New Evidence Supports Early Rhythm Control in Updated Atrial Fibrillation Guidelines: December 2025 AHJP Editorial

This editorial review is published in the American Heart Journal Plus: Cardiology Research and Practice in December 2025.

The Shift to Early Rhythm Control in Progressive AF

Atrial Fibrillation is the most common sustained arrhythmia. The 2023 ACC/AHA/ACCP/HRS guidelines have redefined AF as a progressive disease continuum. This recognition underscores the clinical urgency, as progression is linked to increased cardiovascular (CV) hospitalization and adverse events. Accordingly, recent studies have supported a paradigm shift, demonstrating the benefits of early rhythm control therapy as a preferable alternative or adjunct to rate control. The landmark EAST-AFNET 4 trial showed that the early initiation of rhythm control—primarily AAD therapy or ablation—was associated with a 25% reduction in CV events compared with usual care. Consequently, both the 2023 ACC/AHA/ACCP/HRS and 2024 ESC guidelines now assign Class 2a/IIa recommendations for early rhythm control in recently diagnosed AF patients to reduce major outcomes like hospitalization, stroke, and mortality.

Evaluating Dronedarone through Real-World Pooled Evidence

This review systematically contextualizes Dronedarone's role using recent RWE and post hoc analyses, contrasting these findings with guideline recommendations that rely on AAD safety profiles, underlying heart disease, and comorbidities. A crucial element of the review is the evaluation of Dronedarone against sotalol, an AAD with similar indications. Sotalol has recently been downgraded to a Class 2b recommendation in the 2023 US guidelines due to its documented association with increased mortality risk and pro-arrhythmia. To address this comparative need without relying on direct head-to-head randomized controlled trials (which do not exist), the authors analyzed pooled RWE data. This approach utilized large database retrospective cohort studies that employed propensity score matching (PSM) to compare Dronedarone and sotalol outcomes in AAD-naïve patients and in those post-catheter ablation (CA).

Real World Evidence (RWE) Suggests Dronedarone’s Superior Safety and Efficacy Profile

The pooled RWE data strongly demonstrate Dronedarone's favorable safety profile, particularly when compared to sotalol. A meta-analysis showed Dronedarone's superiority across several hard outcomes, linking it to lower pooled rates of CV hospitalization (pHR 0.91) and ventricular arrhythmia (pHR 0.77). Importantly, RWE indicated that Dronedarone carried a lower risk of severe adverse Class II and III events, including symptomatic bradycardia and ventricular pro-arrhythmia requiring pacemaker insertion, compared to sotalol, even at its lowest recommended therapeutic dose. Furthermore, Dronedarone significantly reduced the composite endpoint of CV death, stroke, or hospitalization with worsening HF. In the heart failure subpopulation, Dronedarone reduced CV events in patients with AF/AFL across the spectrum of HFpEF and HFmrEF (LVEF >40%), demonstrating consistency in efficacy regardless of HF status.

Potential Clinical Implications for Cardiologists

The management of Atrial Fibrillation (AF) is shifting toward early rhythm control, now recommended in the 2023 US and 2024 ESC guidelines (Class 2a/IIa) to slow disease progression and reduce cardiovascular events.

Dronedarone is reaffirmed as a suitable and safe option for rhythm control, consistent with its Class I ESC 2024 recommendation for long-term use in patients with HFmrEF, HFpEF, ischemic heart disease, or valvular disease. This is increasingly important as sotalol has been downgraded (Class 2b/IIb) due to higher risks of mortality and proarrhythmia. Real-world evidence shows Dronedarone has a safer profile than sotalol, with lower rates of ventricular arrhythmia and bradycardia requiring pacemaker placement. It is practical to use, requiring no loading dose, minimal monitoring, and can be initiated in the outpatient setting (400 mg twice daily with a substantial meal). Even when catheter ablation is prioritized (Class 1 in selected patients), short-term Dronedarone for 3–6 months carries a Class 2a recommendation to reduce early recurrence and hospitalization.

Strict safety precautions remain essential: Dronedarone is contraindicated (Class 3: harm) in permanent AF, NYHA Class III/IV heart failure, or recent decompensated heart failure. Final AAD selection should be individualized to patient comorbidities and overall safety considerations.

Reference: Naccarelli GV, Rackley J, Boriani G. New recommendations for rhythm control—What has changed in the 2023 ACC/AHA/ACCP/HRS and 2024 ESC guidelines for atrial fibrillation, and where does dronedarone fit in?. American Heart Journal Plus: Cardiology Research and Practice. 2025 Oct 20:100645.

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