Randomized Evaluation of Beta Blocker and ACEI/ARB Treatment in MINOCA Patients - MINOCA-BAT

Study Overview
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Brief Summary
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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%.

Detailed Description
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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

Official Title
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Randomized Evaluation of Beta Blocker and Angiotensin Converting Enzyme Inhibitor (ACEI) /Angiotensin Receptor Blocker (ARB) Treatment in MINOCA Patients.

Conditions
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Myocardial Infarction With Non-obstructive Coronary Arteries

Intervention / Treatment
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* Drug: Beta blocker
* Drug: ACEI
* Drug: ARB


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2 * 2 Factorial Design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No Beta blocker and no ACEI/ARB<br>No Beta blocker and no ACEI/ARB | |
| Experimental: Beta blocker and ACEI/ARB<br>Beta blocker and either ACE inhibitor or Angiotensin receptor blocker | Drug: Beta blocker<br>* Patients randomized to beta-blockade will be administered the assigned treatment during the rest of the hospital stay and receive a prescription for the continued use at discharge. The treating physician is encouraged to aim for target dose or highest tolerable dose for the drug. Patients will be encouraged to continue the use of the randomized treatment following discharge until contraindications.<br>* Other names: Beta receptor blocker;Drug: ACEI<br>* Patients randomized to ACE inhibitor will be administered the assigned treatment during the rest of the hospital stay and receive a prescription for the continued use at discharge. The treating physician is encouraged to aim for target dose or highest tolerable dose for the drug. Patients will be encouraged to continue the use of the randomized treatment following discharge until contraindications.<br>* Other names: ACE inhibitor;Drug: ARB<br>* Patients randomized to Angiotensin receptor blockers will be administered the assigned treatment during the rest of the hospital stay and receive a prescription for the continued use at discharge. The treating physician is encouraged to aim for target dose or highest tolerable dose for the drug. Patients will be encouraged to continue the use of the randomized treatment following discharge until contraindications<br>* Other names: Angiotensin receptor blocker;|
| Experimental: Beta blocker alone<br>Beta blocker alone | Drug: Beta blocker<br>* Patients randomized to beta-blockade will be administered the assigned treatment during the rest of the hospital stay and receive a prescription for the continued use at discharge. The treating physician is encouraged to aim for target dose or highest tolerable dose for the drug. Patients will be encouraged to continue the use of the randomized treatment following discharge until contraindications.<br>* Other names: Beta receptor blocker;|
| Experimental: ACEI/ARB alone<br>Either ACE inhibitor or Angiotensin receptor blocker alone | Drug: ACEI<br>* Patients randomized to ACE inhibitor will be administered the assigned treatment during the rest of the hospital stay and receive a prescription for the continued use at discharge. The treating physician is encouraged to aim for target dose or highest tolerable dose for the drug. Patients will be encouraged to continue the use of the randomized treatment following discharge until contraindications.<br>* Other names: ACE inhibitor;Drug: ARB<br>* Patients randomized to Angiotensin receptor blockers will be administered the assigned treatment during the rest of the hospital stay and receive a prescription for the continued use at discharge. The treating physician is encouraged to aim for target dose or highest tolerable dose for the drug. Patients will be encouraged to continue the use of the randomized treatment following discharge until contraindications<br>* Other names: Angiotensin receptor blocker;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to death of any cause, or time to readmission because of AMI, ischemic stroke or heart failure | A Composite of time to all-cause Death and time to re-admission because of AMI, ischemic stroke or heart failure | Time to event from the date of enrollment through study completion, an average of 4 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| a All-cause death b Cardiovascular death c Readmission because of AMI d Readmission because of ischemic stroke e Readmission because of heart failure f Readmission because of unstable angina pectoris g Readmission because of atrial fibrillation. |  | a All-cause death: Time to event from the date of enrollment through study completion, an average of 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial infarction, Treatment, ACE inhibitors, Angiotensin receptor blockade, Beta blockers