Randomized Non‑Inferiority Trial of Flecainide Versus Amiodarone and Sotalol for Rhythm Control in Patients with Atrial Fibrillation and Stable Coronary Artery Disease

Primary objective: To demonstrate that, in patients with atrial fibrillation and stable coronary artery disease, the safety profile of flecainide for rhythm control is non‑inferior to that of class III antiarrhythmic drugs, as measured by the primary composite endpoint over a minimum follow‑up of one year. Secondary objectives include:

• Comparison of the incidence of each individual component of the primary composite endpoint between treatment arms.
• Comparison of overall incidence, severity, and type of adverse events and serious adverse events.
• Assessment of treatment discontinuation rates and reasons for discontinuation.
• Evaluation of treatment adherence and persistence over time.
• Comparison of effectiveness in maintaining sinus rhythm and preventing atrial fibrillation recurrence.
• Comparison of rates of unplanned cardiovascular hospitalisations beyond those captured in the primary endpoint.
• Evaluation of changes in cardiac function and biomarkers, including natriuretic peptides and echocardiographic parameters.
• Assessment of patient‑reported outcomes, such as quality of life and symptom burden.
• Comparison of healthcare resource utilisation, including outpatient visits, hospitalisations, and procedures.
• Evaluation of cost‑effectiveness from a healthcare system perspective.

Participants were adults (≥18 years) of both sexes, selected on the basis of documented non‑permanent atrial fibrillation and stable coronary artery disease. The trial required a left‑ventricular ejection fraction of at least 45 % and evidence of stable CAD without ischemia, defined by prior revascularisation procedures or imaging criteria. Inclusion required voluntary written informed consent. The sponsor did not provide the total number of enrolled subjects, and specific age limits beyond the minimum age were not disclosed. Lifestyle factors such as diet or physical activity were not detailed in the available information.

The study is a randomized, parallel‑group, controlled trial comparing oral flecainide prolonged‑release capsules (150 mg, 200 mg) with standard‑of‑care class III antiarrhythmic agents (amiodarone 200 mg tablets and sotalol 80 mg/160 mg tablets) for rhythm control in patients with atrial fibrillation and stable coronary artery disease. After obtaining voluntary written informed consent, participants undergo a screening visit to confirm eligibility criteria, including non‑permanent atrial fibrillation, stable coronary disease, and left ventricular ejection fraction ≥ 45 %. Eligible subjects are then randomized to receive either flecainide or a comparator medication and commence treatment at the baseline visit. Follow‑up assessments are scheduled at regular intervals (e.g., 1, 3, 6, and 12 months) to collect safety data, evaluate the composite safety outcome (all‑cause mortality, severe adverse events leading to drug discontinuation, and unscheduled hospitalization for heart failure or acute coronary syndrome), and record secondary efficacy and quality‑of‑life measures. The end‑of‑study visit occurs after a minimum of 12 months of follow‑up, marking the completion of participant involvement, which typically spans approximately one year. Early termination of individual participation may occur if a participant experiences a severe adverse event, drug‑related discontinuation, death, or other clinical conditions that preclude continued study medication, as defined by the protocol. The overall trial recruitment is planned to start in July 2026 and conclude by December 2029.

The investigational arm utilizes flecainide acetate formulated as hard, prolonged‑release capsules. Capsules are supplied in 100 mg, 150 mg, and 200 mg strengths and are taken orally to achieve a total daily dose of 300 mg. The dosing regimen is defined in the protocol, and adherence is assessed by capsule count and documented dosing diaries.

The comparator arms employ standard‑of‑care antiarrhythmic therapy. One comparator consists of amiodarone hydrochloride tablets (200 mg each) administered orally with a total daily dose of 600 mg. A second comparator uses sotalol tablets (available in 80 mg and 160 mg strengths) administered orally to provide a total daily dose of 320 mg. Both comparator treatments are given according to the study schedule, and participant compliance is monitored through tablet counts and study visit assessments.

Efficacy will be evaluated using a set of secondary endpoints that include freedom from fast atrial arrhythmia post‑treatment (clinical recurrence of AF), incidence of major adverse cardiovascular events (MACE) (cardiovascular mortality, non‑fatal myocardial infarction, non‑fatal stroke), incidence of catheter ablation for atrial fibrillation, total number of days of cardiovascular hospitalisation, and the proportion of participants experiencing any adverse or serious adverse events. Additional efficacy assessments comprise changes from baseline in cardiac function parameters (left ventricular ejection fraction, global longitudinal strain, left atrial volume index), change in N‑terminal‑pro‑brain Natriuretic Peptide (NT‑proBNP) levels, and alterations in QTc interval and QRS duration. Patient‑reported outcome measures will be collected using the Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire, EuroQoL‑5 dimension health utility index (EQ‑5D‑5L), Short Form‑12 (SF‑12) health survey, EHRA symptom score, and the Work Productivity and Activity Impairment (WPAI) questionnaire. An economic evaluation will compare within‑trial healthcare resource utilisation between treatment arms.

Cardiac function parameters will be measured by transthoracic echocardiography, with left ventricular ejection fraction, global longitudinal strain, and left atrial volume index quantified according to standard imaging protocols. NT‑proBNP concentrations will be determined using validated laboratory assays. Electrocardiographic recordings will be employed to assess QTc interval and QRS duration. Patient‑reported outcomes will be captured through the specified validated questionnaires administered at designated study visits. All efficacy data will be analysed using appropriate statistical methods for comparison of treatment groups over the minimum follow‑up period of one year.