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

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

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

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 6 months (median 3 years) with respect to the primary and secondary endpoints. The primary end point, the key secondary end points, and most other secondary end points will be analysed and published jointly with data from the 'Danish Trial of Beta-blocker therapy after myocardial infarction without heart failure' (DANBLOCK) (NCT 03778554) (please see below).

The primary objective is to test whether oral BB therapy reduces the risk of all-cause death, recurrent MI, incident heart failure, unplanned coronary revascularization, ischemic stroke, or malignant ventricular arrhythmia including resuscitated cardiac arrest of cardiac origin compared to no such therapy, in patients with AMI treated with PCI or thrombolysis without reduced LVEF.

The key secondary objectives (planned for the main study) 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 assess clinical outcomes linked BB therapy in the following subgroups: age (tertiles< 70 years vs. ≥70 years), gender sex (men vs. women), country (Denmark vs Norway), BB dosage tertiles (dosage at randomization (<50 mg vs. ≥50 mg), hypertension (yes vs. no), diabetes (yes vs. no), diabetes (yes vs no), type of MI (STEMI vs. NSTEMI), and LVEF subgroups (preserved LVEF: ≥50% vs. mid-range LVEF: 40-49%).
• To study whether oral BB therapy increases the risk of hospitalization for second or third-degree atrioventricular block or implantation of pacemaker.
• To describe BB dosage and adherence at six months following randomization obtained from the national prescription registries
• To assess study safety

Other secondary objectives (for joint BETAMI-DANBLOCK sub-studies) are:

• To study whether oral BB therapy reduces the risk of cardiovascular death compared to no such therapy
• To study whether oral BB therapy reduces the risk of stable and unstable angina compared to no such therapy
• To study whether oral BB therapy reduces the risk of atrial fibrillation, atrial flutter or other atrial tachyarrhythmias compared to no such therapy
• To study whether oral BB therapy increases the risk of hospitalization for bradycardia or syncope.
• To study whether oral BB therapy increases the risk of hospitalization for chronic obstructive pulmonary disease, asthma or peripheral artery disease.
• To study whether oral BB therapy affects the following patient related outcomes:

quality of life, angina, dyspnoea, anxiety, depression, sexual dysfunction or sleep disorders

• To describe long term BB adherence obtained from the national prescription registries
• 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

Exploratory objectives (based on BETAMI data, only):

• 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

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.

Primary safety endpoints:

• To describe the composite endpoint of malignant ventricular arrhythmias including resuscitated cardiac arrest of cardiac origin, incident heart failure, new MI or all-cause death at 30 days after randomization collected from i. direct telephone contact with the patient and from hospital medical records, ii. linkage to the Norwegian Cardiovascular Disease Registry and The Norwegian Population Registry at study end.

Other safety endpoints:

• To describe all-cause death at study end
• To describe Suspected Unexpected Serious Adverse Reaction (SUSARs) during the follow-up period from the study database (continously reported by local investigators).

Rationale for combining data from the BETAMI study with the DANBLOCK (NCT03778554) study from Denmark: The trials have similar designs, only minor differences in study entry criteria, and were, from the very beginning, coordinated with the aim of conducting sub-studies on pooled data. However, the inclusion- and event rates have been lower than expected in both studies. To enhance feasibility, the final decision was made from both Steering Committees in May 2021 to combine the trials and publish initial results jointly. BETAMI and DANBLOCK will remain separate trials until the end of follow-up, where data from the trials will be combined and main results published together.

Sample size: A total of approximately 2900 patients from BETAMI will be recruited and randomized 1:1 to BB treatment (type and dosage according to treating physician) or no BB treatment within 8 days of MI. The study is event driven and a power calculation for the combined DANBLOCK-BETAMI trial has been performed in which 950 events will provide a power of 80% to detect a true treatment effect equal to a hazard ratio of 1.2 for no beta-blocker therapy. Follow-up: Patients will be followed from the randomization date until end of follow-up. The last patient included will be followed for a minimum of 6 months. Estimated mean (non) treatment duration is 3 (0.5-6) years.

Post-trial objective:

• To perform a joint analysis of the data from BETAMI-DANBLOCK with the REDUCE (NCT03278509), CAPITAL-RCT (NCT01155635) and REBOOT (NCT03596385) trials. This analysis will comprise approximately 19000 patients, giving increased power and precision for clinical decisions on both primary and secondary endpoints.

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