Combined Antioxidant Therapy for Acute Myocardial Infarction

Acute myocardial infarction (AMI) remains as a leading cause of morbidity and mortality worldwide. In patients with ST-segment elevation myocardial infarction (STEMI), early reperfusion with primary percutaneous coronary intervention (PCI) is the standard treatment to limit myocardial injury. However, reperfusion induces additional damage, referred to as ischemia-reperfusion injury (IRI), which has been estimated to account for up to 50% of final infarct size. Oxidative stress is a key mechanism in IRI and contributes to lipid peroxidation, inflammation, and regulated cell death pathways. Prior pharmacologic approaches directed at single components of this process have shown limited and inconsistent clinical benefit, supporting evaluation of multitarget strategies.

This study is a phase II, randomized, double-blind, placebo-controlled, parallel-group superiority trial designed to evaluate the efficacy and safety of a combined antioxidant therapy (CAT) in patients with acute STEMI undergoing primary PCI. CAT consists of ascorbate, N-acetylcysteine, and deferoxamine. These agents were selected to target complementary mechanisms relevant to IRI: reactive oxygen species scavenging, glutathione replenishment, redox modulation and inflammatory response, and iron chelation with inhibition of iron-dependent lipid peroxidation. The study will randomly assign participants in a 1:1 ratio to receive CAT or matching placebo in addition to guideline-based STEMI treatment.

The intervention will be initiated before reperfusion and maintained during primary PCI in order to ensure drug exposure during the early reperfusion phase. Both groups will receive standard-of-care treatment for STEMI, including primary PCI and guideline-directed medical therapy.

The trial is designed as a signal-seeking phase II study using infarct size as the primary efficacy endpoint. Infarct size measured by cardiac magnetic resonance (CMR) is a mechanistically relevant endpoint in cardioprotection trials and has established prognostic value. In this study, CMR will be performed during the index hospitalization to quantify infarct size as a percentage of left ventricular mass. Additional imaging variables, myocardial injury biomarkers, oxidative stress and inflammatory biomarkers, pharmacokinetic measurements, short-term clinical outcomes, and safety data will be collected to support interpretation of the primary analysis. These assessments include left ventricular systolic function, hs-cTnI, CK, CK-MB, plasma concentrations of the study drugs, and 30-day follow-up for clinical events and adverse events.

The planned sample size is 46 participants. The study is powered to detect a large between-group difference in infarct size, consistent with its exploratory phase II design. Accordingly, the trial is intended to determine whether CAT demonstrates a sufficiently large efficacy signal, together with an acceptable safety profile, to support further evaluation in a larger trial.

Safety monitoring will include systematic collection of adverse events and serious adverse events during hospitalization and through day 30. Events will be recorded using Medical Dictionary for Regulatory Activities (MedDRA) terminology.

This trial will provide phase II data on the efficacy, safety, pharmacokinetics, and mechanistic effects of a multitarget antioxidant strategy administered during primary PCI in patients with STEMI.

• Combined antioxidant therapy (Drug): Combined Antioxidant Therapy consisting of ascorbate, N-acetylcysteine and deferoxamine
• Placebo (Drug): Matching placebo infusion administered before reperfusion and during primary PCI.

Primary outcomes

• Infarct Size [3-7 days after Primary Coronary Intervention]: Infarct size by CMR: infarct size will be expressed as a percentage of left ventricular (LV) mass (%LV). Infarct size will be measured using late gadolinium enhancement with manual contouring.

Secondary outcomes

• Cardiac Function and structure by CMR [3-7 days after Primary Percutaneous Coronary Intervention]: Left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular mass measured by cardiac magnetic resonance imaging.
• Cardiac function by Transthoracic echocardiography [Before hospital discharge, approximately 3-7 days after Primary Percutaneous Coronary Intervention]: Left ventricular systolic and diastolic function parameters, regional wall motion abnormalities, cardiac chamber sizes, and right ventricle systolic function
• Myocardial Injury Biomarkers [Samples will be obtained at baseline (prior to infusion), immediately after Primary Percutaneous Coronary Intervention (PCI), and at 12 hours, 24 hours, and 48 hours after PCI.]: High sensitivity cardiac Troponin I, creatine kinase (CK), and CK-MB. For each biomarker, peak value, area under the curve (AUC 0-48 hours), and change from baseline will be assessed.
• Biomarkers of oxidative stress [Samples will be obtained at baseline (prior to infusion), immediately after Primary Percutaneous Coronary Intervention (PCI), and at 12 hours, 24 hours, and 48 hours after PCI.]: Ferric reducing ability of plasma (FRAP), malondialdehyde, F2-isoprostanes, reduced glutathione/oxidized glutathione ratio (GSH/GSSG), enzymatic activity of superoxide dismutase, glutathione peroxidase, and catalase.
• Biomarkers of inflammation [Samples will be obtained at baseline, 12 hours, and 24 hours after Primary Percutaneous Coronary Intervention.]: C-reactive protein (CRP) and interleukin (IL)-18
• Clinical outcomes [30 days after PCI]: Clinical outcomes will include all-cause mortality, cardiovascular associated mortality, reinfarction, target-vessel revascularization, and heart failure.
• Safety outcomes [Through hospitalization and up to day 30 after Primary Percutaneous Coronary Intervention.]: Adverse events (AEs) and serious adverse events (SAEs) will be recorded regardless of suspected causality. Events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) standardized terminology.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age 18 years or older
* First anterior ST-segment elevation myocardial infarction (STEMI)
* Symptom onset within 6 hours before presentation
* Eligible for primary percutaneous coronary intervention (PCI)
* Provision of informed consent by the participant or a legally authorized representative, according to local ethics requirements

Exclusion Criteria:

* Prior myocardial infarction
* Cardiogenic shock, defined as Society for Cardiovascular Angiography and Interventions (SCAI) shock class D or E.
* Prior thrombolytic therapy for the index event.
* Chronic kidney disease, defined as serum creatinine greater than 1.5 mg/dL or dialysis.
* Liver cirrhosis
* Advanced heart failure, defined as New York Heart Association (NYHA) class III or IV
* Glucose-6-phosphate dehydrogenase (G6PD) deficiency
* Nephrolithiasis
* Life expectancy less than 6 months
* Implanted cardiac device, including pacemaker, implantable cardioverter-defibrillator, or cardiac resynchronization device
* Prior coronary artery bypass graft (CABG) surgery
* Pregnancy
* Claustrophobia
* Other contraindications to cardiac magnetic resonance imaging (CMR), according to local protocol