Evaluation of Early Rhythm-Control Therapy with Dronedarone Hydrochloride in Combination with Antiarrhythmic Agents for Acute Ischemic Stroke and Atrial Fibrillation

The primary objective of the study is to evaluate whether early **rhythm-control therapy** in addition to usual care can reduce the rate of adverse cardiovascular outcomes in patients with **acute ischemic stroke** and **atrial fibrillation (AF)** compared to usual care alone. This is clinically relevant as it aims to improve cardiovascular outcomes in a population at high risk for recurrent stroke and other cardiovascular events.

Secondary objectives include assessing the benefit of early rhythm-control therapy on health-related quality of life and functional outcomes in patients with acute ischemic stroke and AF. Additionally, the study aims to evaluate the costs associated with therapy in this patient population. These objectives are important for understanding the broader impact of treatment on patient well-being and healthcare resource utilization.

The clinical trial involves a total of **711 participants** diagnosed with **acute ischemic stroke** and **atrial fibrillation (AF)**. The study population includes both male and female subjects, aged over 45 years, who have experienced an acute ischemic stroke confirmed through standard brain imaging or clinical diagnosis. Participants were selected based on the detection of AF within one year prior to randomization, with at least one ECG documenting AF in the past 12 months. The trial population was chosen to include individuals who could provide written informed consent and were randomized within four weeks of their stroke event. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating a careful selection process to ensure ethical standards are maintained.

The clinical trial is designed to evaluate the efficacy of early rhythm-control therapy in addition to usual care in patients with **acute ischemic stroke** and **atrial fibrillation** (AF), compared to usual care alone. This trial is a randomized, double-blind, controlled study, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is categorized as low interventional, as it involves the use of authorized medicinal products in accordance with their marketing authorization. The estimated duration of the trial is from July 2025 to November 2030, with participant involvement expected to last up to 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 45 years, confirmed acute ischemic stroke, and documented AF within the past year. Randomization will occur within four weeks of the stroke event. Follow-up visits will be scheduled at 12 and 24 months to assess primary and secondary endpoints, including recurrent stroke, cardiovascular events, and changes in cardiac rhythm and function. The end-of-study visit will conclude the participant's involvement, with assessments of functional status, quality of life, and cognitive function.

Participants may be withdrawn from the study early if they experience adverse events, withdraw consent, or if the investigator deems it necessary for their safety. The primary endpoint is a composite of first recurrent ischemic stroke, hemorrhagic stroke, unclassified stroke, cardiovascular death, or hospitalization due to worsening heart failure or acute coronary syndrome. Secondary endpoints include individual components of the primary outcome, recurrent disabling stroke, recurrent AF, and various measures of cardiac and overall health. The trial will utilize antiarrhythmic medications such as **dronedarone hydrochloride**, **propafenone hydrochloride**, **amiodarone hydrochloride**, and **flecainide acetate**, administered orally, with specific dosing regimens tailored to each medication.

The clinical trial involves the administration of several **antiarrhythmic** medications, each with specific characteristics and dosing regimens. **Dronedarone hydrochloride** is provided in the form of film-coated tablets. The maximum daily dose is 800 mg, administered orally. The treatment period is limited to one day, and the medication is not formulated for pediatric use. Participant compliance is monitored to ensure adherence to the dosing schedule.

**Propafenone hydrochloride** is also administered as a film-coated tablet, with a maximum daily dose of 600 mg. This medication is taken orally, and the treatment duration is similarly restricted to one day. The formulation is intended for adult use only, and compliance is tracked throughout the trial.

**Amiodarone hydrochloride** is provided in tablet form, with a maximum daily dose of 600 mg. The route of administration is oral, and the treatment period is one day. This medication is not designed for pediatric patients, and adherence to the dosing regimen is closely monitored.

**Flecainide acetate** is administered as a tablet, with a maximum daily dose of 300 mg. The medication is taken orally, and the treatment duration is one day. It is not formulated for pediatric use, and participant compliance is ensured through regular monitoring.

All medications in this trial are classified as antiarrhythmics and are administered orally. The trial aims to evaluate the efficacy of early rhythm-control therapy in patients with acute ischemic stroke and atrial fibrillation, compared to usual care alone. Compliance with the dosing schedule is a critical component of the study, ensuring the reliability of the trial outcomes.

The efficacy of the clinical trial titled "Early treatment of Atrial fibrillation for Stroke prevention Trial in acute STROKE (EAST-STROKE)" will be assessed using a combination of primary and secondary endpoints. The primary endpoint is a composite measure that includes the first occurrence of recurrent **ischemic stroke**, hemorrhagic stroke, unclassified stroke, cardiovascular death, or hospitalization due to worsening heart failure or acute coronary syndrome (ACS). This composite endpoint will be analyzed as the time to the first occurrence of any of these components.

Secondary endpoints will be evaluated individually and include each component of the primary outcome, recurrent disabling stroke, recurrent atrial fibrillation (AF), cardiac rhythm status at 12 and 24 months, unplanned cardiovascular hospitalizations, the number of cardiovascular hospitalizations, and changes in left ventricular function as measured by left ventricular ejection fraction (LVEF) at 24 months. Additional secondary endpoints include functional status assessed with the modified Rankin Scale (mRS), quality of life measured by the EuroQol five-dimensional questionnaire (EQ-5D) and Patient-Reported Outcomes Measurement Information System-10 (PROMIS-10) domains, cognitive function assessed with the Montreal Cognitive Assessment (MoCA), and the cost of therapy. These assessments will be conducted at 12 and 24 months.