The purpose of this trial is to evaluate the safety and maximum tolerable dose (MTD) of sodium thiosulfate in patients presenting with an acute coronary syndrome and treated with primary percutaneous coronary intervention (PPCI) via trans-radial approach in adjunction to standard treatment.

Despite the recent advances in treatment, acute myocardial infarction (AMI) frequently results in permanent myocardial injury imposing an increased risk for adverse cardiac remodelling, diminished cardiac function and the development of heart failure. Decreased cardiac function after PPCI is associated with impaired prognosis.

Although PPCI has a tremendous benefit in AMI, not only ischemia but also reperfusion itself is considered to cause myocardial injury and cardiomyocyte death.This phenomena is referred to as "ischemia reperfusion injury" in literature and is caused by the sudden restoration of blood flow and its accompanying intracellular pH change, calcium overload, cardiomyocyte hypercontracture, myocardial inflammation, oxidative stress generation and mitochondrial permeability transition pore opening. Reducing ischemia reperfusion injury is expected to further decrease infarct size, decrease adverse cardiac remodelling and improve cardiac function as well as clinical outcome.

Hydrogen sulfide (H2S) is the third endogenous gaseous transmitter next to carbon monoxide (CO) and nitric oxide (NO) and is involved as a physiological mediator in several body organ and tissue processes. H2S is synthesized endogenously by enzymatic and non-enzymatic pathways. A non-enzymatic pathway is by the reductive reaction with thiosulfate, with pyruvate acting as a hydrogen donor. Thiosulfate itself acts as an intermediate in the sulfur metabolism of cysteine and is known as a metabolite of H2S and in that way is also able to produce H2S, especially under hypoxic conditions.

H2S has been shown to protect myocardium from ischemia reperfusion injury in various experimental animal models of ischemic heart disease; e.g. it reduces infarct size and apoptosis and attenuates cardiac function. Inhibition of leukocyte endothelial cell interactions, neutralization of reactive oxygen species (ROS) and the reduction of apoptotic signalling are the suggested as additional mechanisms underlying the cardioprotective effect of H2S in this setting.

STS, an H2S donor, is used in humans since 1933 for the treatment of cyanide intoxication and is used since the eighties for treatment of vascular calcifications in end-stage renal disease. It is also used to prevent toxicity of cisplatin treatment. More recently, studies have shown STS can delay the progression of coronary artery calcification in haemodialysis patients. The mechanism of action in these diseases is thought to be based on potential antioxidant properties of STS. In all these cases intravenous STS was used in different doses from 5 to 75 g per day. Side effects of STS include hypotension, nausea and vomiting, gastrointestinal disturbances, hypernatraemia and in 5% of hemodialysis patients metabolic acidosis occurred. Most side effects were mild and manageable.

STS administration has never been tested in the clinical setting of ACS. Cardiac catheterization via trans-radial approach has been increasingly used, instead of trans-femoral approach, resulting in fewer vascular complications, minimal risk of nerve injury and virtually no postprocedural bed rest. However, during radial approach a combination of vasodilating, blood pressure lowering and anticoagulant drugs are given to the patient (verapamil, nitroglycerin, heparin), the "radialis-cocktail". These drugs could potentially interact with STS and data regarding the safety of STS in patients with ACS treated with PCI via radial approach is lacking.

The SAFE ACS is a phase 1/2, open-label, dose-escalation study to test the hypothesis that STS, on top of standard medical treatment, can be safely administered in patients presenting with an ACS and is well-tolerated. We will use a "3+3 design" with a fixed dosing endpoint of 30 gram of STS in 2 gifts of 15 gram, based on the standard dose of 25 gram used for other indications. Additionally we will test the effect of STS treatment on oxidative stress during and after STS infusion by laboratory analysis of various oxidative stress markers.

Inclusion Criteria:

• Age ≥ 18 years;
• The diagnosis ACS defined by: chest pain suggestive for myocardial ischemia for at least 30 minutes, the time from onset of the symptoms less than 24 hours before hospital admission, with (STEMI) or without (nSTEMI/uAP) an electrocardiogram (ECG) recording with ST- segment elevation of more than 0.1 millivolt (mV) in 2 or more contiguous leads;
• PCI via trans-radial approach is being considered as treatment;
• Patient is willing to cooperate with the trial during hospitalization

Exclusion Criteria:

• Known cardiomyopathy or LVEF<35%;
• History of a malignancy treated with chemo- and/or radiotherapy < 1 year;
• Systolic blood pressure under 100 mmHg or over 180 mmHg at presentation;
• Cardiogenic shock at presentation
• Sedated and/or intubated patients;
• Pregnant/breastfeeding at time of presentation
• The existence of a condition with a life expectancy of less than 1 year;
• A condition which, according to the clinical judgment of the investigator and/or treating physician, does not allow the patient to successfully participate in the study.