Timing of Empagliflozin in Primary PCI: Pre-Reperfusion Versus Post-Reperfusion Versus Placebo in South Asian STEMI Patients

Primary PCI opens blocked heart arteries during a heart attack but can cause additional injury when blood flow returns. This is called reperfusion injury and accounts for up to half of the final heart damage. No drug given at the time of this procedure has been proven to reduce this injury in routine practice.

Laboratory studies suggest empagliflozin, a drug approved for diabetes and heart failure, may protect the heart when given before blood flow is restored. It may work by reducing harmful chemical changes inside heart cells, protecting mitochondria, and lowering inflammation. However, it is not known if empagliflozin must be given before the procedure to work, or if giving it afterward works just as well. Prior large studies gave empagliflozin days after heart attacks and could not test this question. Smaller pre-procedure studies had mixed results.

This trial answers one main question: does the timing of empagliflozin matter for protecting the heart during a heart attack? It compares giving the drug before the procedure, within 2 hours after the procedure, or a placebo. This is a Phase II trial designed to provide information needed to plan a larger future trial.

The trial enrolls 480 South Asian adults aged 18 to 75 having their first heart attack and scheduled for primary PCI within 12 hours of symptom onset. Participants are randomly assigned to one of three groups. Group A receives empagliflozin 25 mg before the procedure and placebo afterward. Group B receives placebo before and empagliflozin 25 mg within 2 hours after successful PCI. Group C receives placebo at both times. All groups continue study pills once daily for 90 days. The double-dummy design keeps participants and researchers unaware of group assignments.

Blood samples are taken at the procedure and at 6, 12, 24, and 48 hours afterward. These are sent to a central lab to measure troponin, a protein released when heart muscle is damaged. The total troponin released over 48 hours is the main measure of heart injury. Additional blood tests measure other heart function and inflammation markers.

Echocardiograms, ultrasound images of the heart, are done at Day 3, Day 30, and Day 90 to measure how well the heart pumps blood. At least 120 participants at CMR-capable sites will have a cardiac MRI between Day 3 and Day 5 to confirm troponin findings.

A substudy measures empagliflozin levels in the blood at balloon inflation in all Group A participants. A smaller group has additional blood samples over 24 hours to study drug absorption. These measurements test whether higher drug levels at balloon inflation lead to lower heart injury.

The trial takes place at five heart centres in Pakistan: Peshawar Institute of Cardiology, Lady Reading Hospital, Rehman Medical Institute, and Hayatabad Medical Complex in Peshawar, and Kulsoom International Hospital in Islamabad.

An independent Data Safety Monitoring Board reviews safety at three points during the trial, checking for kidney problems, diabetic ketoacidosis, infections, or other serious side effects. The trial has rules to stop or pause if safety issues arise.

Enrollment runs from August 2026 to May 2027. Each participant is followed for 90 days, with final follow-up completed by August 2027. Results are expected by September 2027.

Primary analysis uses ANCOVA, accounting for differences such as heart attack location, diabetes, symptom duration, and hospital. A fixed-sequence testing hierarchy controls for false positive findings: Arm A compared to Arm C first, then Arm A to Arm B, then Arm B to Arm C.

Inclusion criteria

• Age 18-75 years at presentation.
• South Asian ethnicity (Pakistani, Indian, Bangladeshi, Sri Lankan, or Nepali origin).
• First STEMI: ST-elevation ≥1 mm in ≥2 contiguous limb leads, or ≥2 mm in ≥2 contiguous precordial leads, or new LBBB with consistent presentation.
• Symptom onset to hospital arrival ≤12 hours.
• Scheduled for primary PCI with intent to perform balloon inflation and stenting.
• eGFR ≥45 mL/min/1.73m² (CKD-EPI) from point-of-care creatinine at presentation.
• Able to take oral medication (or crushed tablet with water), swallowing ability confirmed by treating nurse.
• Written informed consent from patient or legally authorised representative

Exclusion criteria

• Cardiogenic shock at presentation (Killip IV: SBP <90 mmHg despite volume, requiring vasopressors, IABP, or mechanical circulatory support).
• Type 1 diabetes mellitus.
• SGLT2 inhibitor use within 3 months of presentation.
• Active urinary tract infection or genital mycotic infection.
• eGFR <45 mL/min/1.73m² at presentation.
• Severe hepatic impairment (Child-Pugh Class C).
• Known hypersensitivity to empagliflozin or any SGLT2 inhibitor.
• History of diabetic ketoacidosis (euglycaemic or classical) at any time.
• Pregnancy, breastfeeding, or refusal of contraception (women of childbearing potential).
• Prior myocardial infarction or prior coronary revascularisation.
• Left main culprit artery as the infarct-related vessel.
• Rescue PCI after fibrinolysis in the current presentation.
• Severe multivessel disease with anticipated need for urgent CABG within 48 hours.
• Cardiac arrest with coma (GCS <8) at presentation consent not obtainable and metabolic state unpredictable.
• Significant metabolic abnormality precluding oral drug: severe vomiting, nil-by-mouth status, or frank dehydration with SBP <100 mmHg on arrival.
• Concurrent participation in another interventional clinical trial.
• Life expectancy <6 months from a non-cardiac cause.
• Expected inability to attend the 90-day follow-up visit.