Comparative clinical effectiveness and safety of amiodarone versus dronedarone in patients with atrial fibrillation

Introduction Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke and other cardiovascular complications. In addition to anticoagulation for stroke prevention, both rate and rhythm control play essential roles in its management. Previous randomized controlled trials have demonstrated greater rhythm control efficacy with amiodarone than dronedarone in patients with AF; however, amiodarone’s long half-life and frequent adverse effects often limit its use. Evidence regarding major clinical outcomes remains inconsistent, and discrepancies between randomized trials and real-world studies contribute to ongoing uncertainty. Further real-world evidence is needed to clarify the balance between effectiveness and safety. Purpose To compare the real-world effectiveness and safety of dronedarone versus amiodarone in patients with AF. Methods This multicenter retrospective cohort study used the TriNetX Research Network database. Adults aged ≥20 years who newly initiated amiodarone or dronedarone between January 1, 2017 and December 31, 2023, were included. Eligible patients had atrial fibrillation diagnosed within 6 months and no prior use of class I or III antiarrhythmic drugs. The primary outcome was a composite of major adverse cardiovascular events (myocardial infarction, ischemic stroke, hemorrhagic stroke, heart failure and all-cause mortality) and hospitalization. Safety outcomes included newly diagnosed thyroid dysfunction, liver disease and dyslipidemia. Baseline covariates were balanced using 1:1 propensity score matching. Results Among 129,363 eligible patients (125,644 using amiodarone and 3,719 using dronedarone), 3,717 patients remained in each group after 1:1 propensity score matching. The median follow-up duration was 2 years. Baseline characteristics were well balanced (mean age 73 years and 51% male). Amiodarone was associated with a significantly higher risk of the composite outcome of major adverse cardiovascular events and hospitalization, compared with dronedarone (HR 1.83, 95% CI 1.72 to 1.93; p<0.001). The increased risk was consistent across individual components of the composite outcome. For safety outcomes, amiodarone was associated with a higher risk of thyroid dysfunction (HR 2.15, 95% CI 1.77 to 2.62; p<0.001) and liver disease (HR 1.95, 95% CI 1.55 to 2.46; p<0.001), whereas no significant difference was observed in the risk of dyslipidemia (HR 1.09, 95% CI 0.93 to 1.28; p=0.301) compared with dronedarone. Conclusion In this real-world cohort of patients with atrial fibrillation, dronedarone was associated with lower risks of mortality, hospitalization, major adverse cardiovascular events, thyroid dysfunction and liver disease compared with amiodarone.