Relevance of CYP2D6 in the Efficacy and Toxicity of Flecainide in Patients With Atrial Fibrillation: A Cohort Study

A 25% flecainide dose reduction has been recommended for intermediate metabolizers (IMs); however, studies have yielded contradictory results, likely because of the lack of standardization in CYP2D6 pharmacogenetic classifications. We aimed to address this gap. This cohort study included atrial fibrillation patients prescribed flecainide between 2017 and 2021. CYP2D6 was analyzed, and patient phenotypes were classified using the current standard. For the primary outcome-6-month toxicity or recurrence-normal metabolizers (NMs) were compared with IMs. As a secondary objective, outcomes in poor metabolizers (PMs) and 12-month results were evaluated. A total of 104 patients were enrolled. Overall, 50% were NMs, 36.5% IMs, 6.7% PMs, and 6.7% others. There were no differences between IMs and NMs in the incidence of the primary outcome (29.0% vs. 28.9%, P = 0.99). No significant differences were observed in multivariate analysis ( P = 0.97) or 12-month follow-up ( P = 0.57). PMs had a lower event rate at 6 months ( P = 0.1), which became significant when the follow-up was extended to 1 year (univariate P = 0.04; multivariate P = 0.03). Using a standardized CYP2D6 classification, IMs and NMs showed similar rates of toxicity and recurrence when treated with 100 mg flecainide every 12 hours. Although the small sample size limits definitive conclusions, our findings challenge current recommendations to adjust dosing between NMs and IMs. By contrast, better outcomes were observed in PMs. This raises the question of whether, in an effort to minimize flecainide toxicity, dosing has inadvertently been standardized to subtherapeutic levels for all groups except PMs.