Evaluation of Carvedilol, Metoprolol Tartrate, and Bisoprolol Fumarate in Post-Myocardial Infarction Patients with Preserved Ejection Fraction

The primary objective of the Danish trial of beta blocker treatment after **myocardial infarction** without reduced ejection fraction (DANBLOCK) is to evaluate the composite outcome of recurrent myocardial infarction (MI), all-cause mortality, revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG), ischemic stroke, incident heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest. This objective is clinically relevant as it aims to assess the efficacy of beta-blocker therapy in reducing significant adverse cardiovascular events in patients who have experienced a myocardial infarction without reduced ejection fraction.

Secondary objectives include:

• Assessing each component of the primary endpoint, such as all-cause mortality, recurrent MI, revascularization with PCI or CABG, ischemic stroke, incident heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest.
• Evaluating clinical outcomes linked to beta-blocker therapy in subgroups based on age, sex, beta-blocker dosage tertiles, STEMI vs. NSTEMI, and left ventricular ejection fraction (LVEF).
• Investigating whether oral beta-blocker therapy reduces the risk of cardiovascular death, stable and unstable angina, atrial fibrillation, atrial flutter, or other atrial tachyarrhythmias compared to no such therapy.
• Determining if oral beta-blocker therapy increases the risk of hospitalization for bradycardia, syncope, pacemaker implantation, chronic obstructive pulmonary disease, asthma, peripheral artery disease, or new-onset or dysregulated diabetes.
• Studying the impact of oral beta-blocker therapy on patient-related outcomes such as quality of life, angina, dyspnea, anxiety, depression, sexual dysfunction, or sleep disorders.
• Conducting a cost-utility analysis related to quality of life and a health economic evaluation including drug use, healthcare utilization, employment, income, and benefit take-up.
• Describing beta-blocker dosage and adherence.
• Assessing study safety.

The clinical trial focuses on individuals who have experienced a **myocardial infarction**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a left ventricular ejection fraction greater than 40%. The trial does not specify the total number of participants, as the sponsor has not provided this information. The selection process for the trial population involves individuals who meet the Universal ESC definition of myocardial infarction, which includes specific criteria related to cardiac biomarker values and symptoms of ischemia. The trial includes a vulnerable population, although specific lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data. The study aims to evaluate outcomes such as recurrent myocardial infarction, all-cause mortality, and other cardiovascular events.

The clinical trial is designed to evaluate the efficacy of **beta-blocker** treatment in patients who have experienced a **myocardial infarction** without reduced ejection fraction. This is a randomized, double-blind, controlled trial, which aims to assess the composite outcome of recurrent myocardial infarction, all-cause mortality, revascularization, ischemic stroke, incident heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest. The trial is expected to run from December 1, 2018, to April 30, 2025, with a maximum treatment period of 77 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older) and left ventricular ejection fraction greater than 40%. Following the screening, participants will be randomized to receive either the active treatment or a placebo. The trial includes regular follow-up visits to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted.

The expected length of participant involvement is up to 77 weeks, depending on the individual's response to treatment and adherence to the study protocol. Conditions that may lead to early termination from the study include significant adverse reactions to the treatment, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with the primary goal of improving clinical outcomes for patients with myocardial infarction.

The clinical trial involves the administration of several **beta-blockers** to evaluate their efficacy in patients post-myocardial infarction without reduced ejection fraction. The experimental medications include **Carvedilol**, **Metoprolol Tartrate**, **Bisoprolol Fumarate**, and **Nebivolol Hydrochloride**. Each medication is administered orally in tablet form, with specific dosages and treatment periods.

**Carvedilol** is provided in various dosages: 3.125 mg, 6.25 mg, 12.5 mg, and 25 mg tablets. The maximum daily dose for Carvedilol is 50 mg, and the treatment period extends up to 77 days. The tablets are manufactured by STADA ARZNEIMITTEL AG and STADAPHARM GMBH, with the active substance being a structurally diverse substance of herbal origin.

**Metoprolol Tartrate** is administered as a prolonged-release tablet, marketed as Metoprololsuccinat "Polpharma". The available dosage is up to 200 mg per day, with a treatment duration of 77 days. The tablets are produced by ZAKLADY FARMACEUTYCZNE POLPHARMA S.A., and the active substance is of chemical origin.

**Bisoprolol Fumarate** is available in 2.5 mg, 5 mg, and 10 mg tablets, with a maximum daily dose of 10 mg. The treatment period for Bisoprolol is 77 days, except for one formulation with a 48-day period. The tablets are manufactured by ORION CORPORATION, and the active substance is chemically derived.

**Nebivolol Hydrochloride** is provided in 5 mg tablets, with a maximum daily dose of 10 mg and a treatment period of 77 days. The tablets are produced by PLIVA HRVATSKA D.O.O., and the active substance is of chemical origin.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as placebo or comparator treatments. The study aims to assess the composite outcome of recurrent myocardial infarction, all-cause mortality, revascularization, ischemic stroke, incident heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest.

The efficacy of the clinical trial will be assessed using a composite primary endpoint, which includes the occurrence of recurrent **myocardial infarction** (MI), all-cause mortality, revascularization with percutaneous coronary intervention or coronary artery bypass graft, ischemic stroke, incident heart failure, malignant ventricular arrhythmia, or resuscitated cardiac arrest. Secondary endpoints will evaluate each component of the primary endpoint individually, as well as additional clinical outcomes related to beta-blocker therapy. These include the risk of cardiovascular death, stable and unstable angina, atrial fibrillation, atrial flutter, other atrial tachyarrhythmias, and hospitalization for various conditions such as bradycardia, syncope, and chronic obstructive pulmonary disease. The trial will also assess patient-related outcomes like quality of life, angina, dyspnea, anxiety, depression, sexual dysfunction, and sleep disorders.

The trial will employ a comprehensive approach to data collection and analysis, focusing on the impact of beta-blocker therapy across different subgroups, including age, sex, dosage tertiles, and specific myocardial infarction types (STEMI vs. NSTEMI). The study will also conduct a cost-utility analysis related to quality of life and a health economic evaluation, considering drug use, healthcare utilization, employment, income, and benefit take-up. The trial is designed to ensure a robust assessment of the efficacy and safety of beta-blocker therapy in the specified patient population.