Wolff-Parkinson-White (WPW) syndrome, characterized by ventricular pre-excitation through accessory conduction pathways, poses significant arrhythmia risks, particularly the risk of ventricular fibrillation (VF) during pre-excited atrial fibrillation (AF). Amiodarone is an antiarrhythmic medication commonly used in the treatment of tachyarrhythmias; however, recent reports have raised concerns regarding its use in this context. Some experts believe that it is not only better to avoid it but also should be considered a contraindication in patients with WPW who present with pre-excited AF. This systematic review assesses the real-world prevalence and risk of VF associated with amiodarone in patients with WPW syndrome including those with pre-excited AF.

Following PRISMA guidelines, we systematically searched PubMed, Embase, Web of Science, and Scopus, without language or date restrictions, up to January 2025. Inclusion criteria encompassed studies involving WPW patients who received amiodarone. Data extraction and bias assessment were independently conducted by two reviewers using NHLBI tools. Outcomes were synthesized narratively, and evidence certainty was evaluated using GRADE criteria.

Out of 1142 identified records, 91 studies (38 original articles and 53 case reports) involving a total of 751 patients met the inclusion criteria. Among the patients treated with amiodarone, no cases of VF were reported in the original studies; however, 10 incidents of VF were documented exclusively in case reports. Six of these cases were directly attributable to amiodarone, primarily in the context of pre-excited AF. For each case, we extracted detailed data on the underlying arrhythmia, the clinical rationale for the use of amiodarone, and the specific treatment regimen employed. A meta-analysis was not performed due to the low incidence of events and the heterogeneity among the studies.

VF following amiodarone administration in patients with WPW syndrome is extremely rare but clinically significant, with the highest risks observed in cases of pre-excited AF. Given the limited and heterogeneous data available, a definitive causal relationship between amiodarone and VF in WPW patients cannot be firmly established. However, in the presence of other available alternatives, amiodarone is generally best avoided in patients with WPW, particularly in the context of pre-excited AF. Indeed, the decision to use amiodarone in the setting of pre-excited AF should be carefully weighed against the potential risks and benefits.