Low inclusion rate.

Myocardial infarction with non-obstructive coronary arteries" (MINOCA) occurs in 5-10% of all patients with AMI. There are neither any randomized clinical trials in MINOCA patients evaluating effects of secondary preventive treatments proven beneficial in patients with classic AMI, nor any treatment guidelines.

The primary objective of this multi-national, multi-center pragmatic randomized clinical trial is to determine whether oral beta-blockade compared to no oral beta-blockade, and whether Angiotensin Converting Enzyme Inhibitors (ACEI/ Angiotensin Receptor Blockers (ARB) compared to no ACEI/ARB, reduce the composite endpoint of death of any cause and readmission because of AMI, ischemic stroke or heart failure in patients discharged with myocardial infarction with non-obstructive coronary artery disease (MINOCA) and with no clinical signs of heart failure and with left ventricular (LV) systolic ejection fraction ≥40%.

Large-scale use of acute coronary angiography has revealed a large portion of AMI without angiographically obstructive (defined as ≥50% diameter stenosis) coronary artery disease (CAD). The term "myocardial infarction with non-obstructive coronary arteries" (MINOCA) has been coined for this entity. MINOCA occurs in 5-10% of all patients with AMI and these patients are younger and more often females compared to patients with AMI and obstructive CAD. The 1-year mortality after MINOCA was found to be 3.5% in the systematic review by Pasupathy et al.. There are no randomized clinical trials in MINOCA patients evaluating effects of secondary preventive treatments proven beneficial in patients with classic AMI. However, in an observational study with propensity score matched comparisons the risk of experiencing a Major Adverse Cardiac Event (MACE) was 18% lower in patients treated with ACEI/ARB compared to no ACEI/ARB; in patients on beta blockers compared to patients not using beta blockers there was a non-significant 14% reduction in MACE.

The primary objective of this multi-national, multi-center pragmatic randomized clinical trial is to determine whether oral beta-blockade compared to no oral beta-blockade, and whether ACEI/ARB compared to no ACEI/ARB, reduce the composite endpoint of death of any cause and readmission because of AMI, ischemic stroke or heart failure in patients discharged with myocardial infarction with non-obstructive coronary artery disease (MINOCA) and with no clinical signs of heart failure and with LV systolic ejection fraction ≥40%.

PRIMARY ENDPOINT: Time to death of any cause or readmission because of myocardial infarction, ischemic stroke or heart failure.

SECONDARY ENDPOINTS:

Time to:

• All-cause mortality
• Cardiovascular mortality
• Readmission because of AMI
• Readmission because of ischemic stroke
• Readmission because of heart failure
• Readmission because of unstable angina pectoris
• Readmission because of atrial fibrillation.

Safety:

Time to readmission because of:

• AV-block II-III, hypotension, syncope or need for pacemaker
• Acute kidney injury
• Ventricular tachycardia/fibrillation

Inclusion Criteria:

• Age >18 years.
• A clinical diagnosis of MINOCA within the last 30 days.
• Left ventricular ejection fraction ≥40% measured with echocardiography, MRI or left ventriculography after admission and prior to randomization.
• Written informed consent obtained

Exclusion Criteria:

• Any condition that may influence the patient's ability to comply with study protocol.
• Previous revascularization (CABG or PCI)
• Clinical signs of heart failure
• MRI-proven myocarditis or a strong clinical suspicion of myocarditis or takotsubo as cause of the index event
• Contraindications for Beta blocker treatment
• Contraindications for ACEI and ARB treatment
• Prior use of ACEI, ARB, or Beta blockers, which must continue according to treating physician.
• New indication for Beta blocker or ACEI/ARB treatment other than as secondary prevention according to treating physician
• Ongoing pregnancy or woman of childbearing potential not using adequate contraceptives
• Participation in a trial evaluating a drug known to interact with Beta blockers or ACEI/ARB

We will make a limited, de-identified set of data available for researchers outside the primary investigators two years after the publication of the primary results of the study. Before data are shared, a data-sharing agreement should be established documenting what data are being shared and how the data can be used. The agreement serves two purposes. First, it protects the agency providing the data, ensuring that the data will not be misused. Second, it prevents miscommunication on the part of the provider of the data and the agency receiving the data by making certain that any questions about data use are discussed. The following items should be covered in the data-sharing agreement:

• Period of agreement
• Intended use of the data
• Constraints on use of the data
• Data confidentiality
• Data security
• Methods of data-sharing