioversion for AF, and use of amiodarone for AF; 12-month dialysis treatment; reported AEs, SAEs, and SUSARs at one week post-discharge (safety endpoint). For continuous outcomes, we will report the frequency, mean, and standard error of the change from baseline by randomized group. The between-group difference in mean change from baseline and 95% CI will be estimated using a linear regression model including the baseline value and randomized treatment as covariates in the model. If the change from baseline is found to seriously violate the required assumption of normality, an appropriate transformation may be applied. These include: change in cardiac and inflammatory biomarkers from baseline to three days after CABG surgery, and change in HbA1c from baseline to three days after CABG surgery. For time-to-event outcomes, the number of subjects with the event and the cumulative percentage (estimated using the Kaplan-Meier method) will be reported by randomized group. Hazard ratios and 95% CIs will be estimated using a Cox proportional hazards model with randomized treatment included as the only covariate in the model, and a p value estimated using a log-rank test. These include: 30-day and 12-month all-cause mortality; 12-month myocardial infarction; 12-month stroke; 12-month hospital admission for AF or heart failure. The length of intensive care unit and hospital stay endpoint will be summarized by randomized group using the median and interquartile range. Geometric mean differences and 95% CIs will be estimated using Poisson or negative binomial regression models, as appropriate, including randomized treatment as a covariate in the model. Two-sided statistical significance levels of 5% will be used and all estimates will be presented with 95% confidence intervals. To account for the stratified randomization, the primary and key secondary endpoint analyses will be stratified by site.

Full detail of the statistical analysis will be described in a statistical analysis plan, which will be completed and signed before the final trial database is locked and unblinded. Any changes to the statistical analysis plan will be documented in amendments to the statistical analysis plan and will be signed off before the database is finalized and unblinded.

Interim Safety Analysis: A maximum of three months following inclusion of the first 100 patients an independent endpoint committee will monitor study endpoints. Variables to be assessed are all-cause death, AKI, dialysis, new onset AF, heart failure, and diabetic ketoacidosis. Premature termination of the study will be mandated in the event that one of the treatment strategies shows statistically significance at the 0.001 alpha level for the composite of the above variables.

• Study Type: Interventional
• Enrollment (Estimated): 800
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ole Fröbert, MD, PhD; Phone Number: 0046196025413; Email: ole.frobert@regionorebrolan.se
• Study Contact Backup: Name: Anna Björkenheim, MD, PhD; Phone Number: 0046196025459; Email: anna.bjorkenheim@regionorebrolan.se

Study Locations

• Czechia
  • Brno, Czechia
    • Not yet recruiting
    • St. Anne University Hospital
    • Contact: Ola Hlinomaz, MD, PhD; Email: ota.hlinomaz@fnusa.cz
• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark
    • Contact: Ivy SI Modrau, MD, PhD; Phone Number: +45 24778856; Email: ivymod@clin.au.dk
  • Copenhagen, Denmark
    • Not yet recruiting
    • Department of Cardiothoracic Surgery, Kobenhavn
    • Contact: Christian L Carranza, MD, PhD; Phone Number: +45 3545 8681; Email: christian.lildal.carranza@regionh.dk
  • Odense, Denmark
    • Not yet recruiting
    • Odense University Hospital
    • Contact: Hanne B Ravn, MD, PhD; Phone Number: +45 2372 5399; Email: Hanne.Berg.Ravn@rsyd.dk
• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Sahlgrenska University Hospital
    • Contact: Anders Jeppsson, MD, PhD; Phone Number: +46-31-3427515; Email: anders.jeppsson@vgregion.se
    • Contact: Entela Bollano, MD, PhD
  • Linköping, Sweden
    • Not yet recruiting
    • Linköping University Hospital
    • Contact: Sofia Sederholm Lawesson, MD, PhD; Email: Sofia.Sederholm.Lawesson@regionostergotland.se
  • Lund, Sweden
    • Recruiting
    • Skåne University Hospital
    • Contact: David Erlinge; Email: david.erlinge@skane.se
  • Örebro, Sweden, 70185
    • Recruiting
    • Department of Cardiology
    • Contact: Anna Björkenheim, MD, PhD; Phone Number: +46196025459 +46196025459; Email: anna.bjorkenheim@regionorebrolan.se
    • Sub-Investigator: Erik Sunnefeldt, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent.
• Patients aged 18 years or older.
• Chronic coronary syndrome scheduled for elective isolated CABG surgery with extra corporeal circulation, or elective CABG surgery with extra corporeal circulation combined with aortic valve replacement, mitral valve surgery, and / or aortic root surgery.

Exclusion Criteria:

• Treatment with an SGLT2 inhibitor within 8 weeks prior to enrolment or planned treatment.
• Intolerance, hypersensitivity, or other contraindications of dapagliflozin.
• Type 1 diabetes mellitus.
• Symptomatic hypotension or systolic blood pressure <95 mmHg at two out of three measurements at enrolment.
• Current acute decompensated heart failure or hospitalization due to decompensated heart failure <4 weeks prior to enrolment.
• Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, or hypertrophic cardiomyopathy.
• Implantation or intent to implant a cardiac resynchronization device within 12 weeks prior to enrolment.
• Stroke or transient ischemic attack within 12 weeks prior to enrolment.
• Symptomatic bradycardia or second or third-degree atrioventricular block without pacemaker treatment.
• Any condition such as, but not limited to, malignancy, with a life expectancy of <2 years based on the investigator's clinical judgement.
• Hepatic impairment (aspartate transaminase or alanine transaminase >3 × the upper limit of normal, or total bilirubin >2 × upper limit of normal at the time of enrolment).
• Severe (estimated glomerular filtration rate < 25 mL/min/1.73 m2), unstable, or rapidly progressing renal disease at the time of enrolment.
• CABG surgery planned within one week.
• Emergency surgery with hemodynamic instability.
• Previous history of AF.

• Women of childbearing potential (i.e., those who are fertile, following menarche and until becoming post-menopausal, unless permanently sterile*)

  1. Who are not willing to use a highly effective method of contraception** judged by the investigator, from the time of signing the informed consent throughout the trial and 4 weeks thereafter, OR
  2. Who have a positive pregnancy test at enrolment or randomization, OR
  3. Who are breast-feeding.
• Participation or recent participation in a clinical trial with an investigational medicinal product within 30 days before randomization.
• Previous randomization in the STENOTYPE trial.
• Previous (within 30 days) or concomitant participation in another clinical trial with an investigational product. Registries and observational studies are allowed.
• Mental inability, reluctance, or language difficulties of the subject, in the opinion of the investigator, that result in difficulty in understanding the meaning of participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active arm; Treatment with dapagliflozin 10 mg once daily.	Drug: Dapagliflozin 10mg Tab; Dapagliflozin once daily for a minimum of seven days while awaiting scheduled CABG and up until discharge with a short interruption for surgery.; Other Names: Forxiga; Farxiga
Placebo Comparator: Placebo arm; Treatment with matching placebo once daily.	Drug: Placebo Tab; Matching placebo once daily for a minimum of seven days while awaiting scheduled CABG and up until discharge with a short interruption for surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of new onset post-operative atrial fibrillation of at least 30 seconds	ECG or telemetry	From CABG to discharge post-operatively up to four weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in glycated haemoglobin	Change from baseline to 3 days after CABG	Baseline and 3 days after CABG surgery
Mortality	Death	30 days after CABG surgery
All-cause death	Death by any cause	12 months after CABG surgery
Stroke	Ischemic stroke including transient ischemic attack	12 months after CABG surgery
Acute kidney injury	Defined as at least a 1.5-fold increase from baseline in serum creatinine within the prior 7 days, an absolute increase in serum creatinine of 26.5 µmol/L, or a urine volume of less than 0.5 mL/kg/h for at least six hours, following Kidney Disease Improving Global Outcomes grade 1 or above before discharge. Key secondary outcome.	From CABG to discharge post-operatively up to four weeks
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Reported AEs, SAEs, and SUSAR	Start of treatment until one-week post-discharge up to 26 weeks
All-cause mortality	Death	From CABG to discharge post-operatively up to four weeks
New onset heart failure	Diagnosis of heart failure for the first time.	From CABG to discharge post-operatively up to four weeks
Stroke	Ischemic stroke including transient ischemic attack	From CABG to discharge post-operatively up to four weeks
Treatment of AF with electrical cardioversion	Electrical cardioversion to treat AF during hospitalization post-operatively, yes or no	From CABG to discharge post-operatively up to four weeks
Treatment of AF with amiodarone	Administration of amiodarone to manage AF during hospitalization post-operatively, yes or no	From CABG to discharge post-operatively up to four weeks
Ventricular arrhythmias	Occurence of ventricular tachycardia (sustained and non-sustained), ventricular fibrillation, or torsade de pointes identified via ECG during hospitalization post-operatively, yes or no	From CABG to discharge post-operatively up to four weeks
Change in cardiac biomarkers	Blood sampling for change in troponin I and N-terminal pro-B-type natriuretic peptide	Baseline and 3 days after CABG surgery
Change in inflammatory biomarkers	Blood sampling for change in interleukin 1 and 6, tumor necrosis factor α, high-sensitivity C-reactive protein	Baseline and 3 days after CABG surgery
Length of hospital stay	Days	From CABG to discharge post-operatively up to four weeks
Length of intensive care unit stay	Days	From CABG to discharge from intensive care unit up to four weeks
Myocardial infarction	Occurence of myocardial infarction	12 months after CABG surgery
Hospital admission with atrial fibrillation, heart failure, or dialysis treatment	Hospital admission	12 months after CABG surgery

Collaborators and Investigators

• Sponsor: Region Örebro County
• Collaborators: London School of Hygiene and Tropical Medicine; Odense University Hospital; Göteborg University; Aarhus University Hospital; Icahn School of Medicine at Mount Sinai; Rigshospitalet, Denmark; University of Leeds; University Hospital, Linkoeping; Örebro University, Sweden; Mount Sinai Hospital, New York; Skane University Hospital; St. Anne's University Hospital Brno, Czech Republic; Sahlgrenska University Hospital
• Investigators: Principal Investigator: Anna Björkenheim, MD, PhD, VO Hjärt- lungmedicin och klinisk fysiologi USÖ

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2024
• Primary Completion (Estimated): December 4, 2027
• Study Completion (Estimated): December 4, 2028

Study Registration Dates

• First Submitted: April 24, 2023
• First Submitted That Met QC Criteria: May 9, 2023
• First Posted (Actual): May 10, 2023

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: April 4, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Atrial fibrillation; Acute Kidney Injury; Coronary artery bypass grafting
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Sodium-Glucose Transporter 2 Inhibitors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Dapagliflozin
• Other Study ID Numbers: 277998

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Demographic Data: Age, sex, ethnicity. Baseline Data: Initial health status, medical history. Outcome Data: Primary and secondary outcomes measured during the trial. Adverse Events: Any side effects or adverse events recorded. Follow-up Data: Information collected during follow-up.
• IPD Sharing Time Frame: Data will be available upon reasonable request starting after the publication of the main results and will remain available for 5 years.
• IPD Sharing Access Criteria: Access to the anonymized dataset will be granted upon request to qualified researchers who provide a methodologically sound proposal. The proposal must be approved by the study's principal investigator and a data access agreement must be signed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No