BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function

Study Overview
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Brief Summary
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The study aims to investigate whether oral betablocker (BB) therapy is superior to no such treatment following an acute myocardial infarction (AMI).

Detailed Description
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This is a prospective, randomized, open blinded end-point (PROBE) study. Patients with AMI will be randomized 1-8 days following PCI or thrombolysis, and allocated to either prescription of a BB or to no such prescription. Subjects will be followed up for at least 2 years with respect to the primary and secondary endpoints. The primary objective is to test whether oral BB therapy reduces the risk of all-cause death or non-fatal MI compared to no such therapy, in patients with AMI treated with PCI or thrombolysis without reduced LVEF. The key secondary objectives are: To study whether oral BB therapy reduces the risk of each of the components of the primary end-point separately, compared to no such therapy To study whether oral BB therapy reduces the risk of hospitalization for ventricular arrhythmias or heart failure compared to no such therapy To study whether oral BB therapy reduces the risk of cardiovascular death compared to no such therapy To assess clinical outcomes linked BB therapy including outcomes in treatment subgroups (i.e. doses), STEMI vs. NSTEMI, betablocker-naive patients vs. those who are not, LVEF subgroups (preserved LVEF: ≥50% vs. mid-range LVEF: 40-49%), drug-related side-effects, drug adherence, cardiovascular risk factors, quality of life, anxiety, depression, symptom burden (angina, dyspnea), sexual dysfunction and sleep disturbance To study sociodemographic, clinical, and psychosocial characteristics (PROMS and clinical data) between the two study arms and in the total sample To conduct cost-utility analysis in relation to quality of life and a health economic evaluation including drug use, health care utilization, employment, income, and benefit take-up To assess study safety Exploratory objectives: To study the proportion and predictors of non-adherence with BB, statins and other cardiovascular drugs assessed by direct methods quantifying drug concentrations in blood Identify pharmacokinetic, pharmacogenetic and pharmacodynamic markers associated with side-effects and suboptimal response to treatment with cardiovascular drugs Post-trial objective: • To perform a joint analysis of the data from this study with that of the REDUCE study (Sweden). This analysis will comprise 17000 patients, giving increased power and precision for clinical decisions on both primary and secondary endpoints. The primary study end-points will be obtained through linkage to the Norwegian Cardiovascular Disease Registry and The Norwegian Population Registry (Folkeregisteret) Secondary endpoints will be obtained by linkage to the following national registries: The Norwegian Population Registry (Folkeregisteret), the Cause of Death Registry, the Norwegian Patient Registry, the Norwegian Cardiovascular Disease Registry, the Norwegian Prescription Database, the Norwegian registry for income, the FD-Trygd database (social security micro data for research) and the Control and payment of reimbursements to health service providers (KUHR) database. Further by collecting self-reported questionnaires and a clinical examination with blood sample collection. Safety endpoints: • Rate of ventricular arrhythmias, heart failure, new MI or all-cause death 30 days after randomization and rate of new MI or all-cause death after 6 and 18 months Safety endpoints will be under the responsibility of the primary investigators at all participating centers and collected by: 30 days: direct telephone contact with the patient and from hospital medical records At 6 and 18 months:, safety assessments at the study visits in addition to linkage to the Norwegian Cardiovascular Disease Registry and The Norwegian Population Registry Continuous surveillance of serious adverse events (SAEs)

Official Title
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BEtablocker Treatment After Acute Myocardial Infarction in Patients Without Reduced Left Ventricular Systolic Function (BETAMI)

Conditions
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Acute Myocardial Infarction, Non-ST Elevation Myocardial Infarction, ST Elevation Myocardial Infarction

Intervention / Treatment
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* Other: Non-betablocker
* Drug: Betablocker


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria To be eligible for inclusion in the study, subjects must fulfill the following criteria at inclusion: 18 years or older Diagnosed with an acute MI type I according to the Universal Definition of MI (Defined as a detection of a rise and/or fall of cardiac biomarker value, preferably troponin, with at least one value above the 99th percentile upper reference limit and with at least one of the following; a) symptoms of ischemia, b) new or presumed new significant ST-segment-T wave changes or new left bundle branch block, c) development of pathological Q waves, d) imaging evidence of new loss of viable myocardium or e) identification of an intracoronary thrombus by coronary angiogram) Must have been treated with PCI or thrombolysis during current hospitalization Signed informed consent and expected cooperation of the patient according to ICH/GCP and national/local regulations Have a national personal identification number and not be expected to emigrate during study Exclusion Criteria Study subjects must not meet any of the following criteria: Having a condition where betablocker-therapy is required, including but not limited to: Arrhythmias Hypertension Cardiomyopathies Clinical diagnosis of heart failure LVEF < 40% by echocardiography (by measurement and not only visual assessment for STEMI patients) Left ventricular akinesia in ≥ 3 segments regardless of the LVEF Contraindications to betablocker-therapy, including but not limited to: Bradyarrhythmias Hypotension Severe peripheral artery disease Previously known side-effects causing withdrawal Severe chronic obstructive pulmonary disease • Women of childbearing potential (a woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) Known hypersensitivity to any ingredient of the IMP Other, according to the responsible investigator End-stage somatic disease with short life expectancy, dementia, psychosis and other conditions could put the subject at significant risk, confound the study results, interfere significantly with the subject participation in the study, or rendering informed consent unfeasible Previous treatment with a betablocker is not an exclusion criterion for enrollment into the BETAMI study. Enrolled patients can participate in any other study that does not directly alter the effect betablocker treatment

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: Parallel Assignment
Interventional Model Description: PROBE - prospective, randomized, open blinded end-point
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Betablocker<br>Patients receiving a betablocker. Any other treatment or management is to be given as per usual care. | Drug: Betablocker<br>* A betablocker will be administered. To reflect contemporary management, for which this study is designed to test, there will not be a defined minimum dosage. The type and dose of BB will be left at the discretion of the PI. Generic drug and accepted dosages will be: Metoprolol succinate up to a total dose of 200mg daily Bisoprolol up to a total dose of 10mg daily Carvedilol up to a total dose of 50mg daily The treating physician will be encouraged to aim for an equipotent dose of 100 mg metoprolol succinate or higher. Any other treatment or management is to be given as per usual care.<br>|
| Experimental: Non-Betablocker<br>No betablocker is given to this arm. Any other treatment or management is to be given as per usual care. | Other: Non-betablocker<br>* No betablocker will be administered. Patients randomized to no beta-blockade will be discouraged to use beta-blockade as long as there is no other indication than strictly secondary prevention after myocardial infarction. Any other treatment or management is to be given as per usual care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the composite of death of any cause and non-fatal myocardial infarction | Incidence of combined endpoint from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years | 2 years minimum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-fatal MI | Time to non-fatal MI from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years | 2 years minimum | 
| All-cause death | Time to a-cause Death from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years | 2 years minimum | 
| Ventricular arrhythmia | Time to ventricular arrhythmia from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years | 2 years minimum | 
| Hospitalization for heart failure | Time to hospitalization for heart failure from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years | 2 years minimum | 
| Cardiovascular death | Time to cardiovascular death from randomization. Estimated maximal follow-up for each patient for this outcome is 1-3 years | 2 years minimum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infarction, Myocardial Infarction, ST Elevation Myocardial Infarction, Non-ST Elevated Myocardial Infarction, Ischemia, Myocardial Ischemia, Heart Diseases, Cardiovascular Diseases, Metoprolol, Bisoprolol, Betablocker, Anti-Arrhythmia Agents, Physiological Effects of Drugs, Beta-blocker, Beta blocker